Systemic Breast Cancer Treatments on the Horizon  

Notes from the Canadian Breast Cancer Symposium

On June 18 2021, I got an awesome opportunity to attend the Canadian Breast Cancer Symposium (CBCS) as a patient guest. The CBCS is a unique meeting because it really focuses on the treatment of breast cancer in Canada. In my former life, I attended many scientific meetings including big meetings on the topics of pharmacology and neuroscience. Attending as a patient is completely different. Before, I was looking for information that could apply to my research and eventual thesis project experiments. Now I am looking for life-saving hope and tidbits about how my treatment may change in the future. I am also looking for research that applies to my specific cancer subtype. As other metastatic breast cancer (MBC) patients, the two most important statistics we are looking at with any potential treatment are the dreaded “overall survival” (OS) and “progression free survival” (PFS). Every time these are casually mentioned by a presenter, the reality of my prognosis is solidified — 3.15 years, 10.2 months, 3.41 years… etc.

As an MBC patient (and maybe a bit of an advocate for others), I was interested in any potential new systemic treatments that I haven’t heard about. Mostly for selfish reasons as I have to plan what my future lines of treatment could look like. I am triple positive (HER2+ and hormone positive). If you have breast cancer you quickly learn that there are various subtypes, and you are sorted into your “houses” at staging. During the symposium, the houses represented were triple negative, HER2+, and hormone positive. The reason they are sorted is mainly because different agents are used to treat the cancer. If you have cancer, you likely know which type you are right after your pathology report.

In the hormone-positive treatment space, Dr. Vietch presented some ongoing results from clinical trials, as well as a quick overview of the general disease landscape. Hormone-positive breast cancers make up the bulk of diagnoses: 72.7% of all stages of breast cancer are hormone positive and so are 61.2% of de novo MBC. For early-stage cancers, the SOFT/TEXT trial showed that there is a benefit to ovarian function suppression (OFS) to extend the disease-free period by a significant amount. If you get Zoladex shots, you know about OFS. The difference was most pronounced in patients that received prior chemotherapy in the early stages of their treatment. So, there is no avoiding chemotherapy just yet! The potential of using CDK4/6 inhibitors in early-stage BC was not as promising. Two trials (PALLAS, PENELOPE-B) did not show a benefit in adding palbociclib (Ibrance) as an additional treatment. The MONARCH-E trial did show a benefit to adding abemaciclib (Verzenio) as a neoadjuvant treatment in early-stage BC. This trial was most hopeful as it included stage 3 patients and showed a benefit in preventing recurrence in a large group of patients.

In the hormone-positive metastatic setting, there are several ongoing trials that are studying the benefits of CDK4/6 inhibitors as 1st line treatment (PALOMA-2, MONALEESA-2, MONARCH-3). All three are showing good PFS benefits. The questions to be answered seem to be on how to treat the disease at the first sign of progression (1st-line). Is chemotherapy a benefit or should it be skipped? The difference seems to lie in pre- vs post-menopausal populations. With the pre-menopausal women gaining the most benefit from immediate CDK4/6 inhibition with endocrine therapy over the use of chemotherapy (young-PEARL and PEARL). Dr. Vietch also covered some new research on targeted treatments for specific mutations (PIK3A, ESR1, gBRCA). Some new treatments in this space are alpelisib (Pikray), Elacestrant/Amcenestrant (newer versions of Fulvestrant) and olaparib (Lynparza). Lastly, FGFR1 was mentioned as the new potentially targetable mutation for treatment options for those keeping an eye on new molecular targets.

In HER2+ breast cancer, there has been a lot of activity in research of new targeted therapies. Simply blocking the receptor with Herceptin has done wonders in treating BC. For MBC patients, a clear path was described by Dr. Simmons. First line of treatment is Herceptin/Perjeta/+docetaxel (CLEOPATRA), second line is TDM-1 (Kadcyla) and the question remains as to what to try as a third line. I am currently in the first-line treatment, so knowing that there are several options for me, if the time of progression comes, is helpful. The agents being studied are tucatinib (Tukysa), margetuximab, and neratinib. So far, only the HER2CLIMB trial is showing significant results (improved OS) with tucatinib. Along with these agents, we also have trastuzumab deruxtecan (Enhertu), which seems to be the newest tangible hope for HER2+ MBC patients. Dr. Simmons also discussed the treatment of early stage and again with the possibility of skipping chemotherapy, (but for early-stage cancers this time). A potential diagnostic tool to help oncologists in making that decision is being studied, called HER2DX from Dr. Alexi Prat.

Dr. Simmons also described the bystander killing effect, which is a new term for me. Drugs designed to deliver a chemotherapy payload by initially attaching to HER2 can essentially kill neighbouring cancer cells, which may or may not have HER2 expression. My concern has always been, what happens to the cells that do not express HER2, as most tumors and cancers are very heterogeneous (meaning the cells are a mixed bag of types). Describing this “bystander killing effect” with some of the newer trastuzumab-combo agents (usually combined with chemo agents) makes a lot of sense as to why they are so effective in controlling MBC.

Lastly, the topic of systemic advances in triple-negative breast cancer (TNBC) were covered by Dr. Hilton from Ottawa. Dr. Hilton started off by explaining that the TNBC population is extremely heterogeneous, and that reproducibility of clinical trials is very difficult because the control arms often swing wildly in each clinical trial. Some control arms have almost double OS vs other trials. This makes it difficult to interpret results and means you need to carefully look at the control arms of trials. He then reviewed mixed findings from the use of immunotherapy in TNBC. IMpassion-130 and IMpassion-131 are trials looking at the benefits of atezolizumab (Tecentriq) for patients that express PD-L1, which had lukewarm results at best. Pembrolizumab (Keytruda) showed much better results overall (KEYNOTE-355 trial). The key takeaway with immunotherapy is that the advantage of treatment is to use it early. The OlympiA trial to study the benefits of Lynparza in BRCA-mutated cancers was discussed. The results showed an overall survival benefit and distant disease-free survival. Lastly, for patients with very advanced MBC, the ASCENT trial (sacituzumab govitecan, Trodelvy) showed promising results in extending PFS, especially in patients with brain metastases.

This being my first time attending this symposium as a patient, it was very good to see that a lot of new agents are on the horizon. How these apply in the clinic to each one of us patients remains to be seen. Are patients being screened for molecular markers (PD-L1)? Are those tests covered? Are these new drugs available and funded in Canada? Are any of these trials happening in Canada? As an MBC patient, I hope that I don’t have progression at all and that my treatments continue to work. I hope that for my MBC sisters, their medical oncologist helps them make the right decisions on treatments with the most up-to-date data available. As well, I hope for the Canadian patients specifically, these diagnostics and new agents become available and reimbursement is decided quickly. — Margaret Loniewska, MBC Advisory Board Member