Advancements in molecular profiling and endocrine therapy (ET) have led to more focused clinical attention on precision medicine. These advances have expanded our understanding of breast cancer (BC) ...pathogenesis and hold promising implications for the future of therapy. The estrogen receptor‐α is a predominant endocrine regulatory protein in the breast and in estrogen‐induced BC. Successful targeting of proteins and genes within estrogen receptor (ER) nuclear and nonnuclear pathways remains a clinical goal. Several classes of antiestrogenic agents are available for patients with early, advanced, or metastatic BC, including selective ER modulators, aromatase inhibitors, and a selective ER degrader. Clinical development is focused upon characterizing the efficacy and tolerability of inhibitors that target the phosphatidylinositol 3 kinase (PI3K)/akt murine thymoma viral oncogene (AKT)/mammalian target of rapamycin inhibitor (mTOR) signaling pathway or the cyclin‐dependent kinase 4/6 (CDK4/6) cell cycle pathway in women with hormone receptor‐positive, human epidermal growth receptor 2‐negative BC who have demonstrated disease recurrence or progression. De novo and acquired resistance remain a major challenge for women with BC receiving antiestrogenic therapy. Therefore, sequential combination of targeted ET is preferred in these patients, and the ever‐increasing understanding of resistance mechanisms may better inform the selection of future therapy. This review describes the intricate roles of the PI3K/AKT/mTOR and CDK4/6 pathways in intracellular signaling and the use of endocrine and endocrine‐based combination therapy in BC.
Implications for Practice
The foundational strategy for treating hormone receptor‐positive, human epidermal growth receptor 2‐negative, advanced breast cancer includes the use of endocrine therapy either alone or in combination with targeted agents. The use of combination therapy aims to downregulate cell‐signaling pathways with the intent of minimizing cellular “crosstalk,” which can otherwise result in continued tumorigenesis or progression through redundant pathways. This review provides the clinician with the molecular rationale and clinical evidence for these treatments and refers to evidence‐based guidelines to inform the decision‐making process.
摘要
分子表达谱和内分泌疗法 (ET) 的进步使得精准医疗获得更为集中的临床关注。这些进步拓展了我们对乳腺癌 (BC) 发病机制的了解, 并预示未来疗法的良好前景。雌激素受体 α 是乳腺及雌激素诱导 BC 中的主要内分泌调节蛋白。对雌激素受体 (ER) 核途径和非核途径中的蛋白质和基因进行成功靶向仍是临床目标。早期、晚期和转移性 BC 患者现可使用多种抗雌激素药物, 包括选择性 ER 调节剂、芳香化酶抑制剂和选择性 ER 降解剂。临床开发专注于表征以磷脂酰肌醇 3 激酶 (PI3K)/akt 鼠胸腺瘤病毒致癌基因 (AKT)/哺乳动物雷帕霉素靶蛋白 (mTOR) 抑制剂信号传导通路或细胞周期依赖性激酶 4/6 (CDK4/6) 细胞周期通路为靶标的抑制剂在显现疾病复发或进展的激素受体阳性、人表皮生长受体 2 阴性 BC 女性中的疗效和耐受性。在接受抗雌激素治疗的 BC 女性中, 原发性及获得性耐药仍是主要挑战。因此, 靶向 ET 的序贯联合治疗是这些患者的首选, 对耐药性机制的理解不断增加可更好地指导未来疗法的选择。本综述介绍了 PI3K/AKT/mTOR 和 CDK4/6 通路在细胞内信号传导中的复杂作用以及内分泌和以内分泌为基础的联合疗法在 BC 中的使用。
对临床实践的启示：激素受体阳性、人表皮生长受体 2 阴性晚期乳腺癌的基本治疗策略包括单独使用内分泌疗法或与靶向药物联用。使用联合疗法旨在下调细胞信号传导通路, 目的最大程度地减少细胞“串扰”, 否则可能会通过冗余途径导致持续肿瘤发生或进展。本综述为临床医生提供了该类治疗的分子依据和临床证据, 并援引循证指南指导决策过程
This review describes the role of intracellular signaling pathways and the estrogen receptor in breast cancer, the role of anti‐estrogens in the treatment of HR1 advanced breast cancer, the development of resistance to anti‐estrogen therapy, and the use of endocrine and endocrine‐based combination therapy in breast cancer.
Imbalance of the cyclin D and cyclin‐dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells ...may increase cyclin D‐dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan‐CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptor‐positive (ER+) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion. We describe the application of such therapy to other breast cancer settings, including HER2‐positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double‐strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.
