Rebecca A. Shatsky, MD

Question

What is the difference between long-lasting remission and a “cure,” in your opinion?

Answer

In general, I really try to steer away from use of the word “cure” with my patients, because, unfortunately, especially with estrogen receptor-positive breast cancer, the truth is we just never know, and cases of breast cancer relapse and development of metastatic disease can happen up to 25 years after an initial breast cancer diagnosis. There are many different types of breast cancer and some are more prone to early relapse, like triple-negative breast cancer, so if a certain amount of time passes, we feel that patients are very low risk for relapse, so it is tempting to use the word cure in that situation. However, estrogen receptor-positive breast cancers can sometimes lay dormant for many, many years without forming obvious tumors or causing symptoms, so because of this phenomenon, I feel using the word cure as opposed to remission can give patients a false sense of security and lead them to feel betrayed by the medical system if an unfortunate relapse many years later does happen.

Question

What is the best strategy for communicating the nature of metastatic disease to patients?

Answer

I try to be as upfront and honest with my patients as possible as soon as we know the disease is metastatic. I use clear, easy to understand terminology and avoid medical jargon. I explain upfront that our entire approach to the disease will be switching, as I no longer consider their breast cancer to be curable and our goal is to control their disease, while maximizing quality of life. I find that it sometimes takes several conversations for patients to really understand what it means to have “stage IV” or “metastatic disease,” so we may not cover everything in just one conversation and that is definitely ok. It is important that they ultimately understand that they may need some form of therapy for breast cancer for the rest of their life, so that their expectations are appropriate and that we are on the same page. It’s also incredibly important if the patient is new to you to immediately identify who serves as their primary support network so that that person or group of people can be involved in their care and help them begin to start coping with what a life-changing diagnosis stage IV cancer can be. I am also lucky enough to have a breast cancer specific licensed clinical social worker directly in the office who works with our team, so often after I give bad news, she is able to help my patients “debrief,” and begin to process what we have just gone over. I also highly recommend early referrals to psychology and psychiatry (cancer-specific if available) to help patients deal with the emotional burden that having a terminal diagnosis presents.

Question

What is the current role of immunotherapy in metastatic breast cancer?

Answer

The role of immunotherapy in the traditional sense ― meaning immune checkpoint inhibitors ― in metastatic breast cancer is rapidly expanding. In October 2018 at the European Society of Medical Oncology (ESMO) Congress, we saw the first impressively positive phase 3 clinical trial results from the IMpassion130 trial (ClinicalTrials.gov Identifier: NCT02425891), which revealed that a combination of chemotherapy and immunotherapy lead to an improvement in both progression-free survival and overall survival in metastatic triple-negative breast cancer.1 The results were most pronounced in the PD-L1-positive cohort, but both groups saw benefit from therapy. This led directly to the recent U.S. Food and Drug Administration (FDA) approval of atezolizumab plus nab-paclitaxel for PD-L1 positive, metastatic, triple-negative breast cancer, which is the first FDA approval of an immune checkpoint inhibitor in breast cancer. Ultimately, I think we will soon be seeing a swift integration of immunotherapy into the standard of care treatment of triple-negative breast cancer, and, possibly PD-L1 positive, HER2-positive breast cancer. For hormone receptor-positive cancers, my excitement about the use of immunotherapy is more tempered; however, I think there will be definite situations where it is beneficial, possibly in the rare PD-L1-positive patient, MSI-high or tumor mutational burden-high disease. I think one of the most impressive studies that clearly supports the use of immunotherapy in all aggressive breast cancers is actually the neoadjuvant I-SPY 2 trial (ClinicalTrials.gov Identifier: NCT01042379) of pembrolizumab plus paclitaxel, which was reported at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting and revealed a benefit of immunotherapy in improving pathologic complete response rates in not only in triple-negative breast cancers, but also in hormone receptor-positive disease.²

Question

What are some of the most promising trials in metastatic breast cancer that are under way?

Answer

This is a complicated question because, as with everything in breast cancer, it depends very much on the disease subtype. For triple-negative breast cancer, I think the most exciting trials currently available are combination trials that include an immunotherapy, chemotherapy, and other investigational agents, whether that means a DNA damage repair agent like a PARP inhibitor or another possible immune-activating molecule. Our goal with the use of immunotherapy in breast cancer is to increase historically low overall response rates to immunotherapy, and so many of the more exciting trials are currently trying to do that with the combination of chemotherapy and potentially immune active agents like injectable vaccines, pegylated IL-2, PIK3CA pathway inhibitors, etc.

For HER2-positive disease, there are a whole host of antibody-drug conjugates that are currently in late-stage clinical trials and will likely be approved in the near future. I was also very happy to see a recent positive phase I trial of pembrolizumab in PD-L1-positive HER2-positive breast cancer.³

For hormone receptor-positive breast cancers, I am personally excited about the investigation of a new CDK2/4/6 inhibitor that may be able to restore sensitivity of hormone receptor-positive breast cancers to CDK inhibition. I am also interested in the combination of hormonal therapy with newer investigational agents that have already been shown to be very biologically active such as the BCL2 inhibitor venetoclax (ClinicalTrials.gov Identifier: NCT03584009) or the AKT inhibitor ipatasertib (ClinicalTrials.gov Identifier: NCT02162719).

Finally, the antibody-drug conjugate sacituzumab govitecan has been proven to be very active in both heavily pretreated triple-negative and aggressive hormone receptor-positive (luminal B) breast cancer and is currently in phase 3 trials for both diseases.⁴ I am hoping this drug will get FDA approval sometime in 2019 or early 2020.

Question

Should all breast cancer patients really get genetic testing, in your opinion?

Answer

I personally offer next-generation sequencing with matched germline genetic testing to all of my patients with metastatic breast cancer because I believe the technology offers important treatment information that can affect clinical care in real time. For example, if a patient has a germline genetic mutation in a BRCA family DNA damage repair gene, they can now receive a PARP inhibitor, which their oncologist would not know if they did not offer testing. In addition, I think next-generation sequencing, whether it is using tumor tissue or ctDNA or both, adds essential information to treatment, as it can inform me in real time about the development of endocrine resistance (ESR1 mutations) or let me know a patient is eligible for a clinical trial or may respond to treatment with a specific targeted therapy, such as a PIK3CA inhibitor.