SABCS 2022: Updates from Noteworthy Clinical Trials

Investigators presented findings for both early-stage and metastatic breast cancer, as well as younger women

This year’s San Antonio Breast Cancer Symposium (SABCS) featured several notable developments from ongoing breast cancer clinical trials—including many that BCRF supports or that involve BCRF investigators.

Trial updates and findings presented at this year’s symposium will potentially change standards of care for certain patients, have important takeaways for patients with both early-stage and metastatic disease, reveal new areas for investigation, and open the door for the FDA to approve a new class of targeted therapies.

Read on for our highlights from this year’s conference.

Risk of recurrence following endocrine therapy with or without chemotherapy: TAILORx follow-up

The original study findings from the BCRF-supported TAILORx clinical trial were confirmed after a 12-year follow-up, reported BCRF investigator Dr. Joseph A. Sparano on behalf of the trial team. The study’s design prespecified a follow-up of 20 years to gain substantially more information regarding late recurrences in people with estrogen receptor (ER)–positive/HER2-negative breast cancer—data that is especially important given that patients’ recurrence risk persists for 20 or more years with at least 50 percent of recurrences (deemed “late recurrences”) developing more than five years after diagnosis.

TAILORx trial patients were stratified based on the Oncotype Dx® assay, which measures the level of 21 genes in a tumor biopsy to determine recurrence risk in newly diagnosed patients with early-stage, hormone receptor (HR)-positive (ER-positive) breast cancer. The resulting Recurrence Score (RS) indicates a patient’s risk that their breast cancer may come back: scores 1-10 are low, 11-25 are mid-range, and 26-100 are high.

In this SABCS update, Dr. Sparano reported that recurrence events—including new primary occurrence, distant or locoregional recurrence, or death—occurred in all groups, but was greatest in the intermediate risk (RS from 11-25) group, which had 50 percent more recurrence events than the other two. In this group, after 12 years, hormone therapy was as effective as hormone therapy plus chemotherapy with no added benefit for those with scores 11-15, marginal benefit to patients with scores 16-20, and a slight benefit for the group with scores ranging 21-25. However, for the intermediate risk group with scores 21-25, chemotherapy continued to benefit women 50 and younger.

While the number of late recurrences exceeded early recurrence rates, racial disparities were observed in early recurrences in Black women compared to white women but not in late recurrences. The reasons for this remain to be investigated. 

Clinical outcomes by race and ethnicity: RxPONDER update  

The BCRF-supported RxPONDER trial has demonstrated that many postmenopausal women with HR-positive/HER2-negative breast cancer who have recurrence scores of 25 or lower as measured by Oncotype Dx® can safely skip chemotherapy after breast cancer surgery. This score has become a valuable tool to guide treatment decisions, but not all patients are benefiting equally.

Dr. Yara Abdou of the University of North Carolina presented findings from a SWOG Cancer Research Network study investigating race and clinical outcomes in the RxPONDER cohort. Researchers analyzed the clinical outcomes of participants by race and ethnicity and found that, despite having similar recurrence scores, non-Hispanic Black women with HR-positive/HER2-negative, lymph node–positive breast cancer had worse outcomes than Asian, Hispanic, and non-Hispanic white women.

The study revealed that although recurrence score, tumor size, and number of positive lymph nodes did not significantly differ among racial groups, tumor aggressiveness—categorized on a scale from one to four—was significantly different. Black and Hispanic women tend to have more grade three tumors than white or Asian women. The study also found that the overall five-year invasive disease–free survival rate was lowest for Black women.

The results of this analysis of RxPONDER participant outcomes highlights the need for novel approaches to improve clinical outcomes, particularly for Black women.

Follow-up studies from the DESTINY-Breast trials confirm T-DXd benefit

Several updates to the DESTINY-Breast trials presented at SABCS were built on prior results seen with the antibody drug conjugates T-DXd (trastuzumab durextecan/Enhertu®) and T-DM1 (trastuzumab emtansine/Kadcycla®) in patients with advanced breast cancer. Investigators tested these drugs over longer periods to confirm their benefit and assess any long-term adverse effects. Among the highlights discussed at the conference:

• DESTINY-Breast02: Dr. Ian Krop presented an update that confirmed the positive benefit of T-DXd seen in DESTINY-Breast01 and demonstrated that this benefit is sustained over three years. This trial tested the use of T-DXd versus treatments of physicians’ choice in people with advanced HER2-positive breast cancer who were previously treated with T-DM1. Assessment revealed that T-DXd significantly reduced the risk of progression or death compared to other treatments with no new adverse effects.

