Triple-negative breast cancer is a particularly devastating subtype of breast cancer, as it is often diagnosed in young women and is associated with an exceptionally poor prognosis. The “triple-negative” designation indicates that the three key features driving most breast cancers (estrogen receptors, progesterone receptors, and/or HER2) are lacking, but it provides no clues as to potential biologic drivers. In the absence of any biologic insights, tailored, targeted treatment decisions have historically not been possible.
Consequently, until as recently as 2018, we have relied exclusively on nonselective cytotoxic agents, with modest success. For example, conventional neoadjuvant chemotherapy confers a pathologic complete response in just 50% to 55% of patients with early-stage triple-negative breast cancer,1-4 and among those who do not achieve a pathologic complete response, approximately one-third will die within 3 years.5 Moreover, patients with metastatic triple-negative breast cancer treated with conventional chemotherapeutics have a median survival of 12 to 18 months and an estimated 5-year overall survival of 11%.6 Thus, therapeutic innovation for early and late triple-negative breast cancer has been desperately needed.
Biologic Insight Leads to Therapies
One of the challenges and opportunities in the treatment of triple-negative breast cancer is biologic heterogeneity. Because “triple-negative” describes only the absence of key features, this designation ultimately captures diverse biologic subsets, as evidenced by the key molecular insights afforded by Perou and others.7 From biologic insight springs hope for therapeutic innovation. For example, approximately 30% of patients with triple-negative breast cancer harbor germline BRCA mutations. The BRCA genes encode proteins essential for homologous recombination DNA repair, and, thus, patients with germline BRCA pathogenic variants have DNA repair deficiencies. Therefore, drugs that target compensatory DNA repair pathways could induce synthetic lethality in cells with preexisting susceptibility.
“From biologic insight springs hope for therapeutic innovation.”— Heather L. McArthur, MD, MPH
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This insight led to the successful development of several PARP (poly [ADP ribose] polymerase) inhibitors including olaparib and talazoparib, both of which were approved by the U.S. Food and Drug Administration (FDA) in 2018 for patients with a deleterious or suspected deleterious germline BRCA mutation and advanced HER2-negative breast cancer previously treated with chemotherapy, after modest progression-free survival benefits were reported in pivotal randomized trials. Thus, for the first time, targeted treatment was available for advanced triple-negative breast cancer, and the arsenal was finally expanded beyond chemotherapy.
The impact of this innovation was further underscored by the results of the OlympiA study of adjuvant olaparib vs placebo in germline BRCA-mutation carriers with HER2-negative early breast cancer, presented as a plenary session at the 2021 ASCO Annual Meeting and concurrently published in The New England Journal of Medicine.8,9 Specifically, the OlympiA study investigators reported 3-year invasive disease–free survival rates of 85.9% and 77.1% for adjuvant olaparib vs placebo in all patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer and 3-year rates of 86.1% vs 76.9% in the triple-negative breast cancer subset. These results represented a landmark improvement in cure rates for these patients.8-10
Immune Modulation Via Checkpoint Blockade
Another recent innovation was the successful development of checkpoint blockade–mediated immune modulation. The first FDA approval for checkpoint blockade in breast cancer was in 2019 for the PD-L1–targeted drug atezolizumab in combination with nab-paclitaxel in the first-line setting for patients with PD-L1–positive advanced triple-negative breast cancer; it was based on an unprecedented 9.5-month improvement in overall survival.11 Specifically, overall survival in the PD-L1–positive subset was 25 months vs 15.5 months for the atezolizumab vs placebo arms in the interim analysis and 25.4 vs 17.9 months in the updated analysis.11,12
Then, in 2020, a PD-1–targeting monoclonal antibody, pembrolizumab, was approved by the FDA in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic PD-L1–positive triple-negative breast cancer.13 Moreover, it is anticipated that pembrolizumab will soon be approved by the FDA in the curative-intent setting regardless of PD-L1 status, based on a recent ESMO plenary presentation of the KEYNOTE-522 phase III study of neoadjuvant chemotherapy with or without pembrolizumab in patients with high-risk early-stage triple-negative breast cancer.14 Specifically, after a median follow-up of 39.1 months, the event free survival at 3 years was 84.5% vs 76.8% in favor of the experimental arm, representing an unprecedented improvement in cure rate for this high-risk population.”
