The American Cancer Society’s Oncology in Practice: clinical management (2018)
Edited by American Cancer Society
Заболеваемость, смертность и выживание
Рак молочной железы является наиболее распространенным злокачественным заболеванием и ведущей причиной смертей от рака среди женщин во всем мире [1]. В Соединенных Штатах и в развитых странах в целом это самый распространенный рак и вторая по распространенности причина канцер-ассоциированной гибели [2, 3]. Приблизительно у 252 710 женщин будет диагностирован, и примерно 40 610 женщин умрут от рака молочной железы в США в 2017 году [3]. Заболеваемость раком молочной железы увеличилась в течение 1980-х годов, в основном отражая повышение выявляемости путем маммографического скрининга [3].
Заболеваемость раком молочной железы снизилась в 2000-х годах, несмотря на более широкое использование скрининга, что может отражать снижение использования менопаузальной гормональной терапии [4]. Тем не менее, по-прежнему считается, что у каждой из восьми женщин в течение их жизни будет диагностирован рак молочной железы. В последние десятилетия показатели выживания улучшились. Общая 5-летняя относительная выживаемость на всех этапах улучшилась с 75,2% для заболевших женщин в 1975 году до 90,6% для заболевших женщин в 2008 году. 5-летняя относительная выживаемость составила 98,9% для пациентов с диагнозом локализованного заболевания, но выживаемость снижается до 26,9% у пациентов с диагнозом отдаленных метастазов [5].
Факторы риска
Возраст, пол и раса
Риск рака молочной железы значительно возрастает с увеличением возраста и у женского пола. Медианный возраст при постановке диагноза составляет 62 года [5]. ~1% случаев рака молочной железы наблюдается у мужчин. [3] Рак молочной железы у мужчин часто является эстрогеновый рецептор-позитивным и часто ассоциируется с генетической предрасположенностью, профессиональным или радиационным воздействием и избытком эстрогенов [6].
Афроамериканские женщины имеют более низкую частоту рака молочной железы, чем светлокожие, однако показатели выживаемости хуже среди чернокожих женщин (5-летняя выживаемость 80% против 91% среди светлокожих женщин с 2005 по 2020 год). У афроамериканок с большей вероятностью диагноз будет выставляться на более поздних стадиях, но они также имеют более низкие показатели выживаемости на каждой стадии, возможно, вследствие социально-экономических факторов [7]. Рак в более молодом возрасте и тройной негативный гистологически также более распространены среди афро-американок [8]. Сочетание генетической предрасположенности и образа жизни, вероятно, способствует повышению заболеваемости среди белых женщин, например, использованию заместительной гормональной терапии, доступу к скринингу, старшему возрасту первой беременности и возрасту менархе (таблица 28.1).
Экзогенные и эндогенные гормоны
Женщины с ранним возрастом менархе, поздним возрастом менопаузы, возрастом первой беременности старше 35 лет или нерожающие, подвергаются повышенному риску рака. Все эти факторы связаны с гормональными факторами и овуляцией.
Доклинические данные показывают, что полносроковая беременность приводит к дифференцированию молочных желез, снижению скорости метаболизма и резистентности к злокачественной трансформации [9]. Чистым эффектом беременности является кратковременное увеличение и долгосрочное снижение риска [10]. Риск рака молочной железы повышается с каждым годом отсрочки родов до 35 лет; также более короткие сроки последующих беременностей могут снизить риск [11]. Ассоциация между риском рака молочной железы и бесплодием или лечением бесплодия неясна [12, 13].
Грудное вскармливание снижает риск вследствие задержки возобновления овуляции после родов [14], а отсроченная менопауза связана с повышенным риском развития рака примерно на 3% в год [15]. Гормональная терапия, состоящая из комбинации эстрогена и прогестина, также связана с повышенным риском рака молочной железы и смертности, независимо от менопаузального статуса [16]. Риск незначительно повышается (относительная скорость 1,6) при использовании гормональной терапии, содержащей только эстроген. Риск снижается после прекращения лечения и возвращается к исходному уровню через 5 лет [17].
Стиль жизни
Роль ожирения, по-видимому, связана с менопаузальным статусом. Женщины в постменопаузе, вес которых повысился на > 10, подвергаются повышенному риску [18]. Это может быть связано с более высокими уровнями циркулирующих эстрогенов у женщин с высоким индексом массы тела (BMI). Потребление алкоголя сильно ассоциировано с риском развития рака молочной железы и более высоким риском рецидива. Потребление одного алкогольного напитка (alcoholic drink) в день может увеличить риск до 7% независимо от типа напитка [15]. Низкая физическая активность связана с повышенным риском, но роль диеты с высоким содержанием жиров менее ясна.
Таблица 28.1. Факторы риска для развития рака молочной железы.
| Немодифицируемые | Модифицируемые |
| Возраст | Экзогенные гормоны |
| Женский пол | Неспособность к деторождению или первая полносроковая беременность > 35 лет |
| Белая раса | Рацион с высоким содержанием жира |
| Семейная история | Ожирение |
| Ранняя менархе | Алкоголь |
| Поздняя менопауза | Неактивный образ жизни |
| Облучение | (Защитное) кормление грудью |
| BRCA1 и BRCA2, PTEN, TP53 мутации | |
| Доброкачественная болезнь молочной железы | |
| Предшествующие биопсии | |
| Уплотнение молочной железы |
Облучение
Экспозиция ионизирующей радиации в раннем возрасте, например, облучение грудной клетки для лечения болезни Ходжкина или пережившие ядерную бомбардировку или ядерную аварию, также связана с высоким риском развития рака молочной железы.
Генетическая предрасположенность
Семейная история рака молочной железы, особенно у родственников первой степени, сильно влияет на риск рака молочной железы. Возраст диагностики также очень важен. Наличие родственника первой степени, у которого диагностирован рак молочной железы в возрасте до 30 лет, повышает риск в три раза; риск увеличивается только в 1,5 раза, если возраст на момент диагностики составил 60 лет и более.
Менее 10% рака молочной железы связаны с наследственными генами, такими как гены восприимчивости к раку молочной железы (breast cancer susceptibility gene, BRCA) 1 или 2, фосфатаза и гомолог тензина (phosphatase and tensin homolog, PTEN) и опухолевый протеин 53 (TP53). BRCA1 и BRCA2 — опухоль-супрессорные гены, которые вовлечены в поддержание интеграции генома, и их функции включают репарацию разрывов двойных нитей ДНК. Свыше одной тысячи различных мутаций BRCA 1 и 2 описано, таким образом очень важно тестировать вовлеченных членов семьи до скрининга родственников. Зародышевые мутации BRCA 1 и 2 наследуются в аутосомно-доминантной манере, и утрата дикой аллели ведет к геномной нестабильности и карциногенезу [19]. Носители имеют высокий риск развития рака молочной железы и яичников; общий риск развития рака молочной железы для носителей BRCA1 составляет 80%, рака яичника — 30-40%, риск немного меньше для BRCA2 мутаций, 50% и 10-15% соответственно. Наличие семейной истории рака молочной железы не обязательно ассоциировано с наследуемой мутацией, но она двукратно повышает риск развития рака молочной железы. Пациенты, заболевшие раком молочной железой и яичника в молодом возрасте, имеющие многих родственников, заболевших в молодом возрасте, и пациенты с родственниками мужского пола, имеющими рак молочной железы, должны пройти генетическое консультирование [20].
Доброкачественная и неинвазивная болезнь молочной железы
История доброкачественной болезни молочной железы, предшествующие биопсии молочной железы и маммографическое уплотнение молочных желез также связаны с более высоким риском. Плотность молочной железы может быть генетически детерминирована и обратно ассоциирована с содержанием жира. Высокая плотность при первом скрининге может сопровождаться повышением риска в пять раз. Имея проведенную биопсию молочной железы до возраста 50-55 лет повышает риск до пяти раз. Наличие доброкачественного заболевания молочной железы, которое включает пролиферативные изменения и/или атипию, далее повышает риск развития рака молочной железы [21]. Персональная история рака молочной железы или протоковой карциномы in situ (DCIS) повышает риск существования рака молочной железы в контралатеральной молочной железе или повторного первичного рака молочной железы в ипсилатеральной молочной железе.
Предотвращение
Изменения образа жизни могут снизить риск развития рака молочной железы у женщины. Операция или химиопрофилактика могут рассматриваться для женщин с высоким риском, таких как носители BRCA мутаций или попадающих в группу согласно моделям определения риска.
Существует несколько моделей, которые предсказывают риск развития рака молочной железы. Модифицированная модель Гейла (Gail) является наиболее широко используемым инструментом для расчета абсолютного риска развития инвазивного рака или рака молочной железы in situ. Эта модель включает такие переменные, как возраст, возраст при менархе, возраст первой доношенной беременности, семейный анамнез, предшествующие биопсии молочной железы и гиперплазия в анамнезе с атипией [22]. Модель также была подтверждена для афроамериканцев [23].
Carriers of BRCA mutations can be counseled on bilateral mastectomy, which decreases the risk of breast cancer by over 90% in these patients. Bilateral salpingo-oophorectomy additionally decreases the risk of ovarian and fallopian tube malignancies. Prophylactic contralateral mastectomy can also decrease the risk of new primary breast cancers in selected patients with sporadic tumors. However, the recognition of the patients who will benefit from a prophylactic mastectomy is challenging, and the discussion should include the absolute risk of cancer involved and the risks associated with the operation [24].
The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the incidence of primary invasive breast cancer when taken for 5 years (7–9 cases per 1,000) [25]. These SERMs reduced the risk of hormone receptor-positive breast cancer but did not decrease the risk of hormone receptornegative or noninvasive cancer and did not reduce mortality. The risk reduction was noted not only during the active treatment period but also during follow-up for up to 10 years. Women with the highest risk and those previously diagnosed with atypical hyperplasia gained the most benefit from chemoprevention. Both drugs increased the risk of thromboembolic events and tamoxifen was also clearly associated with an increased risk of endometrial cancer. Even though a head-to-head comparison of tamoxifen and raloxifene reported that tamoxifen was more effective in preventing the development of breast cancer, raloxifene had less toxicity [26].
