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Breast Cancer Genomics Studies Home In on Intra-Patient Heterogeneity, Racial Gaps


NEW YORK – At the American Society of Clinical Oncology's annual meeting this week, studies highlighted the importance of genomic sequencing of primary and metastatic tumors when deciding appropriate breast cancer treatment and enabling equitable access to precision oncology drugs and clinical trials.

At the meeting, researchers presented studies in which they explored the genomic heterogeneity in breast cancer using different testing modalities, between racial groups, and between primary breast cancer tumors and metastatic lesions.

This research comes at a time when the field's longstanding framework for breast cancer subtyping — characterizing tumors based on whether they're driven by estrogen receptors (ER), progesterone receptors (PR), or HER2 overexpression — is in flux due to the availability of new precision medicines like AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan).

At this meeting a few years ago, the drugmakers showed that Enhertu has activity in breast cancer patients with low HER2 expression, a subset that previously would have been classified has HER-negative and ineligible for HER2-targeted therapy. At this year's meeting, AstraZeneca and Daiichi Sankyo reported that their antibody-drug conjugate appears to work against breast cancers with ultralow HER2 expression, a finding that will challenge pathologists and oncologists as they try to identify patients most likely to benefit from Enhertu and spur new biomarker testing approaches.

One testing approach studied by a research team led by Carolina Schröder, a breast medical oncologist at the University Medical Center Groningen in the Netherlands, involved whole-body assessment of HER2 expression by PET imaging. At the meeting, Schröder said she was surprised by the amount of disease heterogeneity identified in her group's study.

"We've seen the heterogeneity's effect on treatment outcomes," Schröder said. "It's really naïve to think that when you biopsy one lesion that you can disregard the rest of the lesions. We should take into account this spatial heterogeneity because patients with homogeneous disease perform really differently from the ones with heterogeneous disease."

Whole-body HER2 imaging

Two studies presented at ASCO examined the genomics of metastatic lesions in breast cancer. One focused specifically on genomic alterations within brain metastases in breast cancer patients, and the other employed PET imaging to evaluate HER2 and ER status in the whole body.

The PET imaging trial, called IMPACT-MBC, used 18F-fluoroestradiol(18F-FES)-PET and Zirconium-89(89Zr)-trastuzumab-PET scan techniques to visualize ER and HER2 status in metastatic lesions throughout the whole body and inform treatment decisions.

The researchers compared patients' outcomes on treatments selected with the help of whole-body PET imaging or based on standard immunohistochemistry testing that gauged the biomarkers in a biopsy taken from one metastatic lesion. Out of 200 newly diagnosed breast cancer patients in the trial, 174 patients received treatment based on IHC testing of biopsy samples and 26 received treatment based on the PET results. The researchers found that IHC and PET results were discrepant in determining HER2 or ER subtypes for 52 patients (26 percent).

Those with concordant HER2-positive results based on IHC and PET imaging, and who received anti-HER2 therapy (29 patients), had a median progression-free survival of 23.2 months and median overall survival of 41.7 months. However, those who were HER2-positive by IHC but HER2-negative by PET imaging (5 patients) had worse outcomes on standard HER2 treatment with a progression-free survival of 4.5 months and overall survival of 19 months.

"[This discrepancy] affected outcomes. With a positive HER2 biopsy and standard HER2-targeting treatment, patients with a positive HER2 PET scan had a significantly better progression-free survival and overall survival than patients with a negative HER2 PET scan," Schröder said in a presentation of the IMPACT-MBC results. "This [outcome] was similar for the FES-PET scan [to determine ER status], but discrepancies for ER disease were less common than HER2 disease."

Patients' outcomes on HER2 therapy also differed if they had a HER2-negative IHC result but a HER2-positive PET scan. Among the 21 patients who received HER2-targeted therapy based on the PET scan despite having a negative IHC result, median progression-free survival was 11.4 months and median overall survival was 32.9 months. Those who didn't get an anti-HER2 therapy based on PET imaging (14 patients) had poorer outcomes with 7.4 months median progression-free survival and 25.6 months median overall survival.

Schröder suggested that the outcomes seen in patients that received HER2-PET-guided treatment points to a "novel target" in breast cancer. However, she noted that PET-guided treatment was optional in this trial, and the observed benefits would need to be validated in a larger, randomized study. Her team is also trying to establish thresholds for levels of PET imaging-based HER2 expression associated with outcomes and exploring the cost-effectiveness of this approach.

"The biopsy does not reflect the whole-body HER2 or ER subtype in over a quarter of patients, and this discrepancy profoundly affects progression-free survival and overall survival," she said. "For clinical practice and research, we should reconsider [having] one metastasis biopsy as the standard in metastatic breast cancer and incorporate the whole-body context to avoid over and undertreatment."

Subtyping brain metastasis

In another study, researchers explored only brain metastasis in breast cancer and also identified discrepancies in the genomic profile between the brain lesions and the primary tumor.

"While it's well known that late-stage cancers tend to acquire genomic alterations over the disease evolution, the specific interplay mediating the development of brain metastases is still obscure," Dharmini Manogna, a medical oncology fellow at Tulane University School of Medicine, said during a presentation at ASCO.

Manogna and her colleagues conducted a retrospective analysis of more than 14,000 breast cancer samples, including 429 samples from lesions that had spread to the brain, 5,808 samples from primary tumors, and 7,858 samples from other metastatic sites. They analyzed DNA, RNA, tumor mutational burden (TMB), PD-L1 expression, loss of heterozygosity, and molecular breast cancer subtypes across these samples.

The brain metastases samples were more likely to be triple-negative cancer than either the primary or other metastatic samples, which were more frequently HR-positive, HER2-negative. Brain metastases samples were also more likely to have a basal-like or HER2-enriched subtype than the samples from other areas.

Certain molecular alterations were more common in brain metastases samples than primary or other metastatic sites. In the HR-positive, HER2-negative subgroup, ESR1 and GATA3 mutations were more frequent in brain metastases samples than in the others. Across all subtypes, loss of heterozygosity was higher in brain metastases samples and both PD-L1 and androgen receptor expression was lower. Brain metastases samples were also more frequently TMB-high than the other samples.

"Brain metastases in breast cancer more frequently have aggressive variants such as [in] the triple-negative subtype and basal-like phenotype," Manogna said. "There was also an indication towards an immunosuppressive tumor microenvironment [in brain metastases]."

Manogna added that large randomized clinical trials focused on the molecular characteristics of brain metastases in breast cancer are needed. For example, trials could compare the biomarkers in circulating cell-free DNA in cerebrospinal fluid against liquid biopsy ctDNA, Manogna suggested.

Racial gaps in treatment access, trials

In another retrospective cohort study presented at ASCO, researchers evaluated genomic differences between Black and White breast cancer patients and the impact of these biomarker differences on patients' outcomes to targeted therapies like PI3K, CDK4/6, and mTOR inhibitors.

The analysis included 708 White and 87 Black breast cancer patients. Researchers led by Emily Podany, a hematology/oncology fellow at Washington University in St. Louis, gauged circulating tumor DNA (ctDNA) in liquid biopsy samples and considered them alongside other patient data in medical records.

There were some genomic differences found between Black and White patients. In the ER-positive, PR-negative, HER2-negative group, Black patients were more likely to have CCND1 copy number variations. In the ER-positive, PR-negative, HER2-negative subtype, Black patients were more likely to have a GATA3 mutation, while White patients were more likely to have a KRAS mutation.

The researchers found inequities in clinical trial enrollment and the proportion of patients who received a targeted treatment with Black patients being underrepresented in both. One area where the inequity was significant was among patients with PIK3CA variants. There was no racial difference in the proportion of patients who harbored these mutations, but only 5.9 percent of Black patients with these variants received a PI3K inhibitor compared to 28.8 percent of White patients. Moreover, no Black patients enrolled in a clinical trial based on this biomarker versus 11.5 percent of White patients.

"There were no significant differences in the use of CDK4/6 inhibitors and mTOR inhibitors, which do not require a specific mutation found on ctDNA," Podany said. "In this retrospective study, we found these clinical inequities both in the use of PI3K inhibitors in Black patients with metastatic breast cancer and also inequities in the enrollment in clinical trials for Black patients with PIK3CA mutations."

Podany noted that her team will further explore the reasons behind the inequity in biomarker-directed targeted therapy use and clinical trial enrollment. She said they are collecting data on comorbidities that may affect which patients can receive targeted therapy and are hoping to survey and conduct future research to identify the social determinants of health in these patients.