Houston Methodist Researchers Pioneer New Treatment Strategies for Metaplastic Breast Cancer

Houston Methodist Hospital researchers have identified a promising therapeutic approach for metaplastic breast cancer (MpBC), a rare and aggressive subtype of triple-negative breast cancer with the worst prognosis among all breast cancers globally.

The study, recently published in Nature Communications, demonstrates that inhibiting nitric oxide synthase (NOS) sensitizes MpBC to taxane-based chemotherapy and PI3K inhibitors, altering the cellular makeup of the tumors and substantially improving survival in preclinical models.

"This study provides insight into the mechanisms driving treatment resistance in metaplastic breast cancer — namely the heterogeneous makeup of the tumors and ability of the cancer cells to differentiate from mesenchymal to epithelial components — and identifies a promising therapeutic strategy to bypass this defense," said Dr. Tejaswini Reddy, a recent Houston Methodist graduate research fellow and the study's co-first author.

MpBC represents less than 5% of all breast cancer cases and is characterized by high chemoresistance and poor prognostic outcomes, with survival rates often below a year in metastatic cases. This study addresses the significant therapeutic gap in managing this subtype.

"Metaplastic breast cancer poses unique challenges due to its undifferentiated tumor cells, which render standard therapies largely ineffective," said Dr. Akshjot Puri, a Houston Methodist breast medical oncologist and study co-first author. "Our research focuses on developing targeted strategies to overcome this resistance."

Dr. Reddy, now a resident physician at Baylor College of Medicine, and Dr. Puri conducted the research in the lab of Dr. Jenny Chang, director of the Houston Methodist Neal Cancer Center.

A comprehensive approach

The study is notable for its comprehensive approach, featuring contributions from more than 25 researchers nationwide (including 14 at Houston Methodist) and incorporating advanced multiomic analyses, patient-derived xenograft (PDX) models and rigorous in vitro experiments.

The researchers examined a wide range of breast cancer subtypes, confirming the co-activation of NOS and PI3K pathways specifically in MpBC.

The robust methodology, depth and scope of the study allowed the team to validate their findings across multiple platforms, ensuring the reliability of the results and their relevance to clinical applications.

The study highlights NOS inhibition as a critical mechanism to counteract MpBC's resistance to therapy.

Using the NOS inhibitor L-NMMA, researchers demonstrated the reversal of epithelial-to-mesenchymal transition (EMT), a process that contributes to tumor invasiveness and chemoresistance.

The combination of NOS inhibition with the PI3K inhibitor alpelisib and taxane chemotherapy enhanced treatment efficacy.

Identifying therapeutic potential

The study builds on earlier breakthrough trials conducted at Houston Methodist, where L-NMMA combined with taxane chemotherapy demonstrated clinical activity in heavily pretreated triple-negative breast cancer patients. Among 15 MpBC patients within the trial, the combination therapy achieved a 23% overall response rate, median progression-free survival of four months and overall survival of a year.

"Although these results were already unprecedented in that population, we wanted to see if we could do even better," said Dr. Puri. "What Dr. Reddy did that was so instrumental was to figure out that PI3K mutation is present in almost 50% of metaplastic breast cancer cell lines. That was something that was not known beforehand, and it showed us the therapeutic potential of combining NOS and PI3K inhibition."

These findings informed the design of the preclinical study and the ongoing phase II trial led by the Houston Methodist clinical research team.

"We have accrued 10 patients now, and we plan to enroll at least 10 more, but already our early trial data show that incorporating the PI3K inhibitor alpelisib into the regimen has significantly improved response rates and durability," Dr. Puri said.

Preliminary results from the phase II trial, which were presented at the American Association for Cancer Research in 2024, indicate a clinical benefit rate of 70%, with some responses extending well beyond six months. These findings mark a substantial improvement in outcomes for this patient population.

Translational prowess

This research underscores Houston Methodist's role as a leader in translational cancer research. In particular, the institution's expertise in NOS inhibition has paved the way for innovations in treating not just MpBC but other types of triple-negative breast cancer and other challenging cancers.

"It's rewarding to see years of basic science research, under the leadership of Dr. Jenny Chang, translate into clinical trials that are making a real difference in patients' lives," said Dr. Reddy. "The integration of preclinical and clinical efforts has been critical in developing this innovative approach."

Future directions include optimizing the combination therapy to minimize side effects, such as hyperglycemia associated with alpelisib, and exploring more tolerable PI3K inhibitors.

"Our ultimate goal is to establish a new standard of care for metaplastic breast cancer, so that we finally have a viable treatment strategy for one of our most challenging malignancies to treat," said Dr. Puri.

Study co-authors include researchers from Emory University, the National Cancer Institute, MD Anderson Cancer Center and the University of Texas Health Science Center, among others.