Анастрозол (anastrozole) снижает риск рака молочной железы на 53% по сравнению с плацебо у женщин в постменопаузе с высоким риском. Преимущество включает инвазивное заболевание, эстрогеновый рецептор-позитивное заболевание и опухоли in situ [27]. Кроме того, экземестан (exemestane) эффективен в качестве химиопрофилактики у женщин в постменопаузе [28]. Применение ингибиторов ароматазы в первичной профилактике нуждается в дальнейшей оценке, и их использование пока не установлено.
Скрининг
Маммография остается основным методом скрининга на рак молочной железы. Пленочная и цифровая маммография имеют аналогичную эффективность, но цифровая маммография может быть более точной у пациентов в пре- или перименопаузальный период и у пациенов с плотной (dense) грудью. USPSTF (United States Preventive Services Task Force) рекомендует проводить двухлетнюю скрининговую маммографию для женщин в возрасте 50–74 лет, и решение начать скрининг до 50 лет должно быть индивидуальным [29]. ACS рекомендует, чтобы (I) женщины проходили регулярную маммографию, начиная с 45 лет, (II) женщины в возрасте 45–54 лет должны проходить ежегодный скрининг, (III) женщины должны иметь возможность начать ежегодный скрининг в возрасте от 40 до 44 лет, (IV) женщины в возрасте ≥55 лет должны перейти на двухлетний скрининг или иметь возможность продолжать скрининг ежегодно, и (V) женщины должны продолжать маммографический скрининг, если их общее состояние здоровья хорошее, а продолжительность жизни ≥10 лет [ 30, 31].
Ультрасонография часто используется для оценки пальпируемых образований и контроля для пункционных биопсий, но оно не валидизировано как скрининговый инструмент один , или в комбинации с маммографией.
Magnetic resonance imaging (MRI) has been found to be more sensitive but less specific in detecting invasive cancers and is associated with high cost. Studies support that women with high risk for breast cancer (genetic predisposition, history of radiation exposure) should be screened with annual MRI in addition to mammography [32]. Women who are BRCA positive should be referred for genetic counseling and educated on options to decrease their risk surgically and also for methods of intensified surveillance. The current screening recommendation for women who are BRCA carriers is the combination of annual mammography and annual MRI. Other risk groups who benefit from MRI screening are patients who have received chest radiation before the age of 30, who have genetic mutations of TP53 and PTEN, first-degree relatives of BRCA carriers, and women with a lifetime risk of more than 20–25% [31].
Studies on breast self-examination have failed to show a survival benefit; breast self-examination is not currently recommended as a preferred method of breast cancer screening.
Screening can have negative effects, including false positives, unnecessary biopsies, overdiagnosis and overtreatment, which are associated with financial and health outcomes for the patients. For more information refer to The American Cancer Society’s Oncology in Practice: Clinical Management, Chapter 11.
Патология рака молочной железы
Гистологические подтипы
Большинство случаев рака молочной железы — это карциномы, происходящие из эпителия. Карциномы in situ классифицируются как протоковые (дуктальные) или дольковые (лобулярные); наиболее инвазивными карциномами, гистологически, являются инфильтрирующие протоковые, затем идут лобулярные, протоковые/лобулярные, муциновые (коллоидные), медулярные или папиллярные. Другие подтипы встречаются редко и их менее 5% случаев (таблица 28.2). Инфильтрирующая протоковая карцинома (IDC) составляет 70-80% инвазивных раков молочной железы. IDC подразделяют на хорошо дифференцированные (1 степень злокачественности), умеренно дифференцированные (2 степень) или плохо дифференцированные (3 степень). Дуктальные карциномы обычно представляют твердые массы, содержащие клетки, растущие в канальцах и/или листах (sheets).
Инфильтрирующая дольковая карцинома является вторым по распространенности типом рака молочной железы и составляет 5-10% случаев. Он имеет тенденцию быть мультифокальной или двусторонней, а иногда и без очевидной массы. Прогноз, как правило, такой же, как для IDC. Лобулярные карциномы обычно негативно окрашиваются для E-кадгерина; они часто (HR (гормональный рецептор)- позитивны и редко HER2 (рецептор эпидермального фактора роста человека) — позитивны [33].
Тубулярнные карциномы — редкие опухоли. Они, как правило, HR позитивны и HER2 негативны, имеют отличный прогноз и редко метастазируют. Инвазивные ситовидные (cribriform) и муцинозные карциномы также редки и имеют благоприятный прогноз по сравнению с IDC. Инвазивная микропапиллярная карцинома наблюдается менее чем в 2% случаев; он обычно диагностируется на поздних стадиях и ассоциированна с плохим прогнозом. Метапластическая карцинома молочной железы встречается менее чем в 1% случаев и считается вариантом протоковой карциномы. Она может состоять из матрикс-продуцирующих, сквамозных клеток, веретенообразных (spindle) клеток или остеокласт-подобных гигантских клеток. Метапластическая карцинома чаще всего наблюдается у женщин старше 50 лет; она обычно ER/PR-негативна и может быть HER2-позитивной до 46% случаев. Прогноз хуже относительно типичной IDC [34]. Воспалительный рак молочной железы характеризуется воспалительными изменениями кожи груди, а ее инвазивный компонент микроскопически чаще всего демонстрирует IDC [33].
Гормональные рецепторы
Приблизительно две трети рака молочной железы экспрессируют рецепторы эстрогена и/или прогестерона (ER/PR). Наиболее часто используемым анализом для оценки статуса ER/PR является иммуногистохимия (IHC), которая может быть выполнена на парафин-залитых тканях или цитологических препаратах; присутствие по крайней мере 1% окрашивающих ядер определяет HR-позитивное заболевание.
Эстрогеновый рецептор (ER) принадлежит семейству стероидных/тиреоидных ядерных рецепторов и состоит из ER-αи ER-β, которые транскрибируются различными генами и, видимо, играют различные функции. ER-α была описана первой, в литературе она часто используется взаимозаменяемо с ER, поскольку функции ER-β не полностью прояснены. ER активируется при связывании с эстрогеном и ведет к фосфорилированию, димеризации и активации эстроген-элементов (estrogen response elements, ERE), которые локализуются в промоторных таргетных генах [35]. Присутствие ER обычно ассоциируется с медленно растущими и хорошо дифференцированными опухолями и предсказывает ответ на гормональную терапию.
Таблица 28.2. Гистологические подтипы рака молочной железы и влияние на прогноз по сравнению с NOS IDC.
| Гистологический тип (частота) | Черты | Прогноз |
| Инвазивная протоковая карцинома (IDC), не упоминающаяся иным образом (NOS) (70-80%) | Плотная масса, клетки растут в листах или трабекулах | |
| Инвазивная лобулярная карцинома (5-10%) | Может быть плотной, масса может отсутствовать. Негативна для Е-кадгерина. Обычно ER/PR + и HER2- | Подобен IDC |
| Инвазивная тубулярная карцинома (7.7-27%) | Плотная масса, трубочки с одним слоем или эпителиальными клетками. Обычно ER/PR+ и HER2- | Отличный |
| Инвазивная решетчатая (крибриформная) карцинома (1-3%) | Масса может хорошо определяться, со звездчатой/серой поверхностью. Клетки в крибриформной структуре, случайные гигантские клетки | Благоприятный |
| Инвазивная муцинозная карцинома (2%) | Хорошо определенная масса с мягкой поверхностью. Гнездоформирующие клетки, наличие муцина. Обычно ER/PR+ и HER2-. Может ассоциироваться с нейроэндокринными чертами | Благоприятный |
| Инвазивный медуллярная (<1%) | Хорошо определенная масса, без железистых структур, наличие лимфоплазмоцитарной инфильтрации, обычно HR- | Неопределенный |
| Инвазивная микропапиллярная карцинома (<2%) | Клетки формируют трубчатые гнезда, распространены метастазы в LVI и лимфатические узлы. | Плохой |
| Инвазивная метапластическая карцинома (<1%) | Может быть ассоциированна с некрозом, состоит из плоскоклеточных, остеокластических, матрикс-продуцирующих, канцеросаркоматозных или веретенообразных клеток. Часто ER/PR-, до 46% могут экспрессировать HER2 | Хуже, чем для IDC |
| Инвазивная апокринная карцинома (<1%) | Клетки с обильной эозинофильной цитоплазмой, крупными ядрами, выраженными ядрышками. ER/PR-, до 50% HER2+ | Благоприятный |
| Инвазивная папиллярная карцинома (<2%) | Часто ассоциируется с IDC. Обычно ER/PR +, HER2- | Благоприятный |
| Инвазивная аденоидная кистозная (0.1%) | Хорошо очерченные узловые массы. Клетки образуют трубочки, гнезда или ситовидные (крибриформные) области | Отличный |
ER/PR, estrogen receptor/progesterone receptor; HER2, human epidermal growth factor receptor 2; IDC, invasive ductal carcinoma; LVI, lymphovascular invasion; NOS, not otherwise specified.
The progesterone receptor (PR) gene is dependent on estrogen and more than 50% of breast cancers are PR positive. It is unclear why the progesterone receptor is lost in some tumors or metastatic sites but there are clinical data suggesting that hormone therapy is less effective in tumors that are ER positive/ PR negative. PR-negative tumors may be larger, may exhibit a more aggressive clinical behavior, and can be associated with worse outcomes [36, 37].
HER2 (ERBB2)
HER2 belongs to the family of epidermal growth factor receptors (EGFR), which includes HER1, HER2, HER3, and HER4. The HER2 receptor consists of an extracellular, a transmembrane, and an intracellular tyrosine kinase domain. HER2 does not have an identifiable ligand but it has the tendency to heterodimerize with other growth factor receptors and thus activates intracellular downstream pathways, such as mitogen activating protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) [38]. HER2 is overexpressed in approximately 20% of breast cancers and it is associated with shorter disease-free survival and overall survival [39]. The use of targeted agents has significantly improved outcomes in patients with HER2-positive breast cancer [40].