This paper reviews the role of CDK4/6 in tumorigenesis and summarizes the clinical trial experience with inhibitors of these kinases in breast cancer, including key efficacy and toxicity data. The results with oral CDK4/6 inhibitors to date have offered promising glimpses of significant activity in hormone‐sensitive breast cancer. This activity, combined with a favorable toxicity profile, makes this family of novel therapies very exciting.
The majority of breast cancers may be considered hormone responsive due to expression of hormone receptors (HR+). Although endocrine therapy is always considered for advanced HR+ breast cancer, the ...emergence of resistance is inevitable over time and is present from the start in a proportion of patients. In this review, we explore the mechanisms underlying de novo and acquired resistance to endocrine therapy. We comprehensively review newly approved and emerging therapies that have been developed to counteract specific mechanisms of resistance. We discuss the challenges pertinent to this therapeutic arena including the potential relief of negative regulatory feedback inhibition with compensatory pathway activation and the evolution of molecular changes in HR+ breast cancers during treatment. We discuss strategies to address these challenges in order to develop rational therapy approaches for patients with advanced HR+ breast cancer.
To develop recommendations about endocrine therapy for women with hormone receptor (HR) -positive metastatic breast cancer (MBC).
The American Society of Clinical Oncology convened an Expert Panel to ...conduct a systematic review of evidence from 2008 through 2015 to create recommendations informed by that evidence. Outcomes of interest included sequencing of hormonal agents, hormonal agents compared with chemotherapy, targeted biologic therapy, and treatment of premenopausal women. This guideline puts forth recommendations for endocrine therapy as treatment for women with HR-positive MBC.
Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC. Except in cases of immediately life-threatening disease, hormone therapy, alone or in combination, should be used as initial treatment. Patients whose tumors express any level of hormone receptors should be offered hormone therapy. Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and organ function. Tumor markers should not be the sole criteria for determining tumor progression; use of additional biomarkers remains experimental. Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women. For postmenopausal women, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the cyclin-dependent kinase inhibitor palbociclib. As second-line therapy, fulvestrant should be administered at 500 mg with a loading schedule and may be administered with palbociclib. The mammalian target of rapamycin inhibitor everolimus may be administered with exemestane to postmenopausal women with MBC whose disease progresses while receiving nonsteroidal AIs. Among patients with HR-positive, human epidermal growth factor receptor 2-positive MBC, human epidermal growth factor receptor 2-targeted therapy plus an AI can be effective for those who are not chemotherapy candidates.
Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase α (PI3Kα), are frequently found in estrogen receptor (ER)–positive breast cancer. PI3Kα inhibitors, now in late-stage ...clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kα inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.
The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone ...receptor-positive (HR
), HER2
metastatic breast cancer (MBC).
MONARCH 1 was a phase II single-arm open-label study. Women with HR
/HER2
MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS).
Patients (
= 132) had a median of 3 (range, 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3-27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%).
In this poor-prognosis, heavily pretreated population with refractory HR
/HER2
metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity.
.
Activating mutations in
are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to ...these agents, we analyzed
-mutant cancer genomes and observed the presence of multiple
mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double
mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double
mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.
Purpose
To assess sexual/vaginal health issues and educational intervention preferences in women with a history of breast or gynecologic cancer.
Methods
Patients/survivors completed a cross-sectional ...survey at their outpatient visits. Main outcome measures were sexual dysfunction prevalence, type of sexual/vaginal issues, awareness of treatments, and preferred intervention modalities. Descriptive frequencies were performed, and results were dichotomized by age, treatment status, and disease site.
Results
Of 218 eligible participants, 109 (50%) had a history of gynecologic and 109 (50%) a history of breast cancer. Median age was 49 years (range 21–75); 61% were married/cohabitating. Seventy percent (
n
= 153) were somewhat-to-very concerned about sexual function/vaginal health, 55% (
n
= 120) reported vaginal dryness, 39% (
n
= 84) vaginal pain, and 51% (
n
= 112) libido loss. Many had heard of vaginal lubricants, moisturizers, and pelvic floor exercises (97, 72, and 57%, respectively). Seventy-four percent (
n
= 161) had used lubricants, 28% moisturizers (
n
= 61), and 28% pelvic floor exercises (
n
= 60). Seventy percent (
n
= 152) preferred the topic to be raised by the medical team; 48% (
n
= 105) raised the topic themselves. Most preferred written educational material followed by expert discussion (66%,
n
= 144/218). Compared to women ≥50 years old (41%,
n
= 43/105), younger women (54%,
n
= 61/113) preferred to discuss their concerns face-to-face (
p
= 0.054). Older women were less interested in online interventions (52%,
p
< 0.001), despite 94% having computer access.
