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Acknowledgment of Commercial Support
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Community Practice Connections™: 2nd Annual Paris Breast Cancer Conference™
Release Date: January 31, 2019
Expiration Date: January 31, 2020
Media: Internet - based
Community Practice Connections™: 2nd Annual Paris Breast Cancer Conference™ features a summary of clinical evidence guiding the treatment of patients with breast cancer. Topics include the utility of different assays to determine breast cancer relapse risk; recent advancements in the treatment paradigm for patients with luminal breast cancer; current therapeutic options for patients with early-stage and metastatic HER2-positive breast cancer, including the management of brain metastases and patients who are long-term responders to therapy; and emerging therapies for triple-negative breast cancer, such as poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors. This educational activity incorporates didactic reviews of key data accompanied by short video interviews with experts in the field, who share their perspectives on current treatment paradigms, practical patient management insights, and evolving prospects for the future.
Acknowledgement of Commercial Support
This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Oncology Europe GmbH, Eisai Inc., Pfizer, and Seattle Genetics, Inc.
Instructions for This Activity and Receiving Credit
This educational activity is directed toward healthcare professionals who practice primarily outside of the United States. It is specifically designed for medical oncologists and other healthcare professionals (eg, physicians, physicians-in-training, oncology nurses, pharmacists, physician assistants) involved in the treatment and management of patients with breast cancer.
Upon successful completion of this activity, you should be better prepared to:
- Individualize treatment planning for patients with breast cancer based on the appropriate use and interpretation of biomarker results and molecular or genomic assays
- Delineate local treatment approaches, such as surgery and radiation therapy, as well as systemic preoperative therapies, to manage patients with early-stage or locally advanced breast cancer
- Integrate recent clinical trial evidence into personalized treatment strategies for the management of patients with breast cancer
- Discuss emerging data regarding investigational approaches for managing breast cancer in the context of evolving treatment paradigms
- Discuss methods to facilitate awareness of clinical trials among patients who may benefit from inclusion in studies evaluating investigation
Faculty, Staff, and Planners' Disclosures
Department of Medical Oncology
Disclosures: Grant/Research Support: AstraZeneca, Novartis, Pfizer, Lilly, Roche
Head, Familial Cancer Unit
Assistant Breast Cancer Unit
Vall d’Hebron University Hospital
Disclosures: Grant/Research Support: PharmaMar; Consultant/Advisory Board: Clovis Oncology, Tesaro; Speakers Bureau: AstraZeneca; Other: PharmaMar reimbursed travel expenses
Head of the Breast Cancer and Gynecological Tumors
Ramón y Cajal University Hospital
Clinical Investigator, Breast Cancer Research Program
Vall d'Hebron Institute of Oncology
Disclosures: Consultant/Advisory Board: Roche, Celgene, AstraZeneca, Cellestia Biotech, Biothera, Seattle Genetics; Other: Honoraria from Roche, Novartis, Eisai, Celgene, Pfizer
The staff of PER® have no relevant financial relationships with commercial interests to disclose.
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As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.
Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.
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This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.
PER Pulse™ Recaps
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Triple-Negative Breast Cancer
Germline Alteration Assessment
The implications of genetic testing for patients with breast cancer are far-reaching, with the information provided by these tests having the potential to influence estimation of cancer risk, the likelihood of early detection and prevention, and treatment decisions for those who may be candidates for targeted therapies. BRCA1 and BRCA2 mutations have an established association with breast cancer risk, with a cumulative breast cancer risk of 72% for patients with BRCA1 mutations and 69% for BRCA2 mutations in women aged up to 80 years.1 A recent study showed that 13.8% of women with triple-negative breast cancer (TNBC) were noted to have deleterious BRCA1 or BRCA2 mutations, and patients with TNBC should be considered for germline BRCA1 and BRCA2 testing.2 In patients with young-onset breast cancer, survival outcomes are similar regardless of the presence of BRCA mutation status; however, there may be a survival advantage early on (during the first 2 years after diagnosis) for patients with TNBC who have BRCA mutations. This carries implications for decisions regarding additional surgery to mitigate risk for future second primary cancers.3 Studies have also evaluated other breast cancer gene mutations to assess clinical relevance.
