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Liquid Biopsy Study Investigates Treatment for Breast Cancer Patients With Acquired HER2 Mutations

NEW YORK – Although HER2 testing has been part of the repertoire from the early days of precision medicine, investigators are still making inroads into how alterations of the gene can inform individualized treatment. One recent exploration, published last month in NPJ Precision Oncology, found that blood-based testing can pick up HER2 mutations that emerge, or proliferate, in later-stage refractory breast cancer and might confer sensitivity to new anti-HER2 drugs.

In the study, investigators from Massachusetts General Hospital used a liquid biopsy assay — blood-based cancer DNA analysis — to detect and track the emergence of HER2 and other mutations in a group of 143 women with endocrine-resistant metastatic breast cancer.

Although the advent of effