RPS-Optimized Checkpoint Inhibition Bolsters pCR in Patients With Select Rare Breast Cancers

Alexandra Thomas, MD, FACP

Patients with select rare breast cancer subtypes, such as metaplastic and lobular histologies, achieved high pathologic complete response (pCR) rates with response-predictive subtype (RPS)–optimized treatment with a checkpoint inhibitor, although patients with rare breast cancers overall experienced shorter event-free survival (EFS) vs those with no special type (NST), according to data from an analysis of the I-SPY 2 study (NCT01042379).¹

Findings presented during the 2024 ASCO Breakthrough Conference showed pCR rates of 34% and 20% for patients with NST (n = 1974) and rare breast tumors (n = 142), respectively. Rare tumor histologies included metaplastic (n = 59), lobular (n = 55), mucinous (n = 9), micropapillary (n = 8), neuroendocrine (n = 4), and apocrine (n = 4). pCR rates were 27%, 15%, 0%, 25%, 0%, and 50% for these respective subtypes. Other uncommon histologies were also noted.

Further assessment of pCR according to RPS showed high response rates in the HER2-Immune+ ([S3]; NST group, 49%; rare tumor group, 39%) and HER2+ non-luminal ([S5]; 59%; 90%) subtypes. pCR rates were also observed for patients with HR+HER2-negative-Immune-DRD ([S1]; NST group, 10%; rare tumor group, 0%), HR-HER2–Immune-DRD ([S2]; 14%; 0%), HER2+luminal ([S6]; 18%; 0%), and unknown (13%; 33%) subtypes. Notably, a pCR was achieved by 56% of patients with rare tumors in the S3 immune-positive group who received RPS-optimized therapy with an immune checkpoint inhibitor (n = 18). This included 8 patients with metaplastic tumors, 1 patient with a lobular tumor, and 1 patient with an apocrine tumor.

Patients with metaplastic breast cancer in the rare tumor group had a pCR of 27% vs 34% in the NST group. Importantly, pCR rates were higher among patients treated with checkpoint inhibitors (rare tumor group, 37%; NST group, 34%) vs without (32%; 18%). For those with S3 disease who received a checkpoint blockade, there was no statistically significant difference in the pCR rate between the NST group (64%) and the rare tumor group (57%; P = .58).

“We observed high pCR rates in [patients with] metaplastic breast cancer amongst subsets of often difficult-to-treat breast cancer subtypes. This supports novel approaches and provides a roadmap for future study of rare breast cancers,” lead study author Alexandra Thomas, MD, FACP, a professor of medicine at Duke Cancer Institute in Durham, North Carolina, stated in an oral presentation of the data. “Outcomes were also improved when therapy matched RPS vulnerabilities.”

I-SPY 2 is a neoadjuvant platform designed to evaluate novel agents in combination with standard chemotherapy for patients with early-stage, high-risk breast cancer. This trial is particularly significant for patients with uncommon histologies, which are over-represented among high-risk breast cancer cases and represent an area of unmet medical need due to limited trial data. The trial uses a combination of tumor molecular signature and receptor status to determine RPS.

The study enrolled patients 18 years of age or older with high-risk, HER2-positive, triple-negative breast cancer (TNBC) and high molecular–risk hormone receptor (HR)–positive breast cancer.² Other key eligibility criteria included histologically confirmed invasive breast cancer; clinically or radiologically measurable disease in the breast after diagnostic biopsy, defined as longest diameter greater than or equal to 25 mm; no prior exposure to cytotoxic regimens for this malignancy; no prior chemotherapy or prior radiation therapy to the ipsilateral breast for this malignancy; and an ECOG performance status of 0 or 1. Prior treatment with bis-phosphonate therapy was allowed.

The primary objective of the study is to determine whether adding experimental agents to standard neoadjuvant medications increases the probability of pCR over standard neoadjuvant chemotherapy for each biomarker signature established at trial entry.

In the current analysis, investigators assessed pCR and early EFS across different disease subtypes within the I-SPY 2 trial to enhance the understanding of patient outcomes and uncover potential signals of tumor responsiveness.¹

To build the rare breast tumor cohort, investigators reviewed pathology reports and histologic images of research biopsies from 2116 patients enrolled in the trial between 2010 and 2022. Histologic images of research biopsies, local biopsy, and surgical pathology reports were centrally reviewed, and tumors were accordingly classified as either rare or NST.

Most patients in both groups had HR-positive, HER2-negative disease (rare tumor group, 55.0%; NST group, 42.2%), followed by TNBC (36.6%; 35.2%) and HER2-positive disease (8.5%; 22.6%; P = .0002). The median age was 50.9 years in the rare tumor group and 48.3 in the NST group (P = .008); mean weights were 74.8 kg and 75.8 kg, respectively (P = .47). Most patients were White (rare tumor group, 85.5%; NST group, 78.8%; P = .16). Hispanic patients comprised 13.4% and 13.7% of patients in the rare tumor and NST groups, respectively (P = .92).

“The rare breast tumor cohort had an overrepresentation of HR-positive, HER2-negative disease. HER2-positive disease was overrepresented in the NST cohort,” Thomas noted.

Receptor-based subtype distributions among these 2 groups were also assessed. As expected, there was an overrepresentation of TNBC among patients with metaplastic disease, Thomas noted.

There were a total of 6 response predator subtypes, which incorporate immune DNA repair deficiencies and luminal signatures with tumor HR and HER2-positive status. These included S1; S2; S3; HER2-Immune-DRD+ (S4); S5; S6; and unknown.

“Note, for example, S3, or the immune-positive signature, which suggests a vulnerability to immune therapy. [This] is overrepresented in metaplastic breast cancer and seen in several of the other breast cancer subtypes,” Thomas added.

EFS also differed among the groups, with the rare breast tumor group experiencing inferior EFS compared with the NST group (P = .021). Looking at individual tumor histology, patients with metaplastic and lobular breast cancer subtypes had a lower EFS vs those in the NST cohort in this early follow-up period (P = .0004).

Furthermore, pCR was found to correlate with EFS in both the NST (P < .0001) and rare breast tumor cohorts (P = .013). In the NST cohort, 668 patients experienced a pCR, and 28 patients achieved a pCR in the rare breast tumor cohort.

Disclosures: Dr Thomas disclosed the following relationships: stock and other ownership interests with Bristol-Myers Squibb, Doximity, Gilead Sciences, Johnson & Johnson, and Pfizer; serving in a consulting or advisory role for AstraZeneca; receiving institutional research funding from Merck and Sanofi; and having up-to-date royalties.

References

1. Thomas A, Wolf DM, Balassanian R, et al. Therapeutic response and outcomes with uncommon breast cancer subtypes in the I-SPY trial 2010-2022. J Clin Oncol. 2024, 42(suppl 23):1. doi:10.1200/JCO.2024.42.23_suppl.1
2. I-SPY TRIAL: neoadjuvant and personalized adaptive novel agents to treat breast cancer (I-SPY). ClinicalTrials.gov. Updated April 23, 2024. Accessed August 9, 2024. https://clinicaltrials.gov/study/NCT01042379