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Breast Cancer Genomics Study Reveals Recurrent Contributors to Treatment Resistance in Early Disease

NEW YORK – Early-stage estrogen receptor (ER)-positive breast cancers that become resistant to treatment tend to share certain characteristics or pathway alterations, according to a new study that used single-cell sequencing to interrogate tumor samples collected over time from patients on treatment.

"These analyses demonstrate multiple convergent phenotypes conveying resistance to combination therapy," co-senior and co-corresponding authors Andrea Bild, a researcher at the City of Hope National Medical Center, and Qamar Khan, a researcher at the University of Kansas Medical Center, and their colleagues wrote in a study appearing in Nature Cancer on Thursday.

In an effort to understand early-stage breast cancer evolution following treatment, the researchers performed exome sequencing and single-cell RNA sequencing, or scRNA-seq, on serially-collected biopsies from dozens of women with ER-positive breast cancer after treatment with letrozole (Novartis' Femara) endocrine therapy, either on its own or in combination with high or low doses of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib (Kisqali from Novartis).

"[O]ur analysis identifies mechanisms of how tumors circumvent endocrine and CDK4/6 inhibition through phenotypic and subclonal evolution," the authors wrote. "These mechanisms include shifts to alternative proliferative signaling pathways, bypassing dependence on ER and CDK6 activation."

Starting with samples from 60 postmenopausal breast cancer patients with early-stage ER-positive forms of the disease from the FELINE clinical trial, the researchers narrowed in on the subset of cases with sufficient sample and sequence quality, ultimately considering scRNA-seq profiles for almost 176,700 individual cells isolated from 34 ER-positive breast cancer patients, as well as exome sequencing profiles on bulk tumor and blood samples for 24 of the patients.

Patients in the study had breast tumors that exceeded a certain size or had spread to the lymph nodes at the time of diagnosis but lacked enhanced HER2 activity, the authors explained, noting that the analyses were intended to understand whether resistance to endocrine and CDK4/6 inhibitors in early-stage disease were similar to those previously described in metastatic cases.

The analyses focused on tumor features linked to treatment response or resistance over time — based on imaging, ultrasound, mammogram, and physical exam data — in patients undergoing six months of treatment on one of three protocols: letrozole aromatase inhibitor plus placebo, letrozole with intermittent high-dose ribociclib, or a combination of continuous low-dose letrozole and ribociclib.

"This approach provides a method to detect resistance mechanisms early in cancer treatment to identify phenotypic targets directed at surviving tumor subclones in tumors," the authors explained.

Along with recurrent gene and pathway mutations, copy number changes, and mutational signatures identified in the ER-positive breast cancer subtype in the past, the investigators narrowed in on tumor subclones and cancer cell phenotypes that appeared to become more pronounced in samples from some patients over time.

"Despite differences in subclonal diversity evolution across patients and treatments, common resistance phenotypes emerged," they reported.

When it came to cases treated with both letrozole and ribociclib, for example, the team flagged estrogen signaling loss, shifts to low estrogen-responsive states, enhanced JNK mitogen-activated protein kinase, or MAPK, signaling, and a jump in basal-like tumor attributes as key treatment resistance-related features.

Molecular features such as enhanced ERBB4 signaling, related extracellular signal-regulated kinase MAPK upregulation, and CDK4/6 activation or amplification — among other changes — tended to turn up in tumors with persistent estrogen signaling after letrozole or letrozole plus ribociclib treatment.

Given the apparent ties to treatment response, the researchers suggested that tumor features such as altered JNK pathway activation, endocrine signaling patterns, and basal-like tumor features may eventually prove useful as biomarkers for guiding the treatment of some early-stage breast cancers.

"Our results demonstrate that information beyond proliferation can be learned from early biopsies in neoadjuvant therapy trials," the authors wrote.

"Given the potential for additional therapy to increase selective pressure," they added, "it will be imperative to rationally determine optimal dosing and timing of drug treatment regimens to reverse or prevent a resistant state, while minimizing side effects."

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