Release Date: May 31, 2018
Expiration Date: May 31, 2019
Media: Internet - based
Bridging Bench to Bedside: The Potential for Immunotherapeutic Strategies in Breast Cancer was a satellite symposium held adjunct to the 35th Miami Breast Cancer Conference®, a PER® Legacy International Conference. Traditionally, breast cancer has not been seen as an immune-sensitive disease. Over the past 20 years, translational research has taught us that breast cancer includes large numbers of different molecular entities, and that some of them are clearly “immune-related” subtypes. Listen to key experts discuss how an understanding of the basic immunology of breast cancer, neoantigens, and breast cancer’s various subtypes provide a foundation for evaluating the emerging data for patients with hormone receptor‒positive (HR+)/HER2-, HER2+, and triple-negative breast cancer. Enhance your clinicals skills by understanding the rationale for use of immunotherapies in the management of these most difficult-to-treat tumors, and assess how emerging efficacy and safety data should be placed into the context of evolving treatment paradigms for your patients.
Acknowledgment of Commercial Support
This activity is supported by an educational grant from Merck Sharp & Dohme Corp.
Instructions for This Activity and Receiving Credit
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This educational activity is directed toward medical oncologists who treat patients with breast cancer. Nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of breast cancer are also invited to participate
At the conclusion of this activity, you should be better prepared to:
Evaluate the latest data regarding mechanisms of immunotherapeutic strategies as they apply to breast malignancies and emerging biomarkers guiding the optimal selection of patients
Review efficacy and safety data for immunotherapeutic approaches across multiple breast malignancies and patient types
Describe key clinical issues regarding the application of immune checkpoint inhibitors and summarize ongoing associated trials
Determine the occurrence of and methods to mitigate the impact of immune-related adverse events based on recent clinical trial evidence
Faculty, Staff, and Planners' Disclosures
Hope S. Rugo, MD, FASCO
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center
San Francisco, CA
Disclosure: Grant Research Support: Genentech, Mylan, Puma
Leisha A. Emens, MD, PhD
Associate Professor of Oncology
Johns Hopkins University School of Medicine
Disclosure: Grant Research Support: Aduro Biotech, AstraZeneca, Corvus, EMD Serono, Genentech, HeritX, Inc., Roche; Consultant: AbbVie, Amgen, AstraZeneca, Bayer, Celgene, eTHeRNA, Gritstone, Medimmune, Molecuvax, Peregrine, Syndax, Vaccinex
Rita Nanda, MD
Assistant Professor of Medicine
Associate Director, Breast Medical Oncology
University of Chicago
Disclosure: Grant Research Support: Celgene, Corcept Therapeutics, Merck; Consultant: AstraZeneca, Celgene, Genentech, Merck, Puma, Syndax; Other: G1 Therapeutics (DSMB)
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This CME/CE 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/CE 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 Recap™
PER Pulse Recap (1 of 3)
This first of 3 PER Pulse™ Recaps will focus on breast cancer immunobiology and the implications for immunotherapy, including clinical and intrinsic subtypes, immune profiles, effects of drugs on the tumor and immune system, and matching patients to the most appropriate combinations. Below are some highlights from the symposium featuring Dr. Leisha Emens:
“I think there is a lot of excitement about the potential of immunotherapy in breast cancer because of the astounding success of immunotherapy in other solid tumors, particularly lung cancer. Similar to breast cancer, lung cancer for a long time was originally thought to be a non-immunogenic tumor, and it turned out to be one of the big three, which have had nice durable responses to checkpoint blockade.”
-- Leisha Emens, MD, PhD
Traditionally, breast cancer has not been regarded as an immune-sensitive disease. Over the past 20 years, translational research has taught us that breast cancer includes large numbers of different molecular entities, and that some of them are clearly “immune-related” subtypes.