All newly diagnosed patients or patients who develop metastatic disease should be tested for HER2. HER2 is reported positivewhenaspecimenhasascoreof+3 byimmunohistochemistry, and negative if the score is 0 or +1. A score of +2 is considered equivocal and requires reflex testing with an alternate test or testing of a new specimen.
The ISH (in situ hybridization) score is reported as singleprobe average HER2 copy numbers or dual-probe HER/CEP17 ratio (the ratio of HER2 to the centromeric portion of chromosome 17). A positive result is an average of HER2 copy number of =6 signals/cell or HER2/CEP17 ratio of =2. A ratio of <2 in the presence of =6 signals/cell is also considered positive. A negative result is based on a HER2 copy number of <4 signals/cell, while an equivocal test is a single-probe average HER2 copy number of =4 but <6 signals/cell [41]. If ISH was performed first and is equivocal, the recommendation is to perform IHC or test a new sample.
All patients with positive HER2 testing should be considered for HER2-directed therapy in the adjuvant and/or metastatic setting.
Присущие молекулярные подтипы
Breast tumors are classified into HR-positive, HER2-positive, or triple-negative (no ER, PR, or HER2 expression) based on hormone and HER2 receptor status; however, even within these groups, breast cancer is heterogeneous. As a result of an attempt to decipher breast cancer biology, cDNA microarrays revealed that breast tumors could further be subclassified as basal-like, ERBB2-positive, normal breast-like, and luminal subtype A and B. The basal-like subtype is accompanied by a high rate of TP53 mutations and mostly overlaps with the triple-negative tumors. BRCA1-positive tumors also mostly fall into that subtype. The basal-like subtype is clinically associated with the worst overall and relapse-free survival. The ERBB2 subtype shows a high expression of HER2 and high rate of TP53 mutations and is also associated with inferior outcomes. The normal breast-like tumors express genes similar to adipose tissue and nonepithelial cell types and they have intermediate prognosis. It is currently unclear if the normal-like subtype exists or if it is a result of contamination from surrounding tissues. The luminal subtypes are hormone receptor positive and they can be further subclassified according to the degree of HR positivity. The luminal A subtype is characterized by strong expression of ER, while the luminal B subtype has low or moderate ER expression. Luminal A tumors are linked to the best outcomes [42–45].
Диагноз
Most breast cancers will be found during screening with an abnormal mammogram. Rarely, a woman will discover a palpable mass accidentally or during a self-examination.
If a woman less than 30 years old has a palpable mass, it is usually recommended to proceed with an ultrasound, while women over the age of 30 should also have a bilateral mammogram. Ultrasonography will distinguish a solid versus a cystic mass, and simple versus complicated versus complex cysts. In general, simple cysts are followed by imaging and complicated cysts may be followed by imaging or aspirated. Tissue evaluation by core biopsy or fine-needle aspiration (FNA) is recommended for complex cysts and cysts that recur and/or contain hemorrhagic fluid [46]. A solid mass also needs to be evaluated with a biopsy. A core biopsy offers more tissue and is generally preferable to an FNA [46, 47].
Mammographic findings are reported according to the Breast Imaging Reporting and Data System (BI-RADS), which was developed by the American College of Radiology to decrease inconsistency among users. A BI-RADS category 0 means an incomplete evaluation that requires further imaging with additional views. A BI-RADS category 1 or 2 signifies benign or no findings and regular follow-up can resume. A BI-RADS category 3 means that the findings are probably benign but a shorter interval screening is recommended (usually 6 months). BIRADS category 4 and 5 findings are suspicious or highly suspicious for malignancy, respectively [48]. If an abnormality is found on a screening mammogram in the absence of a palpable mass, additional views and/or an ultrasound are often obtained. Suspicious masses are usually spiculated and poorly defined, and they may be associated with microcalcifications or distorted architecture. A nonpalpable mass is usually biopsied under ultrasound guidance or with a stereotactic biopsy. An axillary ultrasound can also help identify and aid in the biopsy of suspicious lymph nodes [49].
MRI is more sensitive than mammography and it can help identify ipsilateral foci and contralateral synchronous breast tumors. These findings can lead to overestimation of the extent of the disease, more aggressive surgery, and overtreatment of lesions that might have never been clinically significant [50]. MRI has not been shown to impact overall survival and it is thus not routinely recommended. However there are individualized cases where preoperative MRI may prove useful, such as highrisk patients, where the risk of contralateral breast cancer is very high, patients who present with an axillary mass and no palpable breast abnormality, patients who have implants that interfere with conventional imaging, and evaluation of response to neoadjuvant chemotherapy [51].
Стадийность/оценка
After the pathologic diagnosis of breast cancer is established, the clinician should proceed with clinical staging evaluation when indicated. It is always recommended to obtain a history and physical examination, complete blood count, and chemistry for evaluation of liver and renal function. Patients who are at high risk for hereditary cancer should be referred for genetic counseling, and young patients who want to maintain fertility should be referred for fertility counseling. For patients with early-stage disease (I–IIB), additional studies are ordered based on symptoms or laboratory abnormalities. Patients with bone pain or elevated alkaline phosphatase should be evaluated with a bone scan, patients with pulmonary symptoms should have computerized tomography (CT) of the chest, and patients with abdominal symptoms or abnormal liver function tests will get a CT or MRI of the abdomen. The National Comprehensive Cancer Network (NCCN) guidelines recommend against positron emission tomography (PET) or PET-CT imaging in these early-stage patients, as the rate of false negatives is high in patients with small lesions [46]. For patients with locally advanced or metastatic disease, imaging with CT and bone scan (or PET-CT) is indicated to determine the extent of the disease and evaluate response to treatment. All patients should have pathologic evaluation of the tumor including hormone receptor and HER2 status.
PET-CT is generally considered optional by NCCN but is used increasingly in clinical practice. PET-CT is not sensitive for small tumors of less than 1 cm. It has been reported that standardized uptake value (SUV) can correlate with histology (IDC has higher uptake than invasive lobular cancer), grade, tumor proliferation index (Ki-67), and the presence of TP53 mutations. Imaging cannot substitute for a pathologic diagnosis and all suspicious axillary or distant findings need to be biopsied. PET is especially efficient in diagnosing recurrence in asymptomatic patients and it has been found to be superior to conventional techniques in that setting. The NCCN recommends to monitor patients for recurrence using a consistent technique [52].
The eighth edition of the tumor node metastasis (TNM) system is currently used to determine the clinical and pathologic stage of breast cancer (Table 28.3) [53].The pathologic staging is designated as pTNM and if the patient has received neoadjuvant chemotherapy, the pathologic staging is recorded as ypTNM. The use of the staging system facilitates clinical decision-making, provides an estimate of prognosis, and helps communication between treating physicians and researchers. The most recently proposed staging system includes two separate classifications, the anatomic stage groups and prognostic stage groups. The anatomic stage groups are based on tumor size and extent of disease and the prognostic stage group includes the biomarkers tested, grade, receptor status, and genomic testing. HR-positive, HER2-negative tumors with no lymph node involvement and low risk of recurrence based on genomic testing are classified to the same risk category as T1a-b tumors regardless of the T size. Cancer registries in the US will be required to use the prognostic stage groups for case reporting. If biomarkers are not available, the cancer will be reported as unstaged.
Таблица 28.3. TNM стадийность для рака молочной железы (анатомическая стадийность).
| Primary tumor (T) | |
| T0 | Нет свидетельства первичной опухоли |
| Tis | Carcinoma in situ |
| Tis (DCIS) | Ductal carcinoma in situ |
| Tis (Paget’s) | Paget’s disease not associated with invasive component |
| T1 | Tumor ≤2 cm in greatest dimension |
| T1mi | Tumor ≤0.1 cm in greatest dimension |
| T1a | Tumor >0.1 cm but ≤0.5 cm in greatest dimension (round any measurement >1.0 1.9 mm to 2 mm) |
| T1b | Tumor >0.5 cm but ≤1 cm in greatest dimension |
| T1c | Tumor >1 cm but ≤2 cm in greatest dimension |
| T2 | Tumor >2 cm but ≤5 cm in greatest dimension |
| T3 | Tumor >5 cm in greatest dimension |
| T4 | Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4 |
| T4a | Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4 |
| T4b | Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinoma |
| T4c | Both T4a and T4b |
| T4d | Inflammatory carcinoma |
| Региональные лимфатические узлы (N) | |
| Clinical | |
| cN0 | No regional lymph node metastases |
| cN1 | Metastasis to movable ipsilateral level I, II axillary lymph node(s) |
| cN2 | Metastasis in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in clinically detected ipsilateral internal mammary (IM) nodes in the absence of clinically evident axillary lymph node metastases |
| cN2a | Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures |
| cN2b | Metastasis only in clinically detected IM nodes in the absence of clinically detected axillary lymph nodes |
| cN3 | Metastasis in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement; or in clinically detected ipsilateral IM lymph nodes with clinically evident level I, II axillary lymph node metastasis; or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or IM lymph node involvement |
| cN3a | Metastasis in infraclavicular lymph node(s) |
| cN3b | Metastasis in internal mammary lymph node(s) and axillary lymph node(s) |
| cN3c | Metastasis in supraclavicular lymph node(s) |
| Pathologic (pN) | |
| pNx | Regional nodes cannot be assessed (e.g., not removed for pathological study or previously removed) |
| pN0 | Нет метастазов в региональные лимфоузлы |
| pN0(i+) | ITCs only (malignant cell clusters no larger than 0.2 mm) in regional lymph node(s) |
| pN0(mol+) | Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs detected |
| pN1 | Micrometastasis; or metastasis in 1–3 axillary lymph nodes; and/or in IM nodes with metastasis detected by SLN biopsy but not clinically detected |
| pN1mi | Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm) |
| pN1a | Metastasis in 1–3 axillary lymph nodes, at least one metastasis greater than 2 mm |
| pN1b | Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs |
| pN1c | pN1a and pN1b combined |
| pN2 | Metastasis in 4–9 axillary lymph nodes; or in clinically detected IM lymph nodes in the absence of axillary lymph node metastasis |
| pN2a | Metastasis in 4–9 ipsilateral axillary lymph nodes (at least one >2.0 mm) |
| pN2b | Metastasis in clinically detected IM lymph nodes in the absence of axillary lymph node metastasis |
| pN3 | Metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes |
| pN3a | Metastasis in ten or more axillary lymph nodes (at least one greater than 2 mm); or metastasis in infraclavicular (level III axillary lymph) nodes |
| pN3b | pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging); or pN2a in the presence of pN1b |
| pN3c | Metastasis in ipsilateral supraclavicular lymph nodes |
Note: (sn) and (f ) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or FNA/core needle biopsy respectively, with NO further resection of nodes.