While patients have shown significant improvements in pathologic complete response (pCR) rates with the use of platinum-based chemotherapy for TNBC, it also imparts greater risk for hematologic toxicities.4 The CALGB 40603 study5 showed a breast/axilla pCR rate of 54% with the addition of carboplatin to standard neoadjuvant chemotherapy compared with 41% for patients receiving standard chemotherapy alone (P = .0029). A pCR benefit was also seen in the GeparSixto study,6 in which patients with TNBC had a pCR rate of 53.2% when receiving carboplatin in addition to taxane-and-anthracycline–based chemotherapy compared with 36.9% in patients who did not receive carboplatin (P = .005). In this study, disease-free survival was also greater for patients with TNBC with the addition of carboplatin (HR, 0.56; 95% CI, 0.34-0.93; P = .022).7 This effect was noted to be independent of germline BRCA (gBRCA) status,8 as patients without gBRCA mutations derived benefit with the use of carboplatin. Homologous recombination deficiency (HRD) has not been shown to predict benefit with carboplatin.7 Compared with intense dose-dependent epirubicin, paclitaxel, and cyclophosphamide therapy, platinum-based chemotherapy has been shown to generate a greater pCR benefit among patients with BRCA1/2 mutations.9 Germline BRCA mutation has demonstrated clinical utility as a selection biomarker for patients with metastatic TNBC to guide choices regarding platinum-based chemotherapy.10 In a recent study of patients with TNBC, basal gene expression also showed promise as a means of potentially guiding therapy, as patients with nonbasal genotype had a greater degree of benefit with docetaxel than with carboplatin.10
In addition to platinum-based compounds, PARP inhibitors also have influenced treatment paradigms for patients with breast cancer. Both platinum compounds and PARP inhibitors have demonstrated efficacy in patients whose cancer is characterized by deficiency in homologous recombination repair mechanisms, as is the case in patients who have gBRCA1/2 mutations. Pathogenic germline mutations are found in approximately 7% of patients with TNBC.11 PARP inhibitors lead to the development of single-strand DNA breaks, which can lead to the subsequent development of double-strand DNA breaks. In patients who are not able to repair the double-strand breaks due to HRD, the disruption creates tumor-selective cytotoxicity and leads to cell death. Currently, 2 PARP inhibitors are approved in the United States for the treatment of patients who have metastatic breast cancer with gBRCA mutations, based on the results of key phase III studies.12,13 PARP inhibitors are also being assessed in combination with immunotherapy.14
Immunotherapy in TNBC
Studies have demonstrated the potential of immune checkpoint inhibitor therapy for patients with TNBC, with a variety of strategies exploring these agents in combination with other therapies. Clinical investigation has assessed the combination of nab-paclitaxel and atezolizumab in the treatment of patients with locally advanced or metastatic TNBC. In the recent IMpassion 130 study,15 patients with metastatic TNBC who had not previously been treated for advanced TNBC were randomized 1:1 to receive either placebo plus paclitaxel or atezolizumab plus paclitaxel. In this study, approximately 40% of patients had PD-L1–positive cancer, which was defined as >1% PD-L1 on tumor-infiltrating immune cells. For the intent-to-treat population, the median progression-free survival (PFS) was 7.2 months in the arm receiving atezolizumab compared with 5.5 months in the arm receiving placebo (HR, 0.80; 95% CI, 0.69-0.92; P = .002). For patients with PD-L1–positive cancer, the median PFS was 7.5 months in the atezolizumab arm and 5.0 months in the placebo arm (HR, 0.62; 95% CI, 0.49-0.78; P <.0001). Neoadjuvant therapy for TNBC with the combination of chemotherapy and immune checkpoint inhibitor (ICPi) therapy is also being evaluated. The KEYNOTE-173 phase I/II trial16 is evaluating the combination of pembrolizumab and chemotherapy as neoadjuvant treatment for patients with TNBC, as is the I-SPY 2 trial.17 Another ICPi, durvalumab, is being studied in combination with neoadjuvant therapy for patients with primary TNBC.18 Numerous other studies are ongoing to help improve outcomes for patients with TNBC.
