It’s clear that the historical boundaries of what was possible in the management of patients with breast cancer continue to be challenged, evidenced by the use of HER2-directed therapies in patients with brain metastases, de-escalated approaches in patients with visceral disease, and less-invasive surgical techniques for patients with lymph node involvement, according to faculty from an OncLive® Institutional Perspectives in Cancer webinar on Precision Medicine in Breast Cancer.
The event, chaired by Vandana G. Abramson, MD, the Donna S. Hall Chair in Breast Cancer, and professor of medicine in the Division of Hematology/Oncology at Vanderbilt University Medical Center, focused on current applications for targeted therapy in metastatic hormone receptor (HR)–positive, and HER2-positive breast cancer, new surgical and radiation techniques in early-stage disease, and the expansion of next-generation sequencing (NGS) throughout the paradigm.
Abramson was joined by her colleagues:
- Sonya Reid, MD, MPH, assistant professor ofmedicine, Division of Hematology/Oncology, Vanderbilt University Medical Center
- Kelly Hewitt, MD, assistant professor ofsurgery, Division of Surgical Oncology, Vanderbilt University Medical Center
- Laura Kennedy, MD, PhD, assistant professor ofmedicine,Vanderbilt University Medical Center
Below, Abramson, Reid, Hewitt, and Kennedy summarize the main messages from their presentations.
Targeted Therapy in HR+ Breast Cancer
Reid: To put it all together, my big take home is that we should be sending NGS, whether that is from the tissue or blood depending on the scenario. If a [tissue] biopsy is not feasible, liquid biopsy is an option for your patient. We need to be sending [NGS] on all patients with metastatic breast cancer because we know there is a survival advantage, for example, with PARP inhibitors in patients with a germline BRCA mutation.
In the first-line [metastatic] setting, it’s hard to argue against the addition of a CDK4/6 inhibitor to endocrine therapy given the overall survival advantage. I do want to mention, however, that in some special circumstances, for example, a patient who has de novo metastatic breast cancer and a low volume of disease, that is a patient for whom you could start with endocrine therapy and hold the CDK4/6 inhibitor, for example, until the second-line setting. For a patient who has visceral crisis, I know some folks may think, “Maybe I need to start with chemotherapy.” However, we have seen from recent studies that CDK4/6 inhibitors have proven to be effective even in patients with visceral disease.
In the second-line [metastatic setting,] if the patient has a PIK3CA mutation, alpelisib [Piqray] plus fulvestrant [Faslodex] would be the more commonly utilized option. If you don’t have a PIK3CA mutation, an mTOR inhibitor plus endocrine therapy, the one that you did not use in the first-line setting, is usually the most commonly utilized option.
In the third-line setting, for patients who have a germline BRCA mutation, a PARP inhibitor is usually the agent of choice in that setting where olaparib [Lynparza] or talazoparib [Talzenna] are both reasonable options.
Updates in Metastatic HER2+ Breast Cancer
Abramson: Today, in terms of [our] approach to therapy for metastatic HER2-positive breast cancer, the taxanes plus trastuzumab [Herceptin] and pertuzumab [Perjeta] remain [the] first-line [standard]. In the second-line setting, in patients with active CNS [central nervous system] disease, probably given the impressive data with tucatinib [Tukysa], that would be my second-line choice or first-line [choice] for active CNS disease.
Fam-trastuzumab deruxtecan-nxki [Enhertu] also, with the impressive data, is the standard for second-line therapy at this point. After that, the third-line setting becomes a little bit murkier, with T-DM1 [ado-trastuzumab emtansine (Kadcyla)], tucatinib/trastuzumab/capecitabine [Xeloda], and trastuzumab deruxtecan are all sort of interchangeable depending on the patient population. Finally, later we get into margetuximab-cmkb [Margenza], neratinib [Nerlynx], and other therapies as well.
Surgery in Early-Stage Breast Cancer: Less Is More
Hewitt: Regarding the management of the axilla, historically, this was through an axillary lymph node dissection, where on average 10 to 20 lymph nodes were removed with the consequent, downstage reactions, meaning people would have lymphedema and issues there. Over time, we have looked at how we can minimize our surgery in the axilla, first with just sentinel lymph node biopsy and now looking at in which situations we can do nothing in the axilla. Based on Choosing Wisely guidelines, women who are 70 years of age or older with early-stage, HR-positive breast cancer, we don’t even do sentinel lymph node biopsy. We’re also looking at some of these newer studies that are looking to expand that population in whom we just leave the axilla alone and merely proceed with removing the cancer from the breast.
In terms of breast conservation vs mastectomy, a big deciding factor is tumor size in relation to breast size. There comes a point where someone just isn’t a candidate for breast conservation. We have really pushed those boundaries with oncoplastic techniques, being able to do large oncoplastic reductions, also in [collaboration] with our plastic surgery partners, but there always does come a point where you say, “This just isn’t feasible.” It always used to be if someone has a multifocal or multicentric cancer, we need to think about mastectomy. People are thinking outside the box in some of those situations. If someone maybe can have a two-site lumpectomy then that can be a possibility to offer. The other things to think about are if someone has some genetic mutation that puts them at an increased risk for cancer in the future, then you have a very informed discussion with the patient about what really is the best way to reduce their risk and take care of this cancer moving forward. The situations in which a patient is a candidate for breast conservation has grown over time.
We know from 20-plus years of data that lumpectomy should be followed by radiation to have acceptable local recurrence rates. We should be thinking about radiation in all these patients who are undergoing breast conservation and then in certain patients who require postmastectomy radiation. What I think is interesting is that we’re looking at how we can make all of this just as good but easier for patients. How can we shorten the course of radiation? How can we improve their cosmetic outcome? That’s what a lot of these newer studies have looked at.
Finally, when it comes to ductal carcinoma in situ [DCIS], we know it’s not all going to go on to cancer. The really the hard part is figuring out who are these patients that are low risk and that can maybe be managed with observation vs those that require surgery. A lot of ongoing studies are looking at this question. To treat something that is not invasive the same way that we treat invasive disease takes us taking a step back and looking at this critically.
One area that I touched on was management in the lymph nodes in this. A patient with DCIS would traditionally have a mastectomy, and then we would also do a sentinel lymph node biopsy if we found invasive cancer in the final specimen. Even removing one lymph node can have effects. When we use the super paramagnetic iron oxide dye and inject it at the time of surgery, it stays there. A relatively large study that looked at this had patients who they did their surgery up to 46 days later, the dye was still there, and they were able to identify a sentinel lymph node. Avoiding a sentinel lymph node biopsy in 75% to 80% of those patients is a really big thing, as is understanding in whom we may not need to do surgery at all.
Biomarker Testing: Lighting the Way
Kennedy: We will continue to work towards developing better biomarkers that will help us individualize treatment for an individual patient who is in front of us rather than a population of patients. NGS is a cost-effective strategy to evaluate for potential therapeutic targets, and every patient with metastatic breast cancer should certainly have NGS at least once if not multiple times over the course of their therapy to help guide their treatment.
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