Carroll Highlights Data Presented at SABCS from the CARRIERS and RIGHT Choice Studies

Jamie Carroll, APRN, CNP, MSN

Advances in the field of breast cancer continue to posit questions that require further evaluation, according to Jamie Carroll, APRN, CNP, MSN.

Specifically, the the RIGHT Choice (NCT03839823) study as well as the CARRIERS study, both of which were presented at the 2022 San Antonio Breast Cancer Symposium have generated discourse regarding the use of the findings.

For instance, although the RIGHT Choice study demonstrated an improvement in progression-free survival (PFS) for pre/perimenopausal patients with aggressive hormone receptor–positive and HER2-negative advanced breast cancer receiving ribociclib (Kisqali) and endocrine therapy (ET) compared with a chemotherapy combination, both arms achieved similar overall response rates (ORR).¹

“[The] investigator’s choice chemotherapy options are interesting because they’re not typical chemotherapy combinations that we use especially in first line metastatic breast cancer,” Carroll, a nurse practitioner at Mayo Clinic in Rochester Minnesota, said in an interview with Oncology Nursing News®. “There are things that you can pull from this study, but I don’t think that it’s going to be practice changing.”

In the RIGHT Choice study, median PFS was 24 months for the ribociclib and endocrine therapy arm (n = 112) compared with 12.3 months in the combination chemotherapy arm (n = 110; HR, 0.54). Median time to treatment failure was 18.6 months vs 8.5 months, respectively (HR, 0.45). Treatment related serious adverse events were lower in the ribociclib and endocrine therapy group with 1.8% of patients experiencing a serious event of all grades compared with 8.0% of the combination chemotherapy group; discontinuation rates were 7.1% and 23.0%, respectively.

The CARRIERS study sought to determine the risk of developing contralateral breast cancer for patients with the germline pathogenic variants BRCA1, BRCA2, ATM, CHEK2, and PALB2. Findings showed that patients with ER-negative disease with PALB2 mutations had a higher risk level for developing contralateral breast cancer, and patients with PALB2 mutations overall and those with ER-positive disease did not.²

Sequencing to identify germline pathogenic variants from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium examined variants in 32,247 patients with breast cancer and 32,544 women who were unaffected.

After a median follow-up of 11 years, patients in the CARRIER study experienced 10-year cumulative incidence of contralateral breast cancer at rates vs noncarriers of BRCA1 (23% vs 4.3%), BRCA2 (4.3% vs 17%), CHEK2 (4.3% vs 8%), ATM (4.3% vs 4.0%), and PALB2 ER-negative (5.4% vs 19.7%). The CARRIERS study demonstrated that patients with CHEK2 mutations are at an increased risk for contralateral breast cancer similar to patients with BRCA1 and BRCA2, but those with ATM mutations are not.

Carroll discussed the 2 trials that were presented at SABCS and how their efficacy data may or may not effect practice.

Oncology Nursing News®:Please discuss the RIGHT Choice trial.

Carroll:This was a phase 2 study that came out of Taiwan looking at patients with aggressive hormone receptor–positive, HER2-negative advanced breast cancer treated with ribociclib and endocrine therapy vs physicians’ choice combination chemotherapy. These were patients [with] either relapsed breast cancer or de novo stage 4 breast cancer and so [investigators] were looking at patients that had symptomatic visceral metastasis, rapid disease progression or impending visceral compromise, or marked symptomatic nonvisceral disease.

It was looking at: what’s the right choice? For patients who have visceral crisis, do we give them physician’s choice chemotherapy vs ribociclib plus aromatase inhibitor [AI] and then goserelin if they’re premenopausal? Do you need a response quickly or is endocrine therapy our mainstay of treatment regardless of visceral crisis or symptomatic assessment of the patient?

With the RIGHT Choice study design, patients could be either pre or perimenopausal. [Patients had] hormone receptor–positive, HER2-negative measurable disease by RECIST [1.1 criteria], an ECOG performance status of 2 or less, and total bilirubin less than or equal to 1.5—the upper limits of normal. IT was a 1:1 randomization with the CDK4/6 plus AI and investigator’s choice of chemotherapy. [Chemotherapy] combinations [included] docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine.

What was notable about the RIGHT Choice trial?