As shown in the Figure
, poor prognostic factors (estrogen receptor [ER]‒negative, progesterone receptor [PR]‒negative, high-grade, lymph node‒positive [LN+]) are associated with higher T-cell infiltrates at diagnosis.1
The recognition that breast tumors are infiltrated by a complex array of immune cells that influence their development, progression, and metastasis, as well as their responsiveness to systemic therapies, has driven the rapid development and evolution of breast cancer immunotherapies.2
The clinical phenotype and immunologic phenotype for breast cancer subtypes luminal A, luminal B, HER2-enriched, and basal-like are shown in the Table
. The successful implementation of immunotherapy to breast cancer management requires the optimization of current immunotherapeutic regimens, and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans.
The future is in combination immunotherapies that should have synergistic clinical activity, which may come at a toxicity cost. Further trials are needed to elucidate immunologic mechanisms of response and resistance in patients.
Gajewski TF. The next hurdle in cancer immunotherapy: Overcoming the non-T-cell-inflamed tumor microenvironment. Semin Oncol. 2015;42:663-671.
Nakasones, ES, Hurvitz SA, McCann KE. Harnessing the immune system in the battle against breast cancer. Drugs Context. 2018;7:212520.
Kroemer G, Senovilla L, Galluzzi L, et al. Natural and therapy-induced immunosurveillance in breast cancer. Nature Med. 2015;21:1128-1138.
PER Pulse Recap (2 of 3)
This second of 3 PER Pulse™ Recaps will focus on immunologic prognostic factors, clinical data, and rationale for immunotherapy combinations for metastatic breast cancer (MBC). Below are some highlights from the symposium featuring Dr. Rugo:
“It appears that there are enough data to suggest that checkpoint inhibitor monotherapy is not the way forward for optimizing outcomes in patients with breast cancer.
Trials that have used checkpoint inhibitor monotherapy reported undistinguished ORRs. Trials that paired immunotherapy with chemotherapy, on the other hand, showed promise, hinting that immunotherapies combined with some targeted agents might also work better than immunotherapy alone.”
-- Hope Rugo, MD, FASCO
Translational research has taught us that breast cancer includes large numbers of different molecular entities, and some of them are clearly “immune-related” subtypes. First, a subgroup of patients with TNBC presents important lymphocytic infiltration, and this is associated with good outcome for those who receive chemotherapy. Second, HER2-overexpressing breast cancers present a similar pattern, and whether this could define a specific sensitivity to trastuzumab is still a matter for debate. Finally, some patients with HR+ disease present with lymphocytic infiltration, but greater effort is needed to better understand its clinical implications. Interestingly, a subgroup (10%) of patients with HR+ MBC presents with a high mutational load, a characteristic that has been associated with sensitivity to anti‒PD-1 and anti‒CTLA-4.
Initial studies shown in the Table
depicting overall response rates by PD-L1 status used different antibodies and cutoffs for determining PD-L1 positivity. Inflamed tumors are most likely to respond to PD-1/PD-L1 blockade.1-3
It is possible that in immunotherapy and chemotherapy combination trials to date, some patients have responded to chemotherapy alone rather than the combination, but emerging evidence suggests that chemotherapy makes checkpoint blockade more effective. Large doses of strong chemotherapies—particularly when administered with steroids—can severely weaken immune systems, but recent research has shown that many chemotherapies have the opposite effect. Indeed, many common chemotherapies increase immune response against cancer by altering dying tumor cells in ways that make them visible to the immune system, reducing the ability of tumors to suppress the immune system and stimulating T cells and other effector cells both directly and indirectly. Moreover, all 3 of these effects would appear likely to increase the effectiveness of checkpoint blockades and other immunotherapies.
Numerous trials in women with MBC are ongoing in the first-line setting for combinations including, for example: atezolizumab + nab
-paclitaxel; pembrolizumab + gemcitabine or carboplatin versus paclitaxel/nab
-paclitaxel; and atezolizumab + paclitaxel/gemcitabine + carboplatin. Combination trials are also currently ongoing in the neoadjuvant and adjuvant settings, as well as additional combinations with: alternate chemotherapy; PARP inhibitors; targeted agents (eg, MEK); CDK 4/6 inhibitors; HDAC inhibitors in woman with ER+ disease; radiation; and in HER2+ disease.
Ribas A, Tumor immunotherapy directed at PD-1. N Engl J. Med. 2012;366:2517-2519.