| Отдаленные метастазы (M) | |
| M0 | No clinical or radiographic evidence of distant metastasis |
| cM0(i+) | No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger than 0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastases |
| M1 | Distant metastases detected by clinical and radiographic means (cM) and/or histologically proven metastases larger than 0.2 mm (pM) |
| Анатомическая стадия (TNM) | |||
| 0 | Tis | N0 | M0 |
| IA | T1 | N0 | M0 |
| IB | T0 | N1mi | M0 |
| T1 | N1mi | M0 | |
| IIA | T0 | N1 | M0 |
| T1 | N1 | M0 | |
| T2 | N0 | M0 | |
| IIB | T2 | N1 | M0 |
| T3 | N0 | M0 | |
| IIIA | T0 | N2 | M0 |
| T1 | N2 | M0 | |
| T2 | N2 | M0 | |
| T3 | N1 | M0 | |
| T3 | N2 | M0 | |
| IIIB | T4 | N0 | M0 |
| T4 | N1 | M0 | |
| T4 | N2 | M0 | |
| IIIC | Any T | N3 | M0 |
| IV | Any T | Any N | M1 |
Tumors >1 mm and <2 mm should be reported rounding to 2 mm.
В случае множественных синхронных опухолей для cT и pT используется только максимальный размер наибольшей опухоли; размер нескольких опухолей не добавляется. H & E, гематоксилин и эозин; RT/PCR, полимеразная цепная реакция с обратной транскриптазой; SLN, пограничные лимфатические узлы.
Прогностические факторы
Анатомические факторы
Важнейшим прогностическим фактором рака молочной железы является стадия и степень вовлеченности лимфатических узлов; прогноз ухудшается по мере увеличения положительных подмышечных узлов, особенно если задействовано более трех узлов. Таким образом, аксиллярная стадийность с FNA или во время операции очень важна [54]. Наличие вовлеченных интернальных узлов (IM) молочной железы также является плохим прогностическим показателем, а присутствие оба IM и подмышечных узлов хуже, чем метастазирование в какую-либо область. В отсутствие поражения лимфатических узлов размер опухоли является наиболее важным прогностическим фактором. Большие опухоли ассоциированы с более короткой выживаемостью без рецидива и общей выживаемостью. Локализованное заболевание с опухолями менее 1 см в диаметре имеет небольшой риск рецидива, тогда как опухоли размером более 1 см обычно подвергаются адъювантной терапии для снижения риска рецидива [55].
Биология
IDC и инвазивная дольковая карцинома являются наиболее распространенными гистологическими подтипами рака молочной железы. Другие подтипы являются нечастыми и обычно ассоциируются с благоприятным прогнозом, за исключением инвазивной микропапиллярной карциномы, которые ассоциируются с очень неблагоприятным прогнозом (таблица 28.2).
Высокая ядерная и гистологическая злокачественность, высокий Ki-67 индекс, наличие лимфоваскулярной инвазии и присутствие некроза, все ассоциированы с худшими исходами [56].
Эстрогеновый и/или прогестероновый рецептор-позитивные опухоли обычно более дифференцированы, растут медленно и имеют лучшие исходы по сравнению с гормональный рецептор-негативными опухолями. HR-позитивные опухоли также отвечают на гормональную терапию. Наилучший прогноз имеют ER-позитивные/PR-позитивные опухоли, ER-негативные и PR-негативные опухоли имеют худший прогноз, тогда как ER-позитивные/PR-негативные опухоли имеют промежуточный прогноз, поскольку есть данные, что эти опухоли могут показывать резистентность к гормональной терапии [37].
HER2 гиперэкспрессия и наличие TP53 мутации также связаны с плохой общей выживаемостью [57].
Профилирование экспрессии генов выделяет присущие молекулярные подтипы рака молочной железы, которые коррелируют с исходами. Люминальные А опухоли, которые высоко экспрессируют ER, имеют лучший прогноз, тогда как базально-подобные и ERBB2-позитивные подтипы, которые совпадают с тройными негативными и HER2-сверхэкспрессирующими опухолями, соответственно, имеют худшие результаты.
Сигнатуры экспрессии генов
The 21-gene recurrence score (Oncotype DX®) is used to predict the likelihood of developing distant metastases in patients with HR-positive, node-negative breast cancer and, more importantly, can determine a subset of these cancers that obtain minimal to no benefit from systemic chemotherapy. Using specimens from the NSABP B-20 trial, which evaluated the addition of systemic chemotherapy to tamoxifen in patients with HR-positive, node-negative breast cancer, approximately 50% of cancers were designated low risk using the 21-gene recurrence score and obtained no significant benefit from the addition of chemotherapy to tamoxifen. In contrast, cancers designated as high risk by the recurrence score assay obtained a significant benefit in preventing the development of distant metastases when chemotherapy was added prior to tamoxifen. Approximately one-quarter of patients with HR-positive, node-negative breast cancer have recurrence scores in the intermediate range. Overall this group does not appear to obtain a significant benefit from the addition of chemotherapy to tamoxifen, and the cut-off score where patients obtain benefit from chemotherapy is being addressed in the TAILORx trial. There are emerging data that the 21-gene recurrence score is prognostic and potentially predictive of chemotherapy benefit in patients with HR-positive, node-positive breast cancer, and this is being addressed in the ongoing RxPONDER trial, in which patients with HR-positive breast cancers with =3 involved lymph nodes and a tumor recurrence score of less than 25 are being randomized to endocrine therapy with or without chemotherapy [58]. Oncotype Dx® can be performed with fixed paraffin-embedded tissues.
The 70-gene prognostic score (MammaPrint®) has been shown to be prognostic of outcome in node-negative and nodepositive breast cancers. Tumors are classified as having a good prognostic or poor prognostic signature, offering the possible advantage of no intermediate risk group [59]. Initially, this assay had to be performed in fresh tissue, but it is now available for paraffin-embedded specimens. Nonrandomized data suggest that the 70-gene score is potentially predictive of benefit of chemotherapy in early-stage breast cancers, and this hypothesis is being addressed in the MINDACT trial, in which patients with cancers that are discordant by classic prognostic factors and the 70-gene score are randomized to receive chemotherapy or not, along with endocrine therapy where appropriate.
The Breast Cancer Index (BCI) is a newer assay that may have the potential to predict which patients with HR-positive breast cancers are most likely to develop late (more than 5 years from diagnosis) metastases and potentially benefit from extended adjuvant endocrine therapy.
In addition, the Predictor Analysis of Microarray (PAM) 50 and the Genomic Grade Index (GCI) are gene signatures developed to predict response to hormonal therapy and survival in patients with breast cancer [60].
Even though these gene signatures are expensive, they can be cost-effective. The Oncotype DX® assay may identify patients who will not benefit from chemotherapy, thus reducing the cost of treatment and decreasing the rate of therapy-related toxicities.
Хирургическое лечение рака молочной железы ранних стадий
Множественные клинические исследования подтвердили, что мастэктомия эквивалентна молочная железа-сохраняющей операции, сопровождаемой лучевой терапией [61]. Грудь- сохраняющая операция установлена как первичное хирургическое лечение для женщин с раком молочной железы ранней стадией, главным образом вследствие преимущества лучших косметических результатов и предпочтения пациентами. Однако женщинам с мультицентричными опухолями, диффузными кальцификатами, воспалительным раком и противопоказаниями к лучевой терапии (например, предшествующая лучевая терапия, беременность) все равно следует лечить мастэктомией. Цель хирургии груди — полное удаление опухоли с некарцерозными краями. Таким образом, рекомендуется соответствующим образом ориентировать хирургические образцы, чтобы сообщать о статусе краев и расстоянии опухоли от ближайшего края.
В настоящее время менеджмент подмышечной впадины развивается. Клинически позитивные подмышечные лимфоузлы при обследовании или ультразвуке должны оцениваться с помощью FNA, или существует стандартная практика оценки пограничных лимфатических узлов (SLN) во время операции [62, 63]. Пациенты с негативными SLN не нуждаются в дальнейшей аксиальной диссекции. Пациенты только с 1-2 вовлеченными узлами также могут не нуждаться в диссекции, так как это, как было показано в исследовании Z11, не улучшает выживаемости [64].
Лучевая терапия
Radiation therapy plays a very significant role in the treatment of breast cancer and it has been shown to decrease local recurrence rates and improve survival in patients undergoing breastconserving surgery and also in some patients with positive axillary lymph nodes [65].
Radiotherapy was found to reduce the 10-year risk of recurrence from 35% to 19% and also reduced the 15-year risk of breast cancer-related death from 25% to 21% in a large metaanalysis [66]. However, some patients with low risk of local recurrence may not require additional therapy after breastconserving surgery. The CALGB 9343 trial demonstrated that in women of at least 70 years of age with clinical stage I ER-positive breast cancer, the addition of radiation decreased locoregional recurrence; however this was not translated in advantage in overall survival, distant disease-free survival, or breast preservation. Thus, in this subset of elderly women, treatment with adjuvant hormonal therapy alone is an acceptable option.
