Breast Cancer Advances in 2022 Shape CFS Agenda

Joseph A. Sparano, MD

Data presented during the 2022 American Society of Clinical Oncology Annual Meeting in June and simultaneously published in the New England Journal of Medicine from the phase 3 DESTINY-Breast04 trial (NCT03734029) reshaped the treatment landscape for patients with metastatic HER2-low disease seemingly overnight.¹ Updated National Comprehensive Cancer Center guidelines, and FDA approval for fam-trastuzumab deruxtecan-nxki (Enhertu), and discussions surrounding immunohistochemistry results, dominated the conversations in the months after the presentation.^2,3

Emerging novel therapies, new stratification factors, and sequencing challenges because of the new classifications for patients with breast cancer will be topics of discussion at the 40th Annual Chemotherapy Foundation Symposium^® (CFS^®) during the breast cancer sessions, beginning today at 1:10 pm.

“This year the story at least thus far has been on the role of antibody-drug conjugates [ADCs] in the treatment of HER2-low metastatic breast cancer where this therapeutic strategy has been shown to prolong progression-free survival [PFS] and overall survival [OS],” Joseph A. Sparano, MD, said.

In an interview with OncLive^®, Sparano, chief of the Division of Hematology and Medical Oncology and deputy director of the Tisch Cancer Institute at Mount Sinai, in New York, New York, highlighted practice changing clinical trials, novel therapies, the evolving treatment landscape, and unmet needs in the field of breast cancer.

What are some of the breast cancer specific topics that you anticipate will be top of mind for faculty and attendees of CFS® to debate and discuss?

Based on some of the major data we have seen this year, there is a lot of interest in the use of ADCs particularly trastuzumab deruxtecan in HER2-low, estrogen receptor [ER]-positive breast cancer and triple-negative breast cancer [TNBC] as well sacituzumab govitecan-hziy [Trodelvy]. The use of PARP inhibitors in the adjuvant setting for patients who have early-stage breast cancer associated with germline BRCA1/2 mutations is an important new development in the last year that has had a big effect.

[Additionally], we now have consistent evidence that the use of CDK4/6 inhibitors in metastatic breast cancer, particularly ribociclib [Kisqali],can not only improve PFS but now OS [overall survival]. There may now be some differences that seem to be emerging for the use of CDK4/6 inhibitors in the metastatic setting that will influence clinical practice.

We also have first data from the [phase 3] monarchE trial [NCT03155997] demonstrating the role of abemaciclib [Verzenio] in high-risk adjuvant setting for patients with ER-positive, HER2-negative breast cancer. Palbociclib [Ibrance] has not been a successful therapeutic strategy in that same setting. We’re waiting to see the results of ribociclib from the ongoing [phase 3] NATALEE trial [NCT03701334], which will help round out the information that we have in this setting.

Another major advance has been the approval of pembrolizumab [Keytruda] for patients with both metastatic TNBC and in the neoadjuvant context where the use of this agent added to standard therapy has been shown to improve both PFS and OS in the metastatic setting in the subset of patients with a CPS [combined positive score] of at least 10. [Pembrolizumab] also improved the pathologic CR [complete response] rate and event-free survival [EFS] in 3 years in patients with localized disease irrespective of CPS. T

here have been a tremendous number of developments within the last year [for which] we need to hear the most recent updates.

As the landscape of clinically actionable mutations in breast cancer has expanded, how has your approach to determine who to test and what to test for changed for patients with early-stage disease and advanced disease?

Currently, the only real actionable somatic mutation that can drive therapy is the PIK3CA mutation in patients with ER-positive, HER2-negative breast cancer which can occur in 30% to 40% of patients. If a patient’s tumor harbors a PIK3CA mutation, [we can expect] there is benefit from the use of the PIK3CA inhibitor such as alpelisib [Piqray] in terms of PFS.

There are other much less common mutations that may be acquired that are supporting the use of panel testing either of the tumor or based on ctDNA [circulating tumor DNA] to look not only for PIK3CA but also other potentially actionable alterations. They are less common, but when present could lead to a specific therapy that could provide benefit for individual patients.

What are some of the challenges for clinicians in determining patients at high-risk of developing aggressive disease?

One of the challenges that we face for those patients who are high clinical risk and high genomic risk is trying to further stratify their risk. A substantial portion of those patients may be cured of their disease, even though they are high risk. We need better tools [and] assays to identify those patients. Typically, we have relied on static biomarkers, to help stratify risk and [then] integrate that information with clinical pathologic features. We are now beginning to move into a realm of using dynamic biomarkers sequentially over time rather than only at one time point. [These] may be useful in identifying which patients are at highest risk for recurrence.