Conclusion
Female cancer patients/survivors have unmet sexual/vaginal health needs. Preferences for receiving sexual health information vary by age. Improved physician–patient communication, awareness, and educational resources using proven sexual health promotion strategies can help women cope with treatment side effects.
IMPORTANCE: Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. OBJECTIVE: ...To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue (“tumor-normal sequencing”) compared with genetic test results based on current guidelines. DESIGN, SETTING, AND PARTICIPANTS: From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. EXPOSURE: Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. MAIN OUTCOMES AND MEASURES: Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. RESULTS: Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. CONCLUSIONS AND RELEVANCE: In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01775072
To assess whether woman who have BRCA mutations (WBM) experience more declines in ovarian reserve after chemotherapy treatment, as it induces oocyte death by deoxyribonucleic acid (DNA) damage, and ...BRCA mutations result in DNA damage repair deficiency.
Longitudinal cohort study.
Academic centers.
The 108 evaluable women with breast cancer were stratified into those never tested (negative family history; n = 35) and those negative (n = 59) or positive (n = 14) for a pathogenic BRCA mutation.
Sera were longitudinally obtained before and 12–24 months after chemotherapy treatment, assayed for antimüllerian hormone (AMH), and adjusted for age at sample collection.
Ovarian recovery, defined as the geometric mean of the after chemotherapy age-adjusted AMH levels compared with baseline levels.
Compared with the controls, the before chemotherapy treatment AMH levels were 24% and 34% lower in those negative or positive for BRCA mutations, consistent with accelerated ovarian aging in WBM. The WBM had a threefold difference in AMH recovery after chemotherapy treatment (1.6%), when compared with BRCA negative (3.7%) and untested/low risk controls (5.2%). Limiting the analysis to the most common regimen, doxorubicin and cyclophosphamide followed by paclitaxel, showed similar results. These findings were mechanistically confirmed in an in vitro mouse oocyte BRCA knockdown bioassay, which showed that BRCA deficiency results in increased oocyte susceptibility to doxorubicin.
Women who have pathogenic BRCA mutations are more likely to lose ovarian reserve after chemotherapy treatment, suggesting an emphasis on fertility preservation. Furthermore, our findings generate the hypothesis that DNA repair deficiency is a shared mechanism between aging, infertility, and cancer.
NCT00823654.
Pérdida de reserva ovárica inducida por la quimioterapia incrementada en mujeres con mutaciones de la línea germinal BRCA debido a deficiencia en la reparación del ácido desoxirribonucleico de doble cadena en el ovocito
Evaluar si las mujeres con mutaciones BRCA (WBM) experimentan una mayor disminución en la reserva ovárica después de tratamiento con quimioterapia, debido a que este provoca la muerte ovocitaria debido a daño del ácido desoxirribonucleico (DNA), y las mutaciones BRCA resultan en deficiencia en la reparación de daños en el DNA.
Estudio longitudinal de cohorte.
Centros académicos.
Las 108 mujeres con cáncer de mama evaluables fueron estratificadas en aquellas que nunca habían sido testadas para mutación BRCA patogénica (historia familiar negativa; (n=35) y aquellas negativas (n=59) o positivas (n=14).
Se obtuvo suero longitudinalmente antes y 12-24 meses después de tratamiento con quimioterapia, utilizado para medir hormona antimülleriana (AMH), y ajustado para la edad en el momento de la obtención de la muestra.
Recuperación ovárica, definida como la media geométrica de los niveles de AMH ajustados a la edad después de la quimioterapia comparados con los basales.
En comparación con los controles, los niveles de AMH antes del tratamiento de quimioterapia fueron 24% y 34% más bajos en aquellos negativos o positivos para mutaciones BRCA, consistente con el envejecimiento ovárico acelerado en WBM. El WBM tuvo una diferencia del triple en la recuperación de AMH después del tratamiento de quimioterapia (1.6%), en comparación con los controles BRCA negativos (3.7%) y no testados/ bajo riesgo (5.2%). Al limitar el análisis al régimen más común, doxorubicina y ciclofosfamida seguido de paclitaxel, se observaron resultados similares. Estos hallazgos se confirmaron mecánicamente en un bioensayo de eliminación de BRCA de ovocitos de ratón in vitro, que mostró que la deficiencia de BRCA resulta en un aumento de la susceptibilidad de los ovocitos a la doxorubicina.
Las mujeres que tienen mutaciones BRCA patogénicas tienen más probabilidades de perder reserva ovárica después del tratamiento de quimioterapia, sugiriendo un énfasis en la preservación de la fertilidad. Además, nuestros hallazgos generan la hipótesis de que la deficiencia de reparación del ADN es un mecanismo compartido entre envejecimiento, infertilidad y cáncer.
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