Following a mastectomy, adjuvant radiation therapy of the chest wall and regional lymph nodes is indicated in patients with 4 or more positive axillary lymph nodes, with tumors more than 5 cm, and with T4 tumors regardless of lymph node status. Women with 4 or more lymph nodes have a high risk of local recurrence and should receive radiotherapy post mastectomy as standard of care. Radiation should also be considered in patients with 1–3 positive nodes [67].
Patients with characteristics putting them at higher risk of recurrence, such as age <50 years, positive axillary lymph nodes, lymphovascular invasion, and close resection margins, should also have the opportunity to discuss the addition of boost to the tumor bed following standard whole-breast radiation therapy [68].
Radiation therapy is associated with short-term and longterm toxicities. Acute toxicities mainly involve damage to the skin/bone/connective tissue, infections, nerve damage, lung injury, and fat necrosis. Chronic toxicities can happen years after treatment and include cardiotoxicity, lung toxicity, and secondary malignancies [69].
Системная терапия рака молочной железы
All systemic therapy decisions in breast cancer are based on ER, PR, and HER2. Adjuvant treatment of early-stage breast cancer has been demonstrated to decrease the risk of distant recurrence and improve survival [70]. Although the majority of patients receive adjuvant treatment following surgery, increasingly more patients receive systemic treatment prior to surgery using a neoadjuvant approach. Molecular profiling of breast cancers in the early-stage setting is used to tailor systemic therapy appropriately, allowing the omission of systemic chemotherapy in a large number of patients [58]. The use of endocrine agents and HER2-directed therapies has improved the outcome for metastatic HR-positive and HER2-positive cancers, respectively [71].
Адъювантные терапии рака молочной железы ранних стадий
Адъювантная химиотерапия для HER2-негативного рака молочной железы
The use of adjuvant chemotherapy has improved outcome for patients with early-stage breast cancer and is routine for triplenegative (HR-negative, HER2-negative) and a subset of HR-positive breast cancers [70]. The use of molecular profiling for node-negative HR-positive breast cancer has decreased the use of systemic chemotherapy for a subset of patients with these cancers. Systemic chemotherapy remains the standard of care for all node-positive breast cancers and node-negative breast cancers measuring greater than 1 cm if triple-negative, HER2-positive, and HR-positive, if designated as high risk by molecular profiling [72].
One of the first adjuvant regimens for early-stage breast cancer was cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), which remains an option for patients today. CMF was largely replaced by anthracycline-based regimens, based on studies that demonstrated their superiority [73]. A trial that utilized an epirubicin-based regimen demonstrated the benefit of an anthracycline [74]. A large trial failed to show superiority of Adriamycin–Cytoxan (AC) over CMF, but the duration of treatment was shorter; anthracycline-based treatment is the treatment of choice, at least in the US [75]. Even though anthracyclines carry the risk of cardiomyopathy, anthracycline– taxane-based regimens remain widely used, particularly for patients with triple-negative breast cancers. The most commonly used regimen is AC, followed by paclitaxel or docetaxel– Adriamycin–Cytoxan (TAC). Pivotal randomized trials in patients with node-positive breast cancer have demonstrated that AC followed by paclitaxel is superior to AC alone [76, 77]; AC followed by paclitaxel given in a dose-dense manner every 2 weeks is superior to the 3-weekly schedule [78]; and TAC is superior to 5-fluorouracil–Adriamycin–Cytoxan (FAC) [79]. Based on these trials the most widely used regimens for patients with node-positive breast cancer in the US are: (i) TAC every 3 weeks for 6 cycles; (ii) AC followed by paclitaxel, each for 4 cycles given dose dense every 2 weeks; (iii) AC given every 2 or 3 weeks for 4 cycles followed by paclitaxel weekly for 12 weeks. TC every 3 weeks, given for 4 cycles, has been widely accepted as an option for patients with lowerrisk node-positive and node-negative breast cancer [80].
In summary, systemic chemotherapy decisions are made based on breast cancer subtype and nodal status, as well as other issues including the patient’s age and general health. Regimens that include an anthracycline and taxane are generally preferred for the majority of patients with node-positive HER2-negative breast cancer, though TC is often used in patients with HR-positive breast cancers deemed lower risk by molecular profiling, especially if they have =3 positive lymph nodes. Patients with node-negative triple-negative cancers are generally recommended an anthracycline–taxane-based regimen or TC, depending on the perceived risk of recurrence. Chemotherapy can be avoided in more than 50% of HR-positive node-negative breast cancers, when molecular profiling is utilized. For the remaining HR-positive, node-negative breast cancers with higher risk profiles, TC is commonly used.
Молекулярное профилирование HR-позитивного рака молочной железы
Historically, systemic chemotherapy was widely used to prevent recurrence in patients with HR-positive breast cancers, regardless of nodal status. However, it was clear from meta-analyses that the benefit of systemic chemotherapy was significantly greater in HRnegative breast cancers. Molecular profiling of early-stage breast cancers has markedly decreased the use of systemic chemotherapy for HR-positive, node-negative breast cancers, and is being investigated in HR-positive, node-positive breast cancers.
The 21-gene recurrence score (Oncotype DX®) is the most commonly used tool that predicts the risk of distant recurrence. Patients with a score =31 have lower ER expression and higher proliferation indices and benefit from adjuvant chemotherapy. Patients with a score <18 do not benefit from chemotherapy and are treated with adjuvant hormone therapy alone. The management of patients with intermediate scores is currently under investigation.
Several other assays are in development but the 21-gene recurrence score and 70-gene prognostic score are the most widely used.
Адъювантная терапия для HER2-позитивного рака молочной железы
The use of trastuzumab-based chemotherapy has dramatically improved outcome for patients with HER2-positive, early-stage breast cancers. The addition of trastuzumab to paclitaxel following AC in patients with predominantly node-positive, HER2-positive breast cancer significantly decreased recurrence rate and improved survival [81]. These results were confirmed in the Breast Cancer International Research Group (BCIRG) trial [82], which included both node-positive and node-negative, HER2-positive breast cancers. The trial additionally included a novel regimen comprised of docetaxel, carboplatin, and trastuzumab (TCH), which was as effective, and carried a decreased risk of cardiomyopathy. All of these regimens included the continuation of single-agent trastuzumab after chemotherapy for a total duration of 1 year. The Herceptin Adjuvant (HERA) trial evaluated the addition of trastuzumab after adjuvant chemotherapy in patients with node-positive and node-negative HER2-positive breast cancer [83]. Updated results of the HERA trial continue to demonstrate a superior outcome for patients treated with 1 year of trastuzumab, compared to the control group [84].
The optimal duration of trastuzumab and whether it is necessary to give trastuzumab as a single agent or just concomitantly with chemotherapy is unclear. The FinHER trial evaluated trastuzumab given for only 9 weeks concurrent with chemotherapy, and demonstrated a significant decrease in recurrence in patients with node-positive, HER2-positive breast cancer [85]. A third arm of the HERA trial in which patients received 2 years of trastuzumab following chemotherapy has demonstrated no advantage over 1 year of trastuzumab. However, 6 months of trastuzumab was found not definitively equivalent to 1 year of trastuzumab [86]. In conclusion, 1 year of trastuzumab in the adjuvant setting remains optimal at this time. The results of the FinHER trial can be used, however, to reassure patients who have to stop trastuzumab early for decreases in left ventricular ejection fraction. Despite the positive results of the HERA trial, the majority of patients treated in the US receive trastuzumab concurrent with chemotherapy. This approach is supported by interim results from the Intergroup trial which demonstrated that patients treated with concurrent chemotherapy plus trastuzumab have an improved outcome compared to patients treated with chemotherapy and trastuzumab given sequentially [87].
Another controversy is which patients, if any, require an anthracycline as part of their trastuzumab-based regimen. The BCIRG trial demonstrated equivalent outcomes for patients receiving an anthracycline-based regimen and those receiving TCH, though there were numerically fewer events in the anthracycline-based arm [82]. Both regimens were equally effective in patients with multiple involved lymph nodes, in whom the additional risk of cardiomyopathy could perhaps be justified. Amplification of TOP2, a gene associated with benefit from anthracyclines, was assessed in tumors from patients enrolled in the BCIRG trial in an attempt to identify patients who may benefit from the addition of an anthracycline to trastuzumab-based chemotherapy. In patients whose tumors had HER2 amplification without TOP2 amplification, the anthracycline-containing arm and TCH were equivalent in disease-free survival; in patients with tumors exhibiting co-amplification of HER2 and TOP2, there were fewer recurrences in patients treated with the anthracycline-containing regimen, but the difference was not significant compared to patients on the TCH arm. The final analysis of the BCIRG-006 trial, as presented in the San Antonio Breast Cancer Symposium, confirmed the efficacy of trastuzumab and also confirmed the increased risk of toxicity of anthracyclines, mainly cardiac toxicity and second malignancies [88].
Currently, either an anthracycline-containing regimen or TCH is a reasonable option for patients with early-stage HER2positive breast cancer. Patients with factors known to be associated with an increased risk of cardiomyopathy, such as coexisting hypertension and borderline baseline ejection fractions, may be best treated with TCH [89].
Lastly there is considerable controversy on how to treat patients with node-negative HER2-positive breast cancers that measure less than 1 cm, particularly when they are HR positive. Retrospective analyses have generally demonstrated that small HER2-positive breast cancers have a worse outcome than small HR-positive breast cancers [90]. However, almost none of the adjuvant trastuzumab trials recruited patients with nodenegative breast cancers measuring <1 cm. Extrapolation of results from the adjuvant trials including patients with higherrisk HER2-positive cancers has led to many patients with T1B, stage 1A, HER2-positive breast cancer being recommended or receiving trastuzumab-based chemotherapy.