• DESTINY-Breast03: After two years of follow-up in patients with advanced HER2-positive breast cancer, T-DXd significantly reduced patients’ risk of death—by 36 percent—and extended progression-free survival four times longer than what has been observed for T-DM1.
• DESTINY-Breast04: After two years of follow-up, investigators confirmed T-DXd’s longer-term benefit in advanced HER2-low breast cancer and reported no additional adverse effects.

Other DESTINY-Breast trials are underway to assure that antibody drug conjugates continue to provide benefit for patients over time.

Interrupting endocrine therapy for pregnancy does not impact short-term breast cancer outcomes  

While breast cancer in women under 40 is rare, the incidence rate has been increasing in recent years. Among several unique challenges for younger women, a breast cancer diagnosis can interrupt or pause family planning. Young women with HR-positive breast cancer must carefully consider the effects of treatment on fertility and pregnancy, especially since standard care for their breast cancer is five to 10 years of adjuvant endocrine therapy, which can affect the ovaries.

The BCRF-supported POSITIVE trial (led by BCRF investigator Dr. Ann Partridge) was designed to evaluate a key question for this group: Does temporarily pausing endocrine therapy to attempt pregnancy increase a woman’s risk of a breast cancer recurrence later?

In this first-of-its-kind clinical trial, POSITIVE accrued 518 patients from 116 centers across 20 countries. The participants were 42 and younger, wanted to get pregnant, and had stage 1-3 HR-positive breast cancers that had been treated with endocrine therapy for 18 to 30 months. Within one month of enrollment, that treatment was stopped for up to two years so patients could get pregnant, carry to term, and breastfeed. The study was designed to evaluate recurrence rates after endocrine therapy interruption, as well as pregnancy and birth outcomes and potential impacts on women’s babies. 

Presenting the study’s initial analysis, Dr. Partridge revealed that temporary interruption of endocrine therapy to attempt pregnancy does not impact short-term disease outcomes. Seventy-four percent of the participants had at least one pregnancy—most within the 2 years of treatment suspension—and no significant increase in adverse outcomes for the child.

Although preliminary, these results are encouraging to young women diagnosed with HR-positive breast cancer that wish to become pregnant. Patients will be followed for seven years to monitor therapy resumption and disease outcomes.

Adding capivasertib to fulvestrant improves survival in advanced HR-positive/HER2-negative breast cancer

Dr. Nicholas Turner of The Institute of Cancer Research in London and The Royal Marsden NHS Foundation Trust in Sutton, United Kingdom presented results from CAPItello-291, a phase 3 clinical trial testing the AKT inhibitor capivasertib plus fulvestrant (an estrogen blocker) against a placebo plus fulvestrant in patients with HR-positive/HER2-negative breast cancer whose disease had progressed on or after aromatase inhibitor therapy with or without a CDK4/6 inhibitor.

Aromatase inhibitors, combined with CDK4/6 inhibitors, are a common first-line treatment for patients with metastatic HR-positive/HER2-negative breast cancer. Most tumors, however, develop resistance to these treatments—and many of these tumors also have genetic alterations in the AKT pathway. AKT is a key component of the PI3K/AKT cell signaling pathway—the most-mutated pathway in breast cancer. This pathway plays a critical role in regulating tumor growth, survival, and invasiveness, making it an attractive treatment target.  

CAPItello-291 evaluated progression-free survival (PFS) of patients with or without AKT pathway–altered tumors. Capivasertib plus fulvestrant significantly improved PFS regardless of tumor mutation status, with a PFS of  7.3 months versus 3.1 months in the AKT-mutant tumors and 7.2 months versus 3.6 months in non-AKT-mutated tumors. The PFS improvement observed in CAPItello-291 is encouraging, and these results will likely lead the FDA to approve the first AKT inhibitor for treating breast cancer.

More from BCRF’s SABCS 2022 Coverage:

• Highlights and Key Takeaways from SABCS 2022
• Three BCRF Investigators Honored at Symposium
• Researchers Share Insights on HER2-Low Breast Cancer
• Antibody-Drug Conjugates Front and Center at SABCS 2022
• SABCS 2022 Features Robust Discussions on Tumor Microenvironment