More Support for Gene Assay to Guide Breast Cancer Treatment

Patients with ultralow-risk breast cancer according to genomic assessment had excellent long-term outcomes regardless of clinical risk or whether they received adjuvant therapy, a new analysis of a randomized trial showed.

The 8-year breast cancer-specific survival (BCSS) was 99.2% among patients classified as clinically high-risk but ultralow-risk by the MammaPrint 70-gene assay. Patients with an ultralow-risk genomic assessment and low clinical risk had an 8-year BCSS of 99.7%. Freedom from distant metastasis at 8 years was 97.6% in patients who were clinically and genomically low-risk versus 95.0% for those who were clinically high-risk but genomically low-risk.

In patients with an ultralow-risk genomic assessment, the 8-year distant metastasis-free interval (DMFI) rate was 97.8% with no adjuvant systemic therapy. That compared with an 8-year DMFI of 97.4% in patients who received only adjuvant endocrine therapy and 94.9% in patients who received chemotherapy with or without endocrine therapy.

“Patients with an ultralow-risk 70-gene signature had an excellent prognosis, with 8-year breast cancer-specific survival rates above 99%, regardless of clinical risk,” said Josephine Lopes Cardozo, MD, of The Netherlands Cancer Institute in Amsterdam, during the virtual American Society of Clinical Oncology annual meeting. “Very few patients develop distant metastases. Furthermore, we observed excellent DMFI rates for the 84% of ultralow-risk patients who received only endocrine therapy or no adjuvant systemic treatment.”

“The clinical implications of this research are that we can confirm that the 70-gene signature can identify patients with an ultralow-risk of recurrence and that these patients could be candidates for further de-escalation of treatments, thus further reducing overtreatment and the risk of side effects,” she added.

Retrospective application of the 70-gene signature to a different patient population revealed potential for identifying low-risk patients who might benefit from extended-duration endocrine therapy. Patients classified as high-risk by the assay did not benefit significantly from extended treatment with letrozole, whereas the low-risk group had a 57% reduction in the relative risk of distant relapse at 10 years.

Division of low-risk patients into ultralow-risk and low-but-not-ultralow (LNUL) groups showed that only the LNUL group benefited from extending adjuvant endocrine therapy beyond 5 years, reported Priya Rastogi, MD, at the University of Pittsburgh.

Assay-Informed Treatment De-Escalation?

Cardozo reported findings from a new analysis of the randomized, phase III MINDACT trial that established the 70-gene signature’s ability to risk-stratify patients by a tumor’s genomic signature. Moreover, the data showed that a substantial proportion of patients with clinically high-risk/genomic low-risk tumors could safely avoid chemotherapy.

MINDACT involved 6,700 patients with early-stage breast cancer: 1,000 patients with ultralow-risk tumors by the 70-gene assay, 3,300 with low-risk tumors, and 2,400 with high-risk tumors. The overall results showed an 8-year DMFI of 97.0% for the genomically ultralow-risk group, 94.5% for the low-risk patients, and 89.2% for the high-risk group. BCSS also was low for the three risk-stratified groups: 99.6%, 98.2%, and 93.7%. The ultralow-risk group had a significantly lower risk of distant metastasis or breast cancer death at 8 years versus low-risk patients (HR 0.65, 95% CI 0.45-0.94).

Cardozo and colleagues took a closer look at the ultralow-risk subgroup. Two thirds of the patients were older than 50, 80% had negative lymph nodes, 96% had grade 1 or 2 tumors, and 97% were hormone receptor-positive and HER2-negative. Additionally, 16% received no adjuvant systemic therapy, 69% received endocrine therapy, and 14% received chemotherapy.

The 1,000-patient ultralow-risk group included 259 patients with clinically high-risk tumors that tended to be larger, higher grade, and lymph-node positive, she said.

The 8-year BCSS and DMFI confirmed and expanded on the primary results of the MINDACT trial, said Cardozo. Comparison of treatment for the ultralow-risk group showed no difference in the risk of breast cancer death or distant metastasis on the basis chemotherapy (yes vs no, HR 0.98, 95% CI 0.37-2.61) or endocrine therapy (yes vs no, HR 0.59, 95% CI 0.27-2.13). Cardozo noted that 92% of patients who received chemotherapy had clinically high-risk tumors.

Extended Endocrine Therapy

Rastogi and colleagues’ retrospective study evaluated the impact of the 70-gene signature on extended aromatase inhibitor (AI) therapy in the randomized phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-42 trial. Patients with stage I-IIIa breast cancer and who were disease free after the standard 5 years adjuvant endocrine therapy were randomized to an additional 5 years of the AI letrozole or placebo.

After 7 years of follow-up, the results that 5 additional years of letrozole did not improve disease-free survival (DFS) or overall survival (OS) but did improve the breast cancer-free interval (BCFI) and reduced the risk of distant metastasis. After 10 years of follow-up, extended letrozole therapy was associated with significantly better DFS but not OS. The favorable effect on BCFI and distant metastasis persisted.

“Genomic classifiers that predict risk of late recurrence and/or benefit from extended endocrine therapy may further assist with the decision to recommend extended aromatase inhibitor therapy,” said Rastogi.

Limited to patients with available primary tumor tissue, the genomic analysis included 1,866 of the original 3,903 NSABP B-42 population and had a median follow-up of 10.4 years. The primary endpoint was distant recurrence and secondary endpoints were DFS and BCFI. Median follow-up was 10.4 years. The 70-gene signature classified 37.8% of the patients as high-risk and 62.2% as low-risk. The assay results classified the low-risk patients into ultralow-risk (13.5%) and LNUL (48.7%) groups.

Extended letrozole did not reduce the risk of distant recurrence in patients classified as high-risk by the gene assay. The 10-year risk was 4.9% with letrozole and 7.3% with placebo (HR 0.65, 95% CI 0.34-1.24, P=0.19). On the other hand, patients with a low-risk genomic assessment had a 10-year distant recurrence rate of 3.5% with extended letrozole and 7.2% with placebo, a statistically significant 57% reduction in the hazard ratio (95% CI 0.25-0.74, P=0.002). Low-risk patients also benefited from extended letrozole with respect to DFS events (P<0.001) and BCFI (P<0.001) but not high-risk patients.

The analysis of the low-risk subcategories showed that patients with ultralow-risk tumors did not benefit from extended letrozole, as the 10-year risk of distant recurrence was 2.9% with letrozole and 5.8% with placebo, a nonsignificant difference (HR 0.53, 95% CI 0.13-2.15, P=0.37). The LNUL group, however had a significantly lower risk of distant recurrence with extended letrozole (3.6% vs 7.6% with placebo; HR 0.42, 95% CI 0.23-0.76, P=0.003). The LNUL group, but not the ultralow-risk patients, also benefited from additional therapy with respect to DFS events and BCFI (P<0.001).

“These results have clinical implications for the utility of MammaPrint in patient selection for extended endocrine therapy,” said Rastogi. “Further confirmation in similar datasets of extended endocrine therapy would be important. Future analyses of the B-42 MammaPrint translational cohort incorporating clinical-pathologic characteristics, such as lymph node status, could further optimize patient selection.”