A single-arm trial of adjuvant paclitaxel and trastuzumab in node-negative, HER2-positive breast cancers measuring 3 cm or less in diameter demonstrated a 3-year survival free from invasive disease of 98.7% (95% CI 97.6–99.8). Even though this was a nonrandomized, single-arm study and the follow-up was only 4 years, it showed that the patients had excellent outcomes with acceptable toxicity and it offers a reasonable option for patients with small HER2-positive breast cancer [91]. A 7-year update of this trial showed that the 7-year disease-free survival (DFS) was 93.3% (95% CI 90.4–96.2), with a 7-year DFS for HR-positive patients of 94.6% (95% CI 91.8–97.5) and for HRnegative patients of 90.7% (95% CI 84.6–97.2). The 7-year overall survival (OS) was 95.0% (95% CI 92.4–97.7). These data confirm the role of adjuvant therapy with paclitaxel and trastuzumab for these patients with early-stage disease [92].
The role of estrogen receptor in HER2-positive breast cancers remains unclear. Historically, HER2-positive breast cancers that express HR have been demonstrated to be intrinsically resistant to endocrine therapy in many cases. However, it seems likely that at least a subset of HR-positive, HER2-positive breast cancers are driven by ER and may, therefore, require less aggressive adjuvant approaches [93]. To date, molecular profiling has not been able to clearly delineate which of HR-positive, HER2positive breast cancers may potentially not benefit from the addition of chemotherapy to trastuzumab and endocrine therapy. Ongoing trials will hopefully address these questions.
A number of HER2-directed agents, such as lapatinib, pertuzumab, and trastuzumab-DM1, have shown promise and are approved for patients with HER2-positive, advanced breast cancer. These agents are being evaluated in the adjuvant setting. The ALLTO trial is evaluating chemotherapy with trastuzumab alone, lapatinib alone, and the combination of trastuzumab and lapatinib, in patients with early-stage HER2-positive breast cancer. Though final results of this trial are not available, the lapatinibalone arm was discontinued following an interim analysis.
Адъювантная эндокринная терапия HR-позитивного рака молочной железы ранних стадий
Multiple studies have demonstrated the benefit of adjuvant endocrine therapy in nonmetastatic, HR-positive breast cancer. Available agents include tamoxifen, a selective estrogen receptor modulator, aromatase inhibitors, and ovarian function suppression (OFS).
Tamoxifen has been the endocrine agent of choice for premenopausal women.
The Early Breast Cancer Trialists have clearly demonstrated the benefit of adjuvant tamoxifen in HR-positive early-stage breast cancer [70]. In postmenopausal women, 5 years of thirdgeneration aromatase inhibitors, which act by preventing the peripheral synthesis of estrogen, improved disease-free survival, compared to 5 years of tamoxifen; there was no improvement in survival when the two were compared [94–96]. Overall, in postmenopausal women, aromatase inhibitors are somewhat safer than tamoxifen and are not associated with endometrial cancer. It is important to remember that women who are premenopausal at diagnosis and undergo temporary cessation of menses from adjuvant chemotherapy are still considered premenopausal. The transition of these women to an aromatase inhibitor should be done only after documentation of menopausal status, by measuring follicle-stimulating hormone (FSH) and estradiol levels, or with the use of surgical or pharmacologic OFS. Aromatase inhibitors have not been demonstrated to be effective in premenopausal women and should not be used in women with intact ovarian function without OFS.
There is now evidence for premenopausal women to be treated with OFS plus endocrine therapy as opposed to tamoxifen alone, and the choice between the two regimens is based on the presence of high-risk factors.
For patients with high-risk features, OFS plus tamoxifen or exemestane is recommended as opposed to tamoxifen alone. This recommendation is based on data from the SOFT trial, which randomized more than 3,000 premenopausal patients to tamoxifen, OFS plus tamoxifen, or OFS plus exemestane [97]. That trial demonstrated that the addition of OFS to tamoxifen resulted in an absolute improvement of DFS of 2% at 5 years. In the higher-risk cohort of patients, tamoxifen plus OFS resulted in an absolute improvement of 4.5% compared to tamoxifen alone; in the patients treated with exemestane plus OFS, the absolute improvement was 7.7%. High-risk features are generally defined as a case in which chemotherapy is indicated, secondary to involved axillary lymph nodes, large tumor size, lymphovascular invasion, high tumor grade, and high recurrence score by Oncotype DX®. In addition, women who are younger than 35 years old also seem to benefit from this more aggressive approach. Premenopausal patients without high-risk features are treated with tamoxifen for 5–10 years. Two large randomized trials [98] have demonstrated a benefit for continuing tamoxifen for 10 years, rather than stopping at 5 years. Interestingly, the additional benefit in outcome for patients receiving 10 years of tamoxifen is seen more than 10 years following diagnosis. One can hypothesize that patients with luminal A cancers may achieve the greatest benefit from extended adjuvant therapy, since these are the cancers destined to late relapses, whereas luminal B cancers tend to recur early within the first 5 years.
Molecular profiling may identify which patients require longer duration of endocrine therapy.
In general, the majority of postmenopausal women are treated with an aromatase inhibitor but sequencing of these agents with tamoxifen can be considered for patients who are unable to tolerate them. Several trials evaluated a sequenced approach of tamoxifen for approximately 2 years followed by an aromatase inhibitor for the remainder of 5 years, compared to 5 years of tamoxifen. These trials demonstrated that patients who switched to an aromatase inhibitor following tamoxifen had an improved disease-free survival, compared to patients treated with tamoxifen alone [99, 100]. The BIG-1-98 trial compared letrozole for 5 years, tamoxifen for 2 years followed by letrozole, letrozole for 2 years followed by tamoxifen, with tamoxifen for 5 years. All three study arms were found to be superior to tamoxifen alone for disease-free survival but, interestingly, there was no significant difference in outcome between the three study arms [101]. Letrozole for 5 years following 5 years of tamoxifen significantly improved outcome, compared to patients who received 5 years of tamoxifen alone [102]. Patients with node-positive breast cancer and those with cancers that expressed both ER and PR achieved the greatest benefit from extended adjuvant letrozole.
A recent study compared extended therapy of aromatase inhibitor for 10 years versus 5 years, in some cases following 5 years of tamoxifen [103]. The 5-year disease-free survival rate was 95% in the letrozole arm, and 91% in the placebo arm (hazard ratio 0.66; P = 0.01]. The 5-year overall survival was 93% with letrozole and 94% with placebo (hazard ratio 0.97; P = 0.83). Extended endocrine therapy significantly decreased the risk of contralateral breast cancer. Bone-related adverse events occurred more frequently in the patients receiving letrozole for 10 years.
The use of adjuvant bisphosphonates remains controversial in the early-stage setting. The use of upfront zoledronic acid was demonstrated to decrease recurrence, compared to delayed use, with a concomitant increase in bone mineral density [104]. The AZURE trial, which evaluated the addition of zoledronic acid to standard therapy in patients with early-stage breast cancer, did not demonstrate a significant improvement in disease-free survival for patients receiving the bisphosphonate [105]. However, a subset analysis demonstrated a significant benefit for the addition of zoledronic acid in patients in the AZURE trial who were definitely postmenopausal. An Austrian study demonstrated that the addition of zoledronic acid to endocrine therapy plus goserelin in premenopausal patients with HR-positive earlystage breast cancer decreased recurrence risk [106]. A metaanalysis of patients from randomized trials reported that the use of adjuvant bisphosphonates reduces bone recurrence and improves breast cancer survival in postmenopausal women [107]. Taken together, these trials suggest that zoledronic acid is effective primarily in a low-estrogen environment.
In a placebo-controlled, phase 3 trial of postmenopausal women with HR-positive breast cancer, more than 3,000 women were randomly assigned to denosumab 60 mg or placebo administered subcutaneously every 6 months [108]. The study demonstrated that denosumab reduced fractures caused by adjuvant endocrine therapy with aromatase inhibitors by 50%, and in addition to the skeletal benefits, patients who received denosumab had an 18% reduced risk of disease recurrence.
Неоадъювантная терапия
Неоадъювантная химиотерапия
The use of preoperative chemotherapy has been demonstrated to down-stage breast cancers, while not impacting long-term outcome, compared to postoperative chemotherapy. The pivotal NSABP B-18 trial demonstrated equivalent outcomes for patients treated with AC for 4 cycles prior to surgery, and patients who had surgery followed by the same chemotherapy [109]. Additionally, a higher percentage of patients treated with neoadjuvant chemotherapy were rendered candidates for breastconserving surgery. This trial was the first to demonstrate the importance of response to chemotherapy, in particular a pathologic complete response (PCR), defined as an absence of residual invasive cancer in the breast and axillary lymph nodes, as a predictor for long-term outcome. The prognostic value of PCR was confirmed in subsequent trials [110]. Importantly, these NSABP trials recruited patients with cancers unselected for subtype or HR status. It is increasingly apparent that obtaining a PCR is of more prognostic importance in patients with HR-negative breast cancers, compared to HR-positive breast cancers [111]. Patients with triple-negative breast cancers who do not achieve a PCR or near PCR following preoperative chemotherapy are highly likely to relapse within 2–3 years of diagnosis [112]. PCR is prognostic in HER2-positive cancers, but appears to be more important in HER2-positive, HR-negative breast cancers, compared to HER2positive, HR-positive breast cancers [111].
In general, similar chemotherapeutic regimens are used in the neoadjuvant setting as in the adjuvant setting. The neoadjuvant setting allows an early assessment of chemosensitivity and is a useful area to evaluate new agents. Additionally, the ability to collect cancer tissue following chemotherapy allows an analysis of mechanisms associated with resistance to specific agents.
Neoadjuvant chemotherapy is used as initial therapy for locally advanced breast cancers, including inflammatory breast cancers. Standard adjuvant chemotherapeutic regimens are typically used, though this is an active area for the evaluation of novel agents and approaches.