Immunotherapy in TNBC
TNBC is a highly heterogeneous molecular entity, a factor that carries therapeutic implications. A variety of strategies for TNBC management have shown promise in recent clinical studies, in addition to PARP inhibitors and immunotherapy. TNBC has been shown to be associated with an increased prevalence of PI3K/AKT activation, and AKT inhibitors have shown promise in 2 recent studies.19,20 Androgen receptor (AR) inhibitors are also garnering interest in the treatment of patients with TNBC. In a phase II study of bicalutamide in the treatment of patients with AR-positive, estrogen receptor–negative, progesterone receptor–negative metastatic breast cancer, the observed 6-month clinical benefit rate (CBR) was 19%.21 Enzalutamide has also demonstrated activity in phase II investigation of patients with AR-positive TNBC, with a CBR of 25% at 16 weeks (primary endpoint).22 The combination of abiraterone acetate plus prednisone has also demonstrated activity for these patients, with a 6-month CBR of 20%.23 New antiandrogen agents are also being studied, as are combinations of established antiandrogens with CDK4/6 inhibitors and PI3K inhibitors. Several ongoing studies are evaluating the role of antibody–drug conjugates (ADCs) in the management of patients with TNBC. Sacituzumab govitecan, which targets the TROP-2 protein expressed in most cases of TNBC, was evaluated in a phase II study of 69 patients with metastatic TNBC who had been treated with a median of 5 prior therapies.24 In this study, the objective response rate (ORR) was 30% (95% CI, 20%-43%). Sacituzumab govitecan is currently being studied in a phase III study as treatment for patients with refractory/relapsed TNBC.25 Another ADC that has shown promise in the treatment of patients with metastatic TNBC is ladiratuzumab vedotin. In a phase I study, 63 of 81 patients with LIV-1–expressing metastatic breast cancer were diagnosed with TNBC. The ORR for these patients was 25%, with a median duration of response of 13.3 weeks.26
- Breast cancer susceptibility is heterogeneous, and timely identification of BRCA1 and BRCA2 germline mutations may have a wide range of clinical implications.
- Several new treatments beyond immunotherapy and PARP inhibitors are being tested in clinical trials. These include AKT inhibitors, androgen receptor–targeting agents, antibody–drug conjugates, and different combinatorial approaches.
- Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402-2416. doi: 10.1001/jama/2017.7112.
- Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304-311. doi: 10.1200/JCO.2014.57.1414.
- Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169-180. doi: 10.1016/S1470-2045(17)30891-4.
- Poggio F, Bruzzone M, Ceppi M, et al. Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. Ann Oncol. 2018;29(7):1497-1508. doi: 10.1093/annonc/mdy127.
- Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015;33(1):13-21. doi: 10.1200/JCO.2014.57.0572.
- von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747-756. doi: 10.1016/S1470-2045(14)70160-3.
- Loibl S, Weber KE, Timms KM, et al. Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response–final results from GeparSixto. Ann Oncol. 2018;29(12):2341-2347. doi: 10.1093/annonc/mdy460.
- Hahnen E, Lederer B, Hauke J, et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial. JAMA Oncol. 2017;3(10):1378-1385. doi: 10.1001/jamaoncol.2017.1007.
- Pohl E, Schneeweiss A, Hauke J, et al. Germline mutation status and therapy response in patients with triple-negative breast cancer (TNBC): results of the GeparOcto study. Presented at: 2018 European Society for Medical Oncology Annual Congress; October 19-23, 2018; Munich, Germany. Abstract 243P.
- Tutt A, Tovey H, Cheang MCU, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial. Nat Med. 2018;24(5):628-637. doi: 10.1038/s41591-018-000907.
- Meric-Bernstam F, Brusco L, Daniels M, et al. Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. Ann Oncol. 2016;27(5):795-800. doi: 10.1093/annonc/mdw018.
- Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi: 10.1056/NEJMoa1706450.
- Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763. doi: 10.1056/NEJMoa1802905.
- Vinayak S, Tolaney SM, Schwartzberg LS, et al. TOPACIO/KEYNOTE-162: niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial. J Clin Oncol. 2018;36(15 suppl; abstr 1011). doi: 10.1200/JCO.2018.36.15_suppl.1011.
- Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615.
- Schmid P, Park YH, Munoz-Couselo E, et al. Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): preliminary results from KEYNOTE-173. Presented at: 2017 American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, IL. Abstract 556.
- Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. Presented at: 2017 American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, IL. Abstract 506.
- Loibl S, Untch M, Burchardi N, et al. Randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab to a taxane-anthracycline containing chemotherapy in triple negative breast cancer (TNBC). Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 104.
- Kim SB, Dent R, Im SA, et al; LOTUS Investigators. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18(10):1360-1372. doi: 10.1016/S1470-2045(17)30450-3.
- Schmid P, Abraham J, Chan S, et al. AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): a randomised, double-blind, placebo-controlled, phase II trial. Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 1007.
- Gucalp A, Tolaney S, Isakoff SJ, et al; Translational Breast Cancer Research Consortium (TBCRC 011). Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res. 2013;19(19):5505-5512. doi: 10.1158/1078-0432.CCR-12-3327.
- Traina TA, Miller K, Yardley DA, et al. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol. 2018;36(9):884-890. doi: 10.1200/JCO.2016.71.3495.