Right away the study design is interesting to me because it’s subjective information and not necessarily objective when you're looking at patients calling it ‘aggressive disease.’ If they’re symptomatic visceral metastasis, that makes sense—they have symptoms, but is the symptom related to burden of disease in their liver? Or are they feeling that capsular push and pressure on their liver, and calling it visceral crisis? If total bilirubin is less than 1.5—the upper limits of normal—is that a visceral crisis?To me, it’s very subjective with the inclusion criteria.

[The] primary end point [investigators] looked at was PFS. Off the bat, we already know that CDK4/6 [inhibitor] ribociclib plus AI has a [median] PFS of 24 months and chemotherapy tends to be less than that.

The question still remains: did patients have a reduction of their disease quicker with chemotherapy vs CDK4/6 and AI? The ORRs were pretty similar, 65% with the ET arm and 60% with the chemotherapy arm; the study wasn’t powered for overall response.

Please describe the CARRIERS study.

Siddhartha Yadav, MD, who is a Mayo Clinic oncologist, presented on the CARRIERS study—where [investigators] are looking at contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2.

We know that [patients with] BRCA1 and BRCA2 have elevated risk and so supplemental breast imaging is recommended if they do not have bilateral mastectomy, but contralateral breast cancer after a primary breast cancer [is not well-defined], and in the past [has primarily been] looked for in women with BRCA1 and BRCA2 and not necessarily ATM, CHEK2, and PALB2.

The CARRIERS study was looking at 32,000 women with a breast cancer diagnosis and then 32,000 matched women that are unaffected as controls. There were 15,000 women with unilateral invasive breast cancer looking at 10 prospective studies in the United States. The inclusion criteria was a preserved contralateral breast and at least 1 year of follow-up. Exclusion was patients who had ductal carcinoma in situ at initial diagnosis. Seventy-three percent [of patients] were postmenopausal at diagnosis which goes along with the median age at 62 years, and 75% of those patients had ER-positive breast cancer and 46% adjuvant endocrine therapy use.

What were the main findings from the CARRIERS study?

Median follow-up was 11 years and Yadav broke down the events by gene. The noncarriers genes events number was 711 out of the 14,444 patients and each one of the genes he broke down on contralateral breast cancer events [was as follows]: ATM, 0.7, BRCA1, 0.9, BRCA2, 1.1, CHEK2, 0.9, PALB2, 0.6 events, so less than the noncarriers.

[Yadav] looked at overall and ER status of a first breast cancer and the incidence of breast cancer from the first breast cancer diagnosis. The overall BRCA carrier has a 3% risk of a contralateral breast cancer; BRCA1 was 23% over those 10 years of a contralateral breast cancer and BRCA2 was 17% over those 10 years.

Interestingly, those [with] PALB2[-mutant disease]had 2 times the risk of a subsequent breast cancer­—with their second breast cancer being ER-negative, regardless of what the first breast cancer was. That was interesting because if somebody has an ER-positive breast cancer and a PALB2 mutation they’re going to be on endocrine therapy, but they still have 2 times the risk of developing a contralateral breast cancer.

It was interesting when they talked about the contralateral breast cancer risk in women over the age of 65 years at first breast cancer diagnosis. The number of contralateral breast cancers in those pathogenic variant carriers was 3 with 6010 women. If you have an 80-year-old whose first breast cancer was diagnosed and she’s got contralateral tissue, then maybe [supplemental breast imaging] does not do her benefit because 3 out of 6000 women is not a very high number.

Can you discuss how this might translate into practice and conversations with patients about breast imaging and what this could mean?

For patients that choose wide local excision or breast conserving therapy and not a contralateral mastectomy, it’s helpful to tell them what their risk of a secondary breast malignancy is in their pathogenic variant subtype because in the past we’ve always said,“Yes, you need a contralateral mastectomy.”

It’s helpful to understand that if they have a PALB2 mutation they're at 2 times the increased risk of an ER-negative breast cancer, but not necessarily an ER-positive breast cancer. ATM mutations do not increase the risk of a contralateral breast cancer, so for those patients, you may not necessarily need a contralateral mastectomy if you’re not at increased risk of a contralateral breast cancer.

References

1. Yadav S, Boddicker NJ, Na J, et al. Population-based estimates of contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Presented at the 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS4-04.
2. Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384(5):440-451. doi:10.1056/NEJMoa2005936