Неоадъювантная терапия HER2-позитивного рака молочной железы
Neoadjuvant trastuzumab-based chemotherapy is widely used in patients with early-stage and locally advanced HER2-positive breast cancer. Most commonly patients are treated with standard adjuvant trastuzumab-based regimens, which may or may not include an anthracycline. Novel approaches have been evaluated including the addition of other HER2-directed agents, such as lapatinib and pertuzumab [113–115]. The addition of these agents to trastuzumab has been demonstrated to increase the rate of PCR. Several trials have evaluated the use of HER2directed agents alone without chemotherapy in the neoadjuvant setting [115, 116]. These trials have demonstrated that a small percentage of patients achieve a PCR without chemotherapy, which supports the concept that not all HER2-positive cancers require chemotherapy in addition to HER2-directed agents. The NCCN guidelines contain a list of regimens, containing HER2-directed agents, from randomized trials. The combination of pertuzumab, trastuzumab, and docetaxel, with or without carboplatin, is among the most commonly used nonanthracycline containing regimens approved for the preoperative treatment of HER2-positive breast cancer [115, 117].
Interestingly, all the randomized trials that have evaluated HER2-directed agents, with or without chemotherapy, consistently demonstrate a lower rate of PCR in HR-positive, HER2-positive breast cancers,compared to HR-negative,HER2-positive breast cancers [93]. ER has been demonstrated to act as an escape mechanism in some HR-positive, HER2-positive cancers, suggesting that in a subset of these cancers inhibition of ER as well as HER2 may be important.
Неоадъювантная эндокринная терапия
It is clear that HR-positive breast cancers are less likely to achieve a PCR compared to HR-negative cancers following preoperative chemotherapy, though many HR-positive tumors exhibit at least a partial response [111]. This is not surprising given the fact that adjuvant chemotherapy does not improve outcome for a subset of HR-positive cancers. There is, therefore, increasing interest in evaluating preoperative endocrine therapy as a means of down-staging HR-positive breast cancers prior to surgery. The majority of clinical trials utilized 3–4 months of endocrine therapy and demonstrated reasonable partial response rates [118, 119]. A randomized trial that compared preoperative chemotherapy with preoperative endocrine therapy demonstrated equivalent response rates in patients with HR-positive breast cancer [120]. There are emerging data to suggest that longer durations of preoperative endocrine therapy (12 months or longer) are associated with higher response rates, including PCR rates, compared to shorter durations of endocrine therapy [121]. Currently the use of preoperative endocrine therapy is largely reserved for older patients with comorbid illnesses that may preclude the use of chemotherapy.
Some studies have demonstrated that decreases in Ki-67 following the institution of preoperative endocrine therapy may be a surrogate for long-term outcome [122]. There is interest in evaluating Ki-67 decreases by immunostaining of biopsies shortly after commencing endocrine therapy and using this as a means of continuing or stopping endocrine therapy [123].
There is interest in combining novel agents with endocrine therapy in the preoperative setting. The addition of the mechanistic target of rapamycin (mTOR) inhibitor, everolimus, to letrozole in the preoperative setting improved response rate, compared to letrozole alone [124]. The preoperative setting can potentially be used to determine sensitivity to endocrine therapy and gain a better understanding of the mechanisms underlying endocrine resistance.
Лечение метастатической болезни
Similar to the early-stage setting, the treatment of metastatic breast cancer is generally dictated by the breast cancer subtype. The use of targeted therapies has improved outcome for patients with HR-positive and HER2-positive breast cancers, with median survivals in the range of 4 and 3 years, respectively. Unfortunately the same is not true for metastatic triple-negative breast cancer, where the absence of targeted agents and inherent chemoresistance result in median survivals of only about 12 months. As with all metastatic cancers, the goals of treatment are improved survival, with as minimal effects on quality of life as possible.
Лечение HR-позитивного метастатического рака молочной железы
Patients with HR-positive metastatic breast cancer are often treated with sequential lines of endocrine therapy until resistance occurs. This offers patients the highest chance of disease control with the lowest toxicity. However, chemotherapy is indicated if patients have life-threatening visceral metastases, such as lymphangitic carcinomatosis, or eventually when resistance to endocrine agents occurs.ThemediansurvivalforpatientswithHR-positive metastatic breast cancer has been demonstrated to be as long as 4 years; factors predictive of a longer survival include long time since initial diagnosis, presence of bone metastases only, older age, postmenopausal status, and presence of both ER and PR.
There are a number of endocrine agents available for postmenopausal patients with HR-positive metastatic breast cancer. Each of the aromatase inhibitors has been compared to tamoxifen in the first-line treatment of HR-positive metastatic breast cancer and found to be superior in most endpoints, though none of these trials demonstrated a clear survival advantage for the aromatase inhibitors [125]. Fulvestrant, an estrogen receptor down-regulator, is approved for patients with HR-positive early-stage breast cancer who have received prior anti-estrogen therapy. Fulvestrant, at 250 mg every 4 weeks, was found to be equivalent to tamoxifen in the first-line treatment of HR-positive metastatic breast cancer [126]. However, fulvestrant at a dose of 500 mg every 4 weeks following a loading dose was found to be superior to the 250 mg dosing schedule, with minimal increase in toxicity, in a randomized trial which accrued patients who had previously received nonsteroidal aromatase inhibitors [127]. This high-dose schedule of fulvestrant was approved by the US Food and Drug Administration (FDA), and is the current optimal dose and schedule of this agent. A randomized trial compared fulvestrant, at the 500 mg dose, to anastrozole in the first-line treatment of
HR-positive metastatic breast cancer and demonstrated a highly significant improvement in progression-free survival (PFS) for patients treated with fulvestrant [128]. Lastly, trials that compared a combination of fulvestrant and anastrozole to anastrozole alone in the first-line treatment of HR-positive metastatic breast cancer had conflicting results [129, 130]. The FACT trial did not show an advantage for the combination, while a SWOG trial demonstrated a significant 1.5-month improvement in PFS for the combination, compared to anastrozole. Notably, patients in the SWOG trial were somewhat less likely to have received adjuvant endocrine therapy, and patients in the control arm had a longer PFS than those on the FACT trial, raising the possibility that the combination of fulvestrant and anastrozole may be especially effective in patients previously untreated with endocrine therapy. The FALCON study is a phase 3 randomized, doubleblind trial of fulvestrant versus anastrozole in HR-positive patients who were endocrine therapy naпve [131]. Fulvestrant significantly improved PFS compared to the anastrozole group (HR 0.797, 95% CI 0.637–0.999, P = 0.0486). The median PFS was 16.6 months in the fulvestrant group versus 13.8 months in the anastrozole group. Notably, a subgroup analysis of FALCON showed that patients without visceral involvement benefitted the most, and they had a PFS of >20 months. This makes fulvestrant a very appealing choice as first-line therapy for some patients.
Finally, CDK 4/6 inhibition plays a significant role in the management of HR-positive breast cancer. One of the hallmarks of cancer is the dysregulation of the cell cycle. In order for a cell to divide while avoiding genetic damage, it has to go through strictly predefined stages in a specific fashion, and this process is called the cell cycle. Cyclin-dependent kinases (CDKs) are a large family of kinases; together with their regulatory protein partners, the cyclins, CDKs play a pivotal role in the progression of the cell through the cell cycle, and specifically in the transition of the cell from G0/G1 to S phase [132]. Palbociclib, abemaciclib, and ribociclib are all orally active, potent, and highly selective inhibitors of CDK4 and CDK6.
Palbociclib was the first CDK4/6 inhibitor approved as a firstline therapy for HR-positive HER2-negative metastatic breast cancer. This was based on the PALOMA trials of oral palbociclib in combination with letrozole compared to letrozole alone. PALOMA-1 was a phase 2 trial that demonstrated an improvement in the PFS from 10.2 months (95% CI 5.7–12.6) in the letrozole group to 20.2 months (13.8–27.5) in the palbociclib plus letrozole group (HR 0.488, 95% CI 0.319–0.748; one-sided P = 0.0004) [133]. PALOMA-2 was a double-blind, phase 3 study that confirmed the findings of PALOMA-1 and showed improvement in the median PFS from 14.5 months in the letrozole group to 24.8 months in the combination arm (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46–0.72; P <0.001) [134]. The most common adverse events seen with palbociclib are neutropenia (occurring in up to 66.4% of patients, though febrile neutropenia is uncommon at 1.8%), leukopenia (24.8%), anemia (5.4%), and fatigue (1.8%).
Ribociclib is the second CDK 4/6 inhibitor approved in the firstline setting. In the Monaleesa-2 trial, ribociclib plus letrozole improved the median PFS compared to letrozole alone; median duration of PFS was not reached in the ribociclib group but was reached in the control group in 14.7months (hazard ratio, 0.56; 95% CI 0.43–0.72; P = 3.29 х 10-6 for superiority) [135]. Ribociclib has a similar structure and similar side effect profile as palbociclib.
Finally, abemaciclib is the third available CDK 4/6 inhibitor, approved in combination with fulvestrant in patients who progressed while on adjuvant endocrine therapy, within 1 year of stopping their endocrine therapy, or during their first-line endocrine therapy for metastatic disease. Abemaciclib plus fulvestrant improved median PFS compared to fulvestrant alone from 9.3 to 16.4 months, with hazard ratio 0.553, 95% CI 0.449–0.681, and P<0.001 [136]. Abemaciclib has a different structure and side effect profile compared to the other two CDK 4/6 inhibitors. The most common adverse events in the abemaciclib group were diarrhea (86.4%), neutropenia (46.0%), nausea (45.1%), and fatigue (39.9%).
In summary, there are a number of options for the first-line treatment of HR-positive metastatic breast cancer, and treatment should be based on whether the patient has previously received adjuvant endocrine therapy, which agents the patient was exposed to in the adjuvant setting, and the timing of relapse. Hormone resistance is usually defined as relapse during or within 1 year after the completion of adjuvant endocrine therapy. Beyond that 1-year mark, cancers are considered sensitive. In general, de novo metastatic disease is considered hormone sensitive.