Antibody-Drug Conjugates
Now antibody-drug conjugates, comprising high-affinity antibodies linked to highly potent payloads, offer the most recent reason to be optimistic about therapeutic innovation for triple-negative breast cancer. For example, sacituzumab govitecan-hziy is a humanized antibody against trophoblast cell surface antigen 2 (Trop-2) linked to the active metabolite of irinotecan (SN-38), a topoisomerase I inhibitor. The antibody moiety binds to Trop-2, which is expressed in approximately 85% to 90% of metastatic triple-negative breast cancers. After internalization and proteolytic cleavage, the release of SN-38 incurs DNA breaks, which inhibit DNA replication and trigger apoptosis.
In April 2020, sacituzumab govitecan received accelerated approval for patients with metastatic triple-negative breast cancer who had received at least two prior therapies for metastatic disease, based on a phase I/II single-arm study in which a 33% objective response rate was observed.15 On April 7, 2021, the FDA granted regular approval to sacituzumab govitecan based on the randomized phase III ASCENT study.
The trial, reported by Bardia et al in The New England Journal of Medicine and summarized in this issue of The ASCO Post, compared sacituzumab govitecan vs investigator’s choice of single-agent chemotherapy in a heavily pretreated metastatic triple-negative breast cancer population in which most patients had received two to three prior lines of chemotherapy (see summary for details).16 Median overall survival was 12.1 months vs 6.7 months in the primary analysis population of patients without brain metastases at baseline and 11.8 months vs 7.7 months in the total population. These findings represent a clinically meaningful and unprecedented improvement in survival in a heavily pretreated population and have secured sacituzumab govitecan as a new standard of care for pretreated metastatic triple-negative breast cancer. This is hopefully just the beginning of a trajectory of progress, as there are numerous other promising antibody-drug conjugates in development that target not only Trop-2, but also LIV-1, HER3, and even HER2 in a new subset of patients with triple-negative breast cancer with low HER2 expression.
Forecast Finally Changing in Triple-Negative Disease
It is remarkable to reflect on how far and how quickly the field has moved forward since the chemotherapy-alone option of 3 years ago. These collective efforts together underscore the importance of well-designed clinical trials and clinically meaningful study endpoints if we are truly going to innovate and move the field forward. In isolation, modest improvements in pathologic complete response and progression-free survival rates in the -curative-intent and metastatic settings, respectively, are generally no longer acceptable; patients and their providers seek improvements in cure rates and overall survival—particularly in young, poor-prognosis populations. It is exciting to note that with the successful clinical development of PARP inhibitors, checkpoint-mediated immune modulation, and antibody-drug conjugates over recent years, we have finally given patients with triple-negative breast cancer and their health-care providers real and meaningful hope that the forecast is finally changing.
Dr. McArthur is Clinical Director of Breast Cancer at UT Southwestern.
DISCLOSURE: Dr. McArthur has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Genomic Health, Immunomedics, Lilly, Merck, Pfizer, Puma Biotechnology, and Seattle Genetics; has received institutional research funding from Bristol Myers Squibb, Lilly, Merck, and Ziopharm Oncology; has been reimbursed for travel, accommodations, or other expenses by Amgen, AstraZeneca, Bristol Myers Squibb, Dava Pharmaceuticals, Genentech, Immunomedics, Lilly, Merck, Pfizer, Puma Biotechnology, and Spectrum Pharmaceuticals; and has held other relationships with Genomic Health and Lilly.
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