- Bonnefoi H, Grellety T, Tredan O, et al. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann Oncol. 2016;27(5):912-818. doi: 10.1093/annonc/mdw067.
- Bardia A, Mayer IA, Diamond JR, et al. Efficacy and safety of anti-trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol. 2017;35(19):2141-2148. doi: 10.1200/JCO.2016.70.8297.
- ClinicalTrials.gov. ASCENT–Study of Sacituzumab Govitecan in Refractory/Relapsed Triple-Negative Breast Cancer (ASCENT). https://www.clinicaltrials.gov/ct2/show/NCT02574455. Accessed January 11, 2019.
- Modi S, Pusztai L, Forero A, et al. Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-negative metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD3-14.
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HER2-Positive Breast Cancer
Early HER2-Positive Breast Cancer
Several advancements in the treatment of patients with early-stage HER2-positive (HER2+) breast cancer have been made over the course of the past decade. The phase III North Central Cancer Treatment Group N9831 study1 compared the use of trastuzumab sequentially or concurrently with chemotherapy in patients with early-stage HER2+ breast cancer. Patients treated with paclitaxel plus sequential trastuzumab weekly for 1 year had a 5-year disease-free survival (DFS) rate of 80.1%, whereas those who were treated with paclitaxel and concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks had a 5-year DFS rate of 84.4%. The P value for this comparison (.02) did not cross a prespecified O’Brien-Fleming boundary. In the ALTTO study,2 the incorporation of lapatinib in adjuvant treatment for patients with early-stage HER2+ breast cancer was evaluated. In this study, patients were randomized to 1 of 4 different treatment arms: trastuzumab, lapatinib, trastuzumab sequentially followed by lapatinib, or the combination of trastuzumab plus lapatinib. The lapatinib-only arm was closed early due to failure to demonstrate noninferiority compared with trastuzumab. In this study, adjuvant treatment options that incorporated lapatinib did not show a significant improvement in DFS compared with trastuzumab alone. Efforts have been made to improve upon outcomes afforded by the standard of chemotherapy and trastuzumab-based adjuvant therapy, with the addition of neratinib, a HER1, HER2, and HER4 tyrosine kinase inhibitor (TKI).3 With respect to neoadjuvant therapy, the use of pertuzumab in combination with trastuzumab and docetaxel has demonstrated efficacy in patients with locally advanced, inflammatory, or early-stage HER2+ breast cancer.
Advanced HER2-Positive Breast Cancer
Current European School of Oncology (ESO)–European Society for Medical Oncology (ESMO) International Consensus Guidelines for Advanced Breast Cancer recommend the utilization of the combination of chemotherapy plus trastuzumab plus pertuzumab as first-line therapy for patients with treatment-naïve, advanced HER2+ breast cancer, given that this combination has demonstrated outcomes superior to those of chemotherapy plus trastuzumab for these patients.4 The CLEOPATRA trial5 compared the use of first-line pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel for patients with HER2+ metastatic breast cancer (MBC). Patients in the group receiving pertuzumab had a median overall survival (OS) of 56.5 months, whereas those in the group that received placebo had a median OS of 40.8 months (HR, 0.68; 95% CI, 0.56-0.84; P <.001). In addition, median PFS was 6.3 months greater in the group treated with pertuzumab (HR, 0.68; 95% CI, 0.58-0.80; P <.0001), and the median duration of response was 7.7 months greater in the group treated with pertuzumab, according to independent assessment. The phase III MARIANNE study6 assessed trastuzumab emtansine (T-DM1) with/without pertuzumab versus the combination of trastuzumab plus a taxane for patients with advanced HER2+ breast cancer who had not received treatment for advanced breast cancer. In this study, patients who received pertuzumab plus T-DM1 had a median PFS of 15.2 months compared with 14.1 months in patients receiving T-DM1, and 13.7 months in patients receiving trastuzumab plus a taxane. T-DM1 was shown to have noninferior, but not superior, efficacy to the combination of a taxane and trastuzumab. The EMILIA study7 randomized patients with HER2+ advanced breast cancer who had previously been treated with trastuzumab and a taxane to receive either trastuzumab or the combination of capecitabine plus lapatinib. In this study, patients who received T-DM1 had a median progression-free survival (PFS) of 9.6 months compared with 6.4 months in patients receiving capecitabine and lapatinib (HR, 0.65; 95% CI, 0.65-0.77; P <.001). The median OS for patients receiving T-DM1 was 30.9 months at the time of the second interim analysis compared with 25.1 months for patients receiving capecitabine and lapatinib. The TH3RESA study8 further demonstrated the efficacy of T-DM1 in significantly improving survival relative to treatment of physician’s choice in patients with previously treated, advanced HER2+ breast cancer who had progressed on ≥2 HER2-directed treatment regimens.