The optimal management of patients with HR-positive metastatic breast cancer is the sequential use of endocrine agents. The optimal sequence, as with the optimal first-line choice of endocrine agent, remains undefined. The EFECT trial compared fulvestrant, at the 250 mg dose, to exemestane in patients who had all received prior nonsteroidal aromatase inhibitors and many of whom had received tamoxifen, prior to study entry [137]. The PFS was identical at 3.7 months on each arm, suggesting that the choice of endocrine agent in the secondand third-line setting may not be that important, since most patients will receive most endocrine agents atsome point during the course of their disease. Importantly, the nonsteroidal aromatase inhibitors, anastrozole and letrozole, have been demonstrated to be cross-resistant in HR-positive metastatic breast cancer. In contrast, the steroidal aromatase inhibitor, exemestane, exhibits activity after nonsteroidal aromatase inhibitors, and the opposite sequence is also effective.
A key component in the management of HR-positive breast cancer in premenopausal patients is ovarian suppression, using luteinizing hormone releasing hormone (LHRH) agonists or bilateral oophorectomies. A randomized trial, which compared tamoxifen alone, ovarian suppression alone, and the combination of tamoxifen and ovarian suppression, demonstrated a significantly improved PFS and survival for patients treated with both ovarian suppression and tamoxifen, and this combination is the optimal choice in the first-line setting for patients who have not received tamoxifen in the adjuvant setting [138]. Toremifene, a chlorinated derivative of tamoxifen, is approved as an alternative to tamoxifen for patients who cannot tolerate tamoxifen. Once menopause has been induced in premenopausal patients, they can be treated with any of the agents used for postmenopausal patients.
Resistance to endocrine therapy is multifactorial, but activation of growth factor pathways and downstream signaling pathways has been shown to be important. The use of growth factor receptor inhibitors, such as gefitinib and bevacizumab, has shown modest activity at best. This may be because the majority of these trials were performed in the first-line setting when only a subset of breast cancers are likely to be truly resistant to endocrine agents. Inhibition of mTOR was demonstrated to be a rational target in endocrine-resistant preclinical models. The BOLERO2 pivotal trial evaluated the addition of everolimus to exemestane in postmenopausal patients previously treated with nonsteroidal aromatase inhibitors. The addition of everolimus to exemestane significantly improved PFS by 6 months, compared to exemestane alone, and everolimus in combination with exemestane is approved for the treatment of HR-positive metastatic breast cancer in patients who have received prior nonsteroidal aromatase inhibitors [139]. Despite the benefit in the PFS, the combination of everolimus and exemestane did not improve overall survival (31 vs 26.6 months, P = 0.14) [140]. Everolimus can cause mucositis, hyperglycemia, rash, and rarely noninfectious pneumonitis, thereby increasing the toxicity associated with endocrine therapy [141]. The optimal timing of everolimus remains unclear and is being evaluated in ongoing trials.
CDK 4/6 inhibitors play a significant role in the management of second-line and beyond metastatic breast cancer. The PALOMA-3 trial compared palbociclib plus fulvestrant versus fulvestrant alone in patients with advanced HR-positive HER2negative breast cancer who had progressed on prior endocrine therapy or within 12 months of adjuvant endocrine therapy [142]. Palbociclib improved the median PFS from 4.6 months to 9.5 months (hazard ratio 0.46, 95% CI 0.36–0.59, P <0.0001).
Abemaciclib as single-agent therapy was shown to be effective in patients with breast cancer who had progressed on prior therapies, with an objective response rate of 19.7%, clinical benefit rate of 42.4%, median PFS of 6.0 months, and median overall survival of 17.7 months [143].
In summary, sequential use of endocrine agents or combination of endocrine therapy with cyclin-dependent kinase (CDK) 4/6 inhibitors or everolimus is the treatment of choice for patients with HR-positive metastatic breast cancer. Premenopausal women may be treated with ovarian suppression, in combination with endocrine agents. Chemotherapy is reserved for patients with life-threatening metastatic disease, and when endocrine therapies no longer are effective.
Лечение HER2-позитивного метастатического рака молочной железы
The use of trastuzumab-based approaches has significantly improved the outcome for patients with HER2-positive metastatic breast cancer, and the median survival is approximately 3 years. The initial pivotal trial that led to the approval of trastuzumab and paclitaxel in the metastatic setting evaluated the addition of trastuzumab to either AC or paclitaxel in the first-line metastatic setting [40]. Due to the unexpected increase in cardiomyopathy in patients treated with AC and trastuzumab, the use of anthracyclines and trastuzumab is generally avoided if possible. Subsequent trials have demonstrated that the addition of trastuzumab to other chemotherapeutic agents is feasible and effective.
Three other HER2-directed agents have been approved for the treatment of patients with metastatic HER2-positive breast cancer. Pertuzumab is a monoclonal antibody that targets the domain of the HER2 receptor, which is involved with dimerization with HER3. The combination of pertuzumab, trastuzumab, and docetaxel improved PFS by 6 months, compared to trastuzumab and docetaxel, in the first-line treatment of patients with HER2positive metastatic breast cancer, and this regimen is approved in the first-line setting [144], The addition of lapatinib, a tyrosine kinase inhibitor that targets HER1 and HER2, to capecitabine improves outcome compared to capecitabine alone in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab-based chemotherapy, and this combination is approved in this setting [145]. The addition of lapatinib to trastuzumab improves overall survival compared to lapatinib alone in patients with metastatic HER2-positive breast cancer previously treated with multiple prior trastuzumab-based regimens [146]. Trastuzumab-DM1 is a conjugate of trastuzumab and maytansine, which has demonstrated single-agent activity in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and lapatinib [147]. A randomized trial demonstrated a 3-month improvement in PFS in patients with trastuzumab pretreated HER2-positive metastatic breast cancer, treated with trastuzumab-DM1 compared to lapatinib and capecitabine [148].
Химиотерапия HER2-негативного метастатического рака молочной железы
The only available systemic treatment for patients with metastatic triple-negative breast cancer is chemotherapy, which results in median survivals in the range of 12 months. Additionally, the majority of patients with hormone receptorpositive metastatic breast cancer will ultimately receive systemic chemotherapy, once endocrine therapy options have been exhausted. Potential chemotherapeutic regimens can be found at nccn.org. It is currently unclear whether combination therapy offers any advantage over single agents. A randomized trial which compared single-agent paclitaxel, single-agent Adriamycin, and combination paclitaxel and Adriamycin demonstrated an improved response rate and PFS for patients treated with the combination compared to the single agents [149]. However, there was no survival advantage for patients treated with the combination since there was a pre-specified crossover from one single agent to the other at the time of disease progression. The combination arm was associated with increased toxicity compared to the single-agent arms. In general, combination therapy should probably be reserved for patients with large-volume metastatic disease, in whom a response to treatment will likely improve quality of life.
Предотвращение скелетных реакций у пациентов с раком молочной железы и метастазами в кости
One of the most common sites of metastases in patients with breast cancer is the bones, which can lead to complications including fractures, pain, and hypercalcemia. The bisphosphonate pamidronate has been demonstrated to decrease the risk of skeletal-related complications, compared to placebo, in patients with breast cancer metastatic to bones [150]. Subsequently, zoledronic acid was found to be equivalent to pamidronate in this setting [151]. Intravenous bisphosphonates can result in renal issues and osteonecrosis of the jaw, and the optimal duration of treatment and frequency of dosing remain unclear.
Denosumab is a RANK-ligand inhibitor, which is equivalent to zoledronic acid in patients with bone metastases [152]. In contrast to bisphosphonates, denosumab is given subcutaneously and does not cause renal toxicity, though the risk of osteonecrosis of the jaw is similar with all these agents.
Рак молочной железы у мужчин
Breast cancer is very rare in males. It is estimated that 2,470 new cases will be diagnosed and 460 men will die with breast cancer in the US during 2017 [3]. Most risk factors are the same as for female breast cancer, such as family history, BRCA 1 and 2 mutations (risk is higher with BRCA2 mutations), radiation exposure, benign breast disease, obesity, and inactive lifestyle. Interestingly, the association with alcohol intake is not as strong as with breast cancer in women. However, some factors are unique to men, such as the diagnosis of Klinefelter syndrome, low bone density, gynecomastia, and orchitis/epididymitis, most of which are conditions associated with high estrogen/ androgen ratio [153, 154]. Almost 90% of male breast cancers are IDC. The importance of estrogen excess in the risk of developing breast cancer in males is explained by the fact that most male tumors are HR-positive. A population-based epidemiologic study reported that among 829 men diagnosed with breast cancer from 2005 to 2009, 82% were HR positive, 15% were HER2 positive, and 3.6% had triple-negative tumors. HER2-positive cancers occur more commonly in young patients, while Hispanic and non-Hispanic Black patients tend to have ER-positive/PR-negative staining [155].
Most cases present as a painless, palpable mass. The workup involves a mammogram with or without an ultrasound and if imaging findings are suspicious, a biopsy is indicated for pathologic diagnosis. After the pathologic diagnosis is established, the staging and workup is the same as with female cancers. The TNM staging system is used, and the most important prognostic factors are the stage, tumor size, and number of involved lymph nodes. The preferred surgical treatment for men is modified radical mastectomy, however patients with sufficient breast tissue may allow for breast-conserving surgery, followed by radiation. Postmastectomy radiation may be also indicated in patients with locally advanced disease and >4 positive axillary nodes [156, 157]. The same principles of adjuvant and metastatic therapy apply in men as in women; the exception is that tamoxifen is the agent of choice for HR-positive tumors in men [158]. There is currently no specific evidence supporting the use of HER2directed therapies in men, however all HER2-positive patients should be offered targeted treatment based on female breast cancer studies.
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