Utility of the 70-Gene MammaPrint Assay for Prediction of Benefit From Extended Letrozole Therapy in the NRG Oncology/NSABP B-42 Trial

Author(s): Priya Rastogi, MD^1,2; Hanna Bandos, PhD^3,4; Peter C. Lucas, MD, PhD¹; Laura J. van ‘t Veer, PhD⁵; Jia-Perng J. Wei, MD, PhD⁵; Charles E. Geyer, Jr, MD¹; Louis Fehrenbacher, MD⁶; Stephen K.L. Chia, MD⁷; Adam M. Brufsky, MD, PhD^1,2; Janice M. Walshe, MD⁸; Gamini S. Soori, MD⁹; Shaker R. Dakhil, MD¹⁰; Soonmyung Paik, MD^11,12; Sandra M. Swain, MD¹³; Andrea R. Menicucci, PhD⁵; M. William Audeh, MD⁵; Norman Wolmark, MD¹; Eleftherios P. Mamounas, MD¹⁴

Source: https://doi.org/10.1200/JCO.23.01995

Dr. Maen Hussein's Thoughts

MammaPrint did not predict distant recurrence, but it did predict patients who may benefit from extended hormonal therapy. We do have breast index, so now we have options. Breast index can predict the possibility of recurrence though by helping to determine the level of risk.

PURPOSE

MammaPrint (MP) determines distant metastatic risk and may improve patient selection for extended endocrine therapy (EET). This study examined MP in predicting extended letrozole therapy (ELT) benefit in patients with early-stage breast cancer (BC) from the NSABP B-42 trial.

PATIENTS AND METHODS

MP was tested in 1,866 patients randomly assigned to receive ELT or placebo. The primary end point was distant recurrence (DR). Secondary end points were disease-free survival (DFS) and BC-free interval (BCFI). Tumors were classified as MP high risk (MP-HR) or low risk (MP-LR). MP-LR tumors were further classified as ultralow risk (MP-UL) or low non-ultralow risk (MP-LNUL).

RESULTS

There was no statistically significant difference in ELT benefit on DR between MP-HR and MP-LR (interaction P = .38). MP-LR tumors (n = 1,160) exhibited a statistically significant 10-year benefit of 3.7% for DR (hazard ratio [HR], 0.43 [95% CI, 0.25 to 0.74]; P = .002), whereas MP-HR tumors (n = 706) exhibited a nonsignificant 2.4% benefit (HR, 0.65 [95% CI, 0.34 to 1.24]; P = .19). The 10-year ELT benefit was significant for DFS (7.8%) and BCFI (7.0%) for MP-LR tumors, whereas MP-HR tumors did not significantly benefit (interaction DFS: P = .015, BCFI: P = .006). In exploratory analysis, the 10-year ELT benefit was significant and more pronounced in MP-LNUL (n = 908) tumors: 4.0% for DR, 9.5% for DFS, and 7.9% for BCFI; the benefit in MP-UL (n = 252) tumors was not significant: 3% for DR, 1.8% for DFS, and 4.1% for BCFI.

CONCLUSION

The primary hypothesis of predictive ability of MP on DR was not confirmed. However, the secondary outcomes demonstrated MP was predictive of ELT response and identified a subset of patients with early-stage hormone receptor–positive BC (MP-LR) with improved outcomes from ELT. These data could have important clinical implications in patient selection beyond clinical risk assessment for EET.

Author Affiliations

¹UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA; ²Magee-Women’s Hospital, Pittsburgh, PA; ³NRG Oncology SDMC, Pittsburgh, PA; ⁴University of Pittsburgh, School of Public Health, Pittsburgh, PA; ⁵Agendia, Inc, Irvine, CA; ⁶Kaiser Permanente Oncology Clinical Trials Northern CA, Novato, CA; ⁷British Columbia Cancer Agency, Vancouver, BC, Canada; ⁸Cancer Trials Ireland, and St Vincent’s University Hospital, Dublin, Ireland; ⁹Florida Cancer Specialists, Fort Myers, FL; ¹⁰Wichita NCORP, Via Christi Regional Medical Center, and Cancer Center of Kansas, Wichita, KS; ¹¹Theragenbio, Inc, Pankyo, Republic of Korea; ¹²Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; ¹³Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC; ¹⁴Advent Health Cancer Center, Orlando, FL

First-Line Camizestrant for Emerging ESR1-Mutated Advanced Breast Cancer

Our site participated in this study, where patients were tested for ESR1 mutations via circulating tumor DNA (ctDNA). Those who tested positive were switched to camizestrant (Cami), which demonstrated improved progression-free survival.

Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer

Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly utilizes the ubiquitin–proteasome system. It was compared to fulvestrant in patients who had received one prior line of hormonal therapy with a CDK4/6 inhibitor. Among patients with ESR1 mutations, Vepdegestrant demonstrated a median progression-free survival (PFS) of 5.0 months versus 2.1 months with fulvestrant. In the overall population, the median PFS was 3.8 months for Vepdegestrant and 3.6 months for fulvestrant, indicating that the drug showed particular efficacy in tumors harboring ESR1 mutations.

Elinzanetant for Vasomotor Symptoms from Endocrine Therapy for Breast Cancer

Elinzanitant, a neurokinin-targeted therapy, has been shown to reduce vasomotor symptoms compared to placebo. These symptoms are one of the reasons some of my patients discontinue aromatase inhibitor (AI) therapy, so Elinzanitant presents a promising alternative to help manage these side effects. Additionally, Fezolinetant is already approved and available on the market.

Overall Survival with Inavolisib in PIK3CA-Mutated Advanced Breast Cancer

The INAVO120 trial evaluated inavolisib + palbociclib–fulvestrant vs placebo + palbociclib–fulvestrant in patients with PIK3CA-mutated, HR+/HER2– advanced breast cancer progressing on or shortly after adjuvant endocrine therapy (ET). Inavolisib significantly improved overall survival (OS) (34.0 vs 27.0 mo) and progression-free survival (PFS) (17.2 vs 7.3 mo), with a higher objective response rate (ORR) (62.7% vs 28.0%) and longer DoR (19.2 vs 11.1 mo). Toxicities were manageable but included more hyperglycemia (63.4%), stomatitis (55.3%), GI, and ocular AEs. Bottom line: this triplet sets a new bar for first-line PIK3CA-mutant HR+ MBC, but we’ll need to stay vigilant about metabolic and mucosal side effects as we bring it into practice.

Second-Line Endocrine Therapy With or Without Palbociclib Rechallenge in Patients With Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: PALMIRA Trial

Adding Palbociclib did not help, revealing that there is no need to continue with different hormonal therapy than the one used in first line. It also added more toxicity.