MBCC Offers Review of Burgeoning Advancements in Breast Cancer Management

Hope S. Rugo, MD, FASCO

In 2020 alone, the FDA approved 6 systemic therapies for novel indications across breast cancer subtypes.¹ With the continuously evolving treatment landscape for this disease, staying up-to-date with the latest changes is of paramount importance.

To assist in this endeavor, the virtual 38th Annual Miami Breast Cancer Conference®(MBCC), hosted by Physicians’ Education Resource®, LLC (PER®) will feature presentations from industry thought leaders on innovations in the arena of breast cancer treatment, including topics about systemic therapy and beyond.

“It includes both the new data in surgery and radiation oncology [as well as that] in medical oncology, in both early-stage and metastatic disease,” Hope S. Rugo, MD, FASCO, one of the program cochairs, said in an interview with Targeted Therapies in Oncology. “We cover all of the clinically pertinent information that’s come out of the most recent presentations and publications, and there’s the ability to discuss this and ask questions of the presenters.

”One of the great advantages of the meeting is its juxtaposition to the San Antonio Breast Cancer Symposium (SABCS). The virtual MBCC follows SABCS by approximately 12 weeks, March 4-7, 2021, giving MBCC faculty the advantage of tailoring the program to the most relevant research updates.

“We can update the agenda to reflect the most recent data that were presented at San Antonio and apply this to the clinic,” Rugo, a professor of medicine and director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, said.

Further Tailoring Therapy to Hormone Receptor–Positive Populations

Rugo detailed abstracts from SABCS in which the validity of standard treatment approaches for hormone receptor–positive disease was tested in more precise patient subpopulations, with the goal of identifying those who derive the greatest benefit.

RxPONDER in Pre/Postmenopausal Patients

The randomized, phase 3 RxPONDER trial (NCT01272037) evaluated the efficacy of standard adjuvant endocrine therapy with or without chemotherapy in patients with hormone receptor–positive, HER2-negative early-stage breast cancer who had 1 to 3 positive nodes and a recurrence score of 25 or less by Oncotype DX screening.²

Results of the study demonstrated that postmenopausal women did not derive further benefit from the addition of chemotherapy, but premenopausal women with the same characteristics experienced a significant relative risk reduction in invasive disease–free survival (iDFS).

“Using the recurrence score is fascinating and will result in a lot more analyses,” Rugo said. “This already will impact our care of patients with node-positive, early-stage hormone receptor–positive, HER2-negative breast cancer.

”Despite no significant difference in iDFS noted with or without chemotherapy in the primary analysis (P=.3), a prespecified subgroup analysis revealed that an interaction between chemotherapy use and menopausal status existed (P=.004). The hazard ratio for the comparison of both treatment arms favored the use of chemotherapy in patients who were premenopausal (HR, 0.54; 95% CI, 0.38-0.76; P =.0004) versus those who were postmenopausal (HR, 0.97; 95% CI 0.78-1.22; P =.82). At 5 years, the iDFS rate in the premenopausal group was 94.2% for those who received versus 89.0% in those who did not.

Ki-67 Further Validated as Marker of CDK4/6 Efficacy

Results of a subanalysis of the randomized phase 3 monarchE trial (NCT03155997) of adjuvant endocrine therapy with or without abemaciclib (Verzenio) in patients with resectable hormone receptor–positive, HER2-negative tumors at high risk suggest that a threshold of 20% or greater Ki-67, which is a marker of cellular proliferation, may be a useful clinicopathological feature of response to the CDK4/6 inhibitor.³

“It’s not just the clinical features, like stage and grade, but Ki-67 also is emerging as an incredibly important factor,” Rugo said of the results, which were also reported at SABCS. “I think this is likely to be practice changing in the next year.”

Patients with high Ki-67 in the overall patient population and patients in cohort 1—those with other high-risk clinicopathological features such as tumor involvement, tumor size, and grade—were assessed for superiority of abemaciclib therapy as determined by iDFS. A statistically significant improvement in the primary end point was seen with the agent in both the overall population (HR, 0.685; 95% CI, 0.462-1.017; P=.0591) and in cohort 1 (HR, 0.643;95% CI, 0.475-0.872; 2-sided P=.0042).