In a trial conducted by Geyer and colleagues,9 patients with HER2+ MBC who had progressed following trastuzumab-based therapy were randomized to receive either the combination of lapatinib plus capecitabine or capecitabine alone. The median time to progression for patients receiving combination therapy was 8.4 months compared with 4.4 months in patients receiving monotherapy (HR, 0.49; 95% CI, 0.34-0.71; P <.001). Even with these advancements, numerous ongoing studies are still exploring new treatments to further improve outcomes for patients with HER2+ breast cancer, including antibody–drug conjugate (ADC) therapy and TKI therapy. Trastuzumab deruxtecan has received a US FDA designation as a breakthrough therapy for patients with HER2+, locally advanced breast cancer or MBC who have previously been treated with trastuzumab and pertuzumab, and who have had disease progression after T-DM1 therapy. It is an ADC that combines trastuzumab and a topoisomerase-I inhibitor; it was designed to have a high drug-to-antibody ratio.10 Trastuzumab deruxtecan has been evaluated in a phase I dose-escalation study, which included a cohort with HER2+ MBC previously treated with T-DM1 and a cohort with low HER2-expression MBC. The objective response rate was 54.5% for the 111 patients with HER2+ MBC and 50% for patients with HER2-low breast cancer.10 In the overall safety population, gastrointestinal and hematologic treatment-related adverse effects were among the most commonly reported.10
HER2+ Breast Cancer and Long-Term Responders
According to the most recent ESO-ESMO guidelines for advanced breast cancer, for patients with HER2+ MBC who achieve complete remission (CR), uncertainty still exists regarding the optimal duration of maintenance anti-HER2 therapy. Those patients who progress on anti-HER2 therapy in combination with a cytotoxic or endocrine therapy should be offered additional anti-HER2 therapy in later lines of treatment. Stopping HER2 therapy after several years of CR may be considered for some patients, as in scenarios where treatment rechallenge may be available.4 In patients with ER+/HER2+ MBC who derived benefit from first-line chemotherapy and anti-HER2 therapy, it may be appropriate to use endocrine therapy and anti-HER2 therapy for maintenance therapy after discontinuation of chemotherapy. ESO-ESMO guidelines recommend that for these patients, maintenance therapy should occur until progression, patient request, or unacceptable toxicity, and duration needs to be evaluated in clinical trials. In a new statement accompanying the 2018 guidelines, the advanced breast cancer community supported the use of biosimilars for breast cancer treatment, as well as supportive care.4
HER2+ Breast Cancer With Brain Metastases
For patients with HER2+ breast cancer, studies have estimated that the development of central nervous system (CNS) metastases occurs in one-third to more than half of cases.11 Patients with HER2+, hormone receptor–positive breast cancer have a median OS of 19 months from the time of brain metastasis diagnosis, and patients with HER2+, hormone receptor–negative breast cancer have a median OS of 13 months from the time of brain metastasis diagnosis.12 According to French-Speaking Association for Neuro-oncology (ANOCEF) recommendations, a wide range of treatment options should be considered, involving multidisciplinary discussion.13 Improved surgical and stereotactic radiotherapy approaches have the potential to improve outcomes for patients, as do advancements in pharmacologic therapy.
Results from the phase III CLEOPATRA study14 indicate that the utilization of pertuzumab, trastuzumab, and docetaxel could potentially have a role in delaying the emergence of CNS disease relative to the use of placebo, trastuzumab, and docetaxel for patients with HER2+ MBC. In this study, the median time to emergence of CNS metastasis was 15.0 months in patients treated with pertuzumab compared with 11.9 months in patients in the placebo arm (HR, 0.58; 95% CI, 0.39-0.85; P = .0049). Several other studies have assessed the influence of medical therapies on patients with HER2+ breast cancer with CNS metastases, including several that are ongoing. In a study of these patients who were treated with T-DM1, the median PFS was 6.1 months, with a 1-year PFS rate of 33% and a 2-year PFS rate of 17%.15 The therapeutic approach of tucatinib in combination with capecitabine and trastuzumab has also demonstrated clinical activity in patients with HER2+ breast cancer with CNS metastases and is being evaluated in a phase II study.16 Clinical evidence has suggested that eribulin may potentially be beneficial in patients with breast cancer who have CNS metastases.17
- Several advancements in the treatment of patients with early-stage HER2-positive (HER2+) breast cancer have been made over the course of the past decade.
