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Clinical Insights in Metastatic Breast Cancer
What is the difference between long-lasting remission and a “cur,” in your opinion?
Remission isn’t a term that I typically use when discussing breast cancer. I talk to patients about cure as we embark on neoadjuvant or adjuvant systemic therapy planning and underscore the fact that we are doing everything that we can with curative intent. But, the probability of cure depends on the subtype of breast cancer. Triple-negative breast cancer (TNBC) typically has a very high recurrence rate between year 2 and year 3, such that after 4 to 5 years, patients typically are cured of their disease if they haven’t had a recurrence. So, that would be a subset of patients for whom I would be more comfortable in using the word “cure” after 5 years. However, for the human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor (HR)–positive subsets, recurrence risk persists beyond 5 to 10 years and so, even though risk is reduced over time, I still adhere to continued vigilance.
What is the best strategy for communicating the nature of metastatic disease to patients?
Most of my conversations about metastatic disease focus on education. I spend a lot of time explaining the natural history of metastatic disease to patients who are newly diagnosed. I highlight the fact that it is a chronic disease that typically requires a lifetime of attention and management. I think it’s important to explain upfront that any treatment has a limited durability. So, I try to impart early on that multiple systemic therapies will be required and that it’s not a failure when we have to move on to the next treatment, but rather it is an indication that the cancer has mutated and changed over time and requires a different line of attack. Thus, the first meeting with a newly diagnosed patient focuses on education about the natural history of the disease and establishing expectations for management over time.
What is the current role of immunotherapy in metastatic breast cancer?
It is a really exciting new era for us in the treatment of breast cancer with the recent U.S. Food and Drug Administration (FDA) approval of the programmed death-ligand 1 (PD-L1)-directed antibody atezolizumab in combination with chemotherapy for first-line metastatic TNBC. The FDA approval was based on the IMpassion130 data (ClinicalTrials.gov Identifier: NCT02425891), wherein an overall survival benefit of 9.5 months was demonstrated with the addition of atezolizumab to chemotherapy, in this case nab-paclitaxel, in the first-line setting in a subset of metastatic TNBC patients. In this study, about 40% of patients had tumors that were positive for the biomarker PD-L1 and it was the PD-L1–positive subset who derived that notable survival benefit. Although this was an informal survival analysis, it represents a particularly remarkable finding given that we had not previously seen a clinically meaningful improvement in survival for metastatic TNBC with prior strategies. So, this really is the hallmark of a promising new era. It is incredibly encouraging to see durable responses that translate into survival benefit for some patients.
We have some data in HER2-positive and HR-positive breast cancers as well, but really the most robust data we have to date is in the TNBC setting. There are huge numbers of studies underway because we need to make immunotherapy relevant for the majority population and not a minority population. So, it is a very exciting time whereby rational combinations with chemotherapy, biologic agents, targeted therapies and local modalities such as radiation are currently underway.
What are some of the most promising trials in metastatic breast cancer that are under way?
There are so many promising strategies under development, it’s an exciting time, particularly for HER2-positive and triple-negative disease. One of the most active areas of research right now is probably the immune therapy landscape. Immune therapy strategies in combination with numerous partners, including other biologic agents and local strategies like radiation are currently being explored across breast cancer subtypes. For example, preliminary data from a study investigating a novel agent called NKTR-214 in combination with the anti–PD-1 antibody nivolumab is interesting is because it seems to convert PD-L1–negative tumors into PD-L1–positive tumors and may consequently render immune therapy relevant to patients whose tumors are not naturally sensitive.
We are also seeing considerable innovation in targeted therapies. The AKT inhibitors, for example, exploit a key signaling pathway for tumors. We saw 2 studies presented at the 2018 American Society of Clinical Oncology Annual Meeting describing AKT inhibition in combination with chemotherapy in metastatic TNBC with incredibly promising results.1,2 In addition, there are a number of antibody-drug conjugates in development that are exciting, including a drug called sacituzumab govitecan, that demonstrated encouraging results in chemotherapy resistant metastatic TNBC.3
Antibody-drug conjugates for the treatment of HER2-positive disease are also incredibly promising. For example, trastuzumab deruxtecan has a unique payload, a topoisomerase inhibitor, and demonstrated durable responses in a phase 1 study that included pre-treated metastatic HER2-positive and HER2-“low” cohorts.4 In addition, the drug ZW25 is a bispecific antibody that can simultaneously bind two HER2 epitopes and has generated promising responses in an early phase study of heavily pretreated patients with metastatic HER2-positive disease.5 There’s another drug called margetuximab, which is another anti-HER2 directed antibody that has the same target as trastuzumab, but which seems to activate immune effectors and is therefore an optimized drug for inducing antibody-dependent cell kill.6
Tyrosine kinase inhibitors for HER2-positive disease are also exciting, including tucatinib, which is particularly relevant potentially because it seems to cross the blood-brain barrier and may provide a new therapeutic strategy for patients with brain metastases or who are at risk of developing brain metastasis—which to date has represented an unmet need.7
For HR-positive disease, CDK4/6 inhibitors administered alone or in combination with hormone therapy have conferred consistent benefits across clinical trials and have ultimately become an integral component of the management of that subtype of breast cancer.
So there a lot of exciting strategies in development and there is incredible overlap with immunotherapies. If you think about trastuzumab, for example, it is a HER2-directed antibody, but it was probably the first immune therapy that we used but we didn’t realize it. It induces antibody-dependent cell kill as one of its mechanisms of action and that might be why it is so synergistic with these modern immune checkpoint blockage strategies. It’s an exciting time because rational biologic combinations are incredibly promising across all subtypes of breast cancer.
Should all breast cancer patients really get genetic testing, in your opinion?
I think that patients who meet guidelines for testing — strong family history, history of breast or ovarian cancer in self or in family members, male breast cancer, breast cancer at a young age, all of the usual indications — should get genetic testing. Notably, however, a study reported in late 2018, indicated that about 8% of patients with breast cancer who did not meet NCCN guidelines for testing actually had a deleterious mutation.8 So, there has been discussion in the academic community and in the broader community about whether we need to revisit guidelines for testing.
I typically still adhere to the guidelines for testing of patients undergoing treatment with curative intent, but I generally consider testing for patients with metastatic breast cancer because of the indication for PARP inhibitors, which conferred a 3-month improvement in progression-free survival in patients with a deleterious mutation. I’m really pragmatic — if there is an action that I’m going to take in response to testing, or if it’s a question of getting access to a promising drug on a clinical trial, then I consider testing. But, typically, I still adhere to the national guidelines for testing recommendations outside of those indications.
1. Dent R, Im S-A, Espie M, et al. Overall survival (OS) update of the double-blind placebo (PBO)-controlled randomized phase 2 LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for locally advanced/metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2018;36:(suppl; abstr 1008).
2. 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. J Clin Oncol. 2018;36:(suppl; abstr 1007).
3. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741-751. doi: 10.1056/NEJMoa1814213
4. 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; abstr 2501).
5. Meric-Bernstam F, Beeram M, Ignacio Mayordomo J, et al. Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers. J Clin Oncol. 2018;36:(suppl; abstr 2500).
6. Bang YJ, Giaccone G, Im SA, et al. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol. 2017;28:855-861. doi: 10.1093/annonc/mdx002
7. 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
8. Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2018;37:1-8.