J101 Reveals HER2-Low Populations

The phase 1 J101 trial (NCT02564900) of fam-trastuzumab deruxtecan-nxki (Enhertu) indicated that certain patients with low HER2 expression, defined as those with an immunohistochemistry (IHC) score of 2+/1+ and negativity by in situ hybridization, may derive benefit from treatment with the antibody-drug conjugate. These data, which were also presented at SABCS, may help potentially define a patient population of medical unmet need who would otherwise not be treated with anti-HER2 therapy.⁴

“We’re going to see data in the next year about the efficacy of these antibody-drug conjugates in other populations, such as patients who have newly-defined HER2-low disease,” Rugo said. “[These patients are] not HER2 positive but not 0 by IHC.”

Patients in the analysis were assessed using deep learning–based digital analysis to produce a novel HER2 quantitative continuous score (QCS), a method found to be more predictive of response to trastuzumab deruxtecan versus manual assessment by pathologists.

Out of 151 patients, 65 were identified as having HER2-low expression by conventional IHC scoring; the response rate in this group was 42%. When investigators further stratified the patients into QCS-high and QCS-low subgroups, they were able to identify 21 of the 27 responders who were missed by conventional screening methods. To validate these promising results, further studies into the use of QCS are ongoing.

Looking Ahead: Immunotherapy and Beyond

Rugo said several immunotherapy agents could possibly become available for use in the adjuvant/neoadjuvant setting in the near future, mirroring the success seen in advanced tumors.

Namely, results of one investigational arm of the open-label, randomized, phase 2 I-SPY 2platform study that were published in JAMA Oncology in February 2020 showed that the addition of pembrolizumab (Keytruda) to standard neoadjuvant chemotherapy more than doubled pathologic complete response rates in patients with hormone receptor–positive/HER2-negative and triple-negative breast cancer.⁵ Further exploration of this data set examined surrogate markers of this regimen and were presented at SABCS.⁶ Larger studies are ongoing.

“I think the analyses of immunotherapy in the metastatic setting are already practice changing and in the next year will potentially be practice changing for the neoadjuvant setting as well,” Rugo said.

Other agents to watch for are antibody-drug conjugates, such as trastuzumab deruxtecan and sacituzumab govitecanhziy (Trodelvy), as therapy for patients with triple-negative breast cancer. Rugo said data from trials involving these agents are likely to be reported this year and have the potential to change the treatment paradigm for triple-negative disease.

To conclude, Rugo reflected on the advantages of MBCC for those treating patients with breast cancer across clinical settings. “You will get that great interaction with the speakers and timely updates of [the latest] data put into perspective.”

_References:

_{1. Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated December 18, 2020. Accessed December 21, 2020. https://bit.ly/3avuIwR}

_{2. Kalinsky K, Barlow WE, Meric-Bernstam F, et al. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; virtual. Abstract GS3-0 . https://bit.ly/2WsISGT}

_{3. Harbeck N, Johnston S, Fasching P, et al. High Ki-67 as a biomarker for identifying patients with high risk early breast cancer treated in monarchE. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; virtual. https://bit.ly/2WsISGT}

_{4. Gustavson M, Hanedar S, Spitzmeuller A, et al. Novel approach to HER2 quantification: digital pathology coupled with AI-based image and data analysis delivers objective and quantitative HER2 expression analysis for enrichment of responders to trastuzumab deruxtecan (T-DXd; DS-8201), specifically in HER2-low patients. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; virtual. https://bit.ly/2WsISGT}

_{5. Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6(5):676-684. doi:10.1001/jamaoncol.2019.6650}

_{6. Magbanua MJM, Wolf D, Renner D, et al. Personalized ctDNA as a predictive biomarker in high-risk early stage breast cancer (EBC) treated with neoadjuvant chemotherapy (NAC) with or without pembrolizumab (P). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; virtual. https://bit.ly/2WsISGT}