- In addition, new classes of therapy are demonstrating efficacy in the treatment of patients with advanced HER2+ breast cancer.
- Some treatment options have shown promise in mitigating the impact of central nervous system metastases for patients with HER2+ breast cancer.
- Perez EA, Suman VJ, Davidson NE, et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011;29(34):4491-4497. doi: 10.1200/JCO.2011.36.7045.
- Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial [published correction appears in J Clin Oncol. 2019;37(4):356]. J Clin Oncol. 2016;34(10):1034-1042. doi: 10.1200/JCO.2015.62.1797.
- Chan A, Delaloge S, Holmes FA, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377. doi: 10.1016/S1470-2045(15)00551-3.
- Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC4). Ann Oncol. 2018;29(8):1634-1657. doi: 10.1093/annonc/mdy192.
- Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734. doi: 10.1056/NEJMoa1413513.
- Perez EA, Barrios C, Eiermann W, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017;35(2):141-148. doi: 10.1200/JCO.2016.67.4887.
- Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368(25):2442]. N Engl J Med. 2012;367(19):1783-1791. doi: 10.1056/NEJMoa1209124.
- Krop IE, Kim SB, Martin AG, et al. Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18(6):743-754. doi: 10.1016/S1470-2045(17)30313-3.
- Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2007;356(14):1487]. N Engl J Med. 2006;355(26):2733-2743. doi: 10.1056/NEJMoa064320.
- Iwata H, Tamura K, Doi T, et al. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing solid tumors: long-term results of a large phase 1 study with multiple expansion cohorts. J Clin Oncol. 2018;36(suppl 15; abstr 2501). doi: 10.1200/JCO.2018.36.15_suppl.2501.
- Olson EM, Najita JS, Sohl J, et al. Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 2013;22(4):525-531. doi: 10.1016/j.breast.2012.12.006.
- Jacot W, Louvel G, Darlix A, et al. Impact of breast cancer molecular subtypes on the occurrence, kinetics and prognosis of central nervous system metastases in a large multicenter cohort. Ann Oncol. 2018;29(suppl 8):viii90-viii121. doi: 10.1093/annonc/mdy272.
- Le Rhun É, Dhermain F, Noël G, et al; ANOCEF: l’Association des neuro-oncologues d’expression française. ANOCEF guidelines for the management of brain metastases [French]. Cancer Radiother. 2015;19(1):66-71. doi: 10.1016.j.canrad.2014.11.006.
- Swain SM, Baselga J, Miles D, et al. Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA. Ann Oncol. 2014;25(6):1116-1121. doi: 10.1093/annonc/mdu133.
- Jacot W, Pons E, Frenel JS, et al. Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. Breast Cancer Res Treat. 2016;157(2):307-318. doi: 10.1007/s10549-016-3828-6.
- Murthy R, Borges VF, Conlin A, et al. Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(7):880-888. doi: 10.1016/S1470-2045(18)30256-0.
- Fabi A, Moscetti L, Ciccarese M, et al. Eribulin in heavily pretreated metastatic breast cancer patients and clinical/biological feature correlations: impact on the practice. Future Oncol. 2015;11(3):431-438. doi: 10.2217/fon.14.271.
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Luminal Breast Cancer
Determining Relapse Risk in Early-Stage Luminal Breast Cancer
Proliferation genes drive the prognostic power of gene expression profile signatures. These are particularly useful in the case of patients with estrogen receptor–positive (ER+), HER2-negative breast cancer. Cutoff points for these assays remain challenging. A key question concerns the evaluation of the performance of different prognostic signatures. A recent analysis from a study of 774 postmenopausal women with HER2-negative breast cancer assessed multiple signatures.1 Three of the signatures, including EndoPredict, Breast Cancer Index, and the PAM50-based Prosigna Risk of Recurrence, provided the most prognostic information; of note, all studies provided significantly more information than the clinical treatment score.1 The TAILORx study2 recently provided additional guidance in assessing the benefit of chemotherapy in patients with hormone receptor–positive (HR+), HER2-negative, axillary node–negative breast cancer who had a midrange score on a 21-gene expression assay. In this study, the efficacy of chemoendocrine therapy and endocrine therapy were noted to be similar in women with HR+, HER2-negative breast cancer. However, some benefit with chemotherapy was found among some patients who were aged ≤50 years. The MINDACT study3 evaluated the clinical utility of a 70-gene signature test in women with early-stage breast cancer as an additional tool to standard criteria to determine selection of adjuvant chemotherapy. For the 1550 patients who were deemed to have a high clinical risk but a low genomic risk who were not treated with adjuvant chemotherapy, the 5-year rate of survival without distant metastasis was 94.7%. While gene expression profiling assays may be used to guide treatment decisions for patients with HR+, lymph node–negative breast cancer, evidence also suggests that the incorporation of molecular and histopathologic information can help to hone the application of these assays.4 Gene expression profiles may help to predict early recurrence; clinical/pathologic parameters should also be considered to help select cases where gene expression profiles may not need to be ordered automatically.4
Endocrine Therapy for Luminal Breast Cancer
Relapse-free survival outcomes have improved significantly in patients with breast cancer over the past few decades.5 Key studies that have demonstrated improvements in reducing the risk of recurrence for women with ER+ breast cancer include the ATLAS and aTTom studies. The ATLAS study6 randomized 6846 patients with early-stage ER+ breast cancer who had completed 5 years of tamoxifen to either receive an additional 5 years of tamoxifen or stop at 5 years. For patients who continued tamoxifen, significant reductions in risk of breast cancer recurrence and breast cancer mortality were observed. The aTTom study7 followed a similar design, randomizing 2755 patients with early-stage ER+ breast cancer who had received 5 years of tamoxifen to either continue tamoxifen for an additional 5 years or stop after 5 years of therapy. Again, benefits with respect to breast cancer recurrence and breast cancer mortality were seen.