There is certainly a substantial body of literature showing that the presence of circulating tumor cells in the blood or ctDNA in the blood for patients in this context is associated with a higher risk of recurrence. What we have not figured out yet is how many of [these patients] have overt metastatic disease and what proportion of them do not.

That is an area of investigation that we should see substantial advances in the next few years. This has already made its way into the surveillance of colorectal cancer, but I think we are a bit behind in breast cancer in applying that technology.

What are some of the novel therapies that you are looking forward to seeing integrated into practice?

Certainly, the CDK4/6 inhibitors in the early setting. We have evidence that the use of adjuvant abemaciclib can reduce the risk of recurrence in patients with high-risk, ER-positive, HER2-negative breast cancer. There are some concerns about whether benefit in disease-free survival will be durable and will translate into an OS benefit. We need longer follow up because patients with this subtype of breast cancer tend to be at continuous risk of recurrence. We also are waiting for information regarding the role of other CDK4/6 inhibitors in this context from the results of ongoing trials.

With regard to ADCs,there has been striking activity in patients with metastatic breast cancer in the setting of ER-positive HER2-negative breast cancer, TNBC, and HER2-positive breast cancer. The next challenge is going to be developing more effective ADCs [and] testing those that have been shown to be effective in the more advanced disease settings in the early disease settings. That is another area of investigation [for which] we will be seeing more clinical trials.

There is also new information about the use of drugs such as olaparib [Lynparza], a PARP inhibitor, in the adjuvant setting that has been shown to reduce the risk of disease recurrence and improve OS in patients who have germline BRCA mutations. That’s another important advance.

Finally, immune checkpoint inhibitors have been shown to have a proven role in prolonging OS in the metastatic triple-negative setting for patients who have a CPS of at least 10. [They have] also been shown to have a role in improving pathologic CR rate and EFS irrespective of CPS when added to neoadjuvant chemotherapy. Those are all major developments that have had a profound impact on the treatment of both early stage and advanced breast cancer.

With the recent approval of trastuzumab deruxtecan for HER2-low breast cancer, what anticipated shifts do you see in terms of working with pathologists and selecting assays changing to guide treatment recommendations?

For institutions such as [Mount Sinai] where the level of HER2 expression is [done] by immunohistochemistry, it is routinely reported for those tumors that are HER2-low. There [is not] a big impact [at my institution]/

For the institutions, centers, and laboratories where it is not reported, there needs to be a change in the reporting to adhere to the ASCO/College of American Physician guidelines in reporting by the level of protein expression because right now we have not demonstrated that drugs such as trastuzumab deruxtecan have activity in patients who have HER20 level of protein expression. There are some signals that there may be some activity in that in that context, but definitive evidence is lacking in that context. This clearly needs to be integrated into standard practice and reporting.

What are the unmet needs in terms of genetic testing at the community level?

Germline testing for BRCA1/2 and other mutations, has become an essential part of the care of women with early-stage breast cancer for a variety of reasons. The tests are widely available and relatively inexpensive. They have a high degree of analytic validity [and] the results from these tests can have substantial clinical implications for the [surgical] management of the primary tumor, management of the contralateral breast, and possible screening for and prevention of other secondary cancers.

In addition, we now know that women who have germline BRCA1/2 mutations can benefit from the use of adjuvant olaparib, with improvements demonstrated in disease-free OS for those who are at highest risk of recurrence. We need to make sure that every patient who could potentially benefit from that information has that information available.

You have had several studies published this year with a focus on identifying racial disparities among women with breast cancer. What have been some of the trends observed in conducting these analyses and what do you see as the first steps to closing the gaps?

There are racial disparities in [clinical] outcomes [for patients with breast cancer] and that there is a racial divide. The good news is that breast cancer mortality has been declining substantially; it has declined approximately 40% over the past 20 years.

The bad news is that there despite this declining mortality in both White women and Black women, there remains this persistent racial divide: Black women have worse outcomes. There are many reasons for that. Black women are more likely to present with TNBC, more advanced stage disease, have more comorbidities, and may have less access to care.

When you study clinical trial populations, that is patients who were healthy enough to participate in clinical trials, have access to care, and get the best available therapy, you find that some of these disparities remain. Not so much so in TNBC but for patients with ER-positive, HER2-negative breast cancer. This disparity does not appear to be because of differences in adherence to endocrine therapy or chemotherapy or other factors. We need to do more work to better understand what are the factors that are driving those disparities.

References

1. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
2. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2022. Accessed October 27, 2022. bit.ly/3bgJ070
3. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed October 27, 2022. bit.ly/3zGfOPt