Cimino-Mathews A, Thompson E, Taube JM, et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum Pathol. 2016;47:52-63.
Thompson ED, Taube JM, Asch-Kendrick RJ, et al. PD-L1 expression and the immune microenvironment in primary invasive lobular carcinomas of the breast. Mod Pathol. 2017;30;1151-1560.
PER Pulse Recap (3 of 3)
This third of 3 PER Pulse™ Recaps will focus on neoadjuvant clinical data, biomarkers for response, ongoing trials/approaches, and the safety implications of checkpoint inhibitors.
Below are some highlights from the symposium featuring Dr. Rita Nanda:
“We are all very excited by the I-SPY 2 clinical trial data, which has shown that pembrolizumab when added to standard neoadjuvant chemotherapy can increase the pCR rates in patients with aggressive forms of breast cancer, both TNBC and HR+ high-risk disease. However, this advantage does not come without a cost. There were certainly some toxicities that were seen, notably adrenal insufficiency.”
-- Rita Nanda, MD
Data presented at the ASCO 2017 Annual Meeting included findings in patients with locally advanced TNBC and HR+/HER2-negative breast cancers. The results from the phase II I-SPY 2 trial1
investigating pembrolizumab, anti‒PD-1 therapy, in combination with standard therapy (paclitaxel followed by doxorubicin + cyclophosphamide [AC]) as a neoadjuvant treatment for patients with locally advanced TNBC or HR+/HER2-negative breast cancer, showed an increase in the estimated pathologic complete response rate nearly 3-fold in patients with TNBC (60% vs 20%) and in patients with HR+/HER2-negative breast cancer (34% vs 13%) compared with standard therapy.1
Preliminary results from KEYNOTE-1733
presented at ASCO 2017 suggest that pembrolizumab plus chemotherapy as neoadjuvant therapy for TNBC results in manageable toxicity and promising antitumor activity.
is an ongoing phase III study of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab versus neoadjuvant placebo plus chemotherapy followed by adjuvant placebo in approximately 855 patients with TNBC stratified by tumor nodal status, size, and carboplatin choice (Q3W vs QW). IMpassion031,5
a global phase III, double-blind, randomized, multicenter, placebo-controlled ongoing study, is being conducted to evaluate the efficacy and safety of neoadjuvant treatment with nab
-paclitaxel → doxorubicin plus cyclophosphamide and either atezolizumab or placebo in invasive, stage II/III, early TNBC.
Immune checkpoint inhibitors (Table
) have gained approval in a multitude of solid tumors, as well as for some hematologic malignancies.
The wide range of immune-related adverse events (irAEs) associated with immune checkpoint blockade can $ this effective therapy and limit its use in patients with cancer (Figure
). The majority of irAEs are mild-to-moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by immune checkpoint inhibitor.
Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. J Clin Oncol. 2017;35(suppl; abstr 506).
Yau C, Wolf D, Brown-Swigart L, et al. Analysis of DNA repair deficiency biomarkers as predictors of response to the PD-1 inhibitor pembrolizumab: results from the neoadjuvant I-SPY 2 trial for stage II-III high-risk breast cancer. Presented at the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD6-14.
Schmid P, Park YH, Muñoz-Couselo E, et al. Pembrolizumab plus chemotherapy as neoadjuvant treatment for triple negative breast cancer: preliminary results from KEYNOTE-173. J Clin Oncol. 2017;35(15_suppl; abstr 556).
KEYNOTE-522: Phase III study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant followed by pembro vs placebo as adjuvant therapy for triple-negative breast cancer. Ann Oncol. 2017;28(suppl_5).
Mittendorf EA, Barrios CH, Harbeck N, et al. IMpassion130: a phase III randomized trial of atezolizumab with nab-paclitaxel for first-line treatment of patients with metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2017;28(suppl_5):v43-v67. 10.1093/annonc/mdx362.
For additional commentary about these topics and others, visit www.gotoper.com
to access more resources from the archived Community Practice Connections™: 35th Annual Miami Breast Cancer Conference: Bridging Bench to Bedside: The Potential for Immunotherapeutic Strategies in Breast Cancer.