Other studies have evaluated the role of extended aromatase inhibitor (AI) therapy for patients with breast cancer. With these data evaluating different AI agents of different durations, some degree of uncertainty still remains regarding the use of extended adjuvant endocrine therapy. Individual risk of recurrence after 5 years of adjuvant therapy needs to be determined, as well as how much risk of recurrence will be reduced with additional intervention. Studies evaluating clinical and tumor pathologic characteristics as a means of identifying those patients more likely to have recurrent disease are ongoing. Risk of distant recurrence has been shown to correlate with original tumor diameter and nodal status.8 Other factors associated with disease biology, such as tumor grade, have also been incorporated in the development of models that may help to evaluate the efficacy of extended endocrine therapy for individual patients.9
CDK4/6 Inhibition in Metastatic Luminal Breast Cancer
CDK4/6 inhibitors have shaped the treatment paradigm for patients with HR+ MBC. All 3 FDA-approved CDK4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) have demonstrated efficacy in combination with endocrine therapy in the treatment of HR+, HER2-negative breast cancer, with comparable improvements in progression-free survival (PFS) and overall response rate across multiple phase III studies. Investigation into overall survival (OS) benefit with CDK4/6 inhibitors has also been conducted. In the PALOMA-3 study,10 patients with HR+, HER2-negative breast cancer who experienced disease progression on prior endocrine therapy were randomized to receive palbociclib plus fulvestrant or placebo plus fulvestrant. While patients who received palbociclib plus fulvestrant had a median OS 6.9 months greater than patients receiving placebo plus fulvestrant (34.9 vs 28.0 months), this result was not statistically significant.10 The identification of biomarkers to help predict sensitivity to CDK4/6 inhibition remains an active area of clinical investigation. Advantages with the combination of endocrine therapy and CDK4/6 inhibition relative to endocrine therapy alone for these patients have been demonstrated across multiple different subgroups. A few promising biomarkers have been studied in the preclinical setting, but no validated biomarkers of sensitivity are currently established.11
Mutation-Directed Therapy in ER+ Breast Cancer
For patients with ER+ breast cancer who have developed resistance to endocrine therapy, PI3K pathway activation is common. PI3K inhibitors have demonstrated efficacy in the treatment of patients with PIK3CA-mutated breast cancer. In the BELLE-2 study,12 postmenopausal women with HR+, HER2-negative, advanced breast cancer or MBC who had progressive disease on or following AI therapy were randomized 1:1 to receive buparlisib plus fulvestrant or placebo plus fulvestrant. Among patients who had PIK3CA-mutated breast cancer, a median PFS of 6.8 months was observed in the buparlisib arm compared with 4.0 months in the placebo group. However, treatment toxicity was considerable with this combination. Taselisib has also demonstrated efficacy with respect to PFS in patients with ER+, HER2-negative, PIK3CA-mutated breast cancer. The SANDPIPER study13 randomized patients with these cancer characteristics 2:1 to receive taselisib plus fulvestrant or placebo plus fulvestrant. In this study, patients in the taselisib-plus-fulvestrant arm had a median investigator-assessed PFS of 7.4 months compared with 5.4 months in patients who received placebo plus fulvestrant. The addition of taselisib also increased the response rate and clinical benefit rate. However, treatment toxicities were again a concern.
The combination of alpelisib and fulvestrant has also been evaluated in patients with HR+, HER2-negative breast cancer in the phase III SOLAR-1 trial.14 In the PIK3CA-mutated cohort, median PFS was 11.0 months for patients receiving alpelisib plus fulvestrant compared with 5.7 months in patients receiving placebo plus fulvestrant (P = .00065). The overall response rate (ORR; complete response + partial response) was significantly greater for patients receiving alpelisib in the PIK3CA-mutated cohort. Among patients with measurable disease in this cohort, the ORR was 35.7% for patients receiving alpelisib plus fulvestrant and 16.2% in patients receiving placebo plus fulvestrant. For patients in the PIK3CA wild-type cohort, proof-of-concept criteria were not met, but these patients were followed as a part of the safety evaluation. Commonly reported adverse effects in patients receiving the combination of alpelisib plus fulvestrant were hyperglycemia, diarrhea, nausea, decreased appetite, and rash. ESR1 mutations are more prevalent when prior AI therapy is used to treat advanced cancer.15 These mutations are targetable with high doses of fulvestrant. In the SoFEA trial,15 ESR1 mutations were detected in 39.1% of patients with HR+ advanced breast cancer. These patients had a greater median PFS with fulvestrant-containing therapy than with exemestane (5.7 vs 2.6 months; hazard ratio, 0.52; P = .02).
- Recent studies have helped to provide insights into determining risk for cancer recurrence in patients with breast cancer.
- Approaches to endocrine therapy for patients are being honed, as is the implementation of newer agents such as CDK4/6 inhibitors.
- Multiple targetable mutations exist in patients with estrogen receptor–positive (ER+) breast cancer.
- Research analyzing genetic variations in patients with ER+ breast cancer is ongoing.
- Aromatase inhibitor–resistant cancer is genetically diverse, with the potential for numerous treatments on the horizon.
- Sestak I, Buus R, Cuzick J, et al. Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2018;4(4):545-553. doi: 10.1001/jamaoncol.2017.5524.
- Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi: 10.1056/NEJMoa1804710.
- Cardoso F, van’t Veer LJ, Bogaerts J, et al; MINDACT Investigators. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729. doi: 10.1056/NEJMoa1602253.
- Kim HS, Umbricht CB, Illei PB, et al. Optimizing the use of gene expression profiling in early-stage breast cancer. J Clin Oncol. 2016;34(36):4390-4397. doi: 10.1200/JCO.2016.67.7195.
- Cossetti RJ, Tyldesley SK, Speers CH, et al. Comparison of breast cancer recurrence and outcome patterns between patients treated from 1986 to 1992 and from 2004 to 2008. J Clin Oncol. 2015;33(1):65-73. doi: 10.1200/JCO.2014.57.2461.
- Davies C, Pan H, Godwin J, et al; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial [published correction appears in Lancet. 2013;381(9869):804]. Lancet. 2013;381(9869):805-816. doi: 10.1016/S0140-6736(12)61963-1.
- Gray RG, Rea D, Handley K, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL. Abstract 5.
- Pan H, Gray R, Braybrooke J, et al; EBCTCG. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846. doi: 10.1056/NEJMoa1701830.
- Dowsett M, Sestak I, Regan MM, et al. Integration of clinical variables for the prediction of late distant recurrence in patients with estrogen receptor-positive breast cancer treated with 5 years of endocrine therapy: CTS5. J Clin Oncol. 2018;36(19):1941-1948. doi: 10.1200/JCO.2017.76.4258.
- Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20):1926-1936. doi: 10.1056/NEJMoa1810527.
- Robert M, Frenel JS, Bourbouloux E, et al. An update on the clinical use of CDK4/6 inhibitors in breast cancer. Drugs. 2018;78(13):1353-1362. doi: 10.1007/s40265-018-0972-9.
- Baselga J, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2019;20(2):e71-e72]. Lancet Oncol. 2017;18(7):904-916. doi: 10.1016/S1470-2045(17)30376-5.
- Baselga J, Dent SF, Cortès J, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract LBA1006.
- Andre F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) plus fulvestrant (FUL) for HR+, HER2– advanced breast cancer: results of the phase III SOLAR-1 trial. Presented at: 2018 European Society for Medical Oncology Annual Congress; October 19-23, 2018; Munich, Germany. Abstract LBA3_PR.
- Fribbens C, O’Leary B, Kilburn L, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016;34(25):2961-2968. doi: 10.1200/JCO.2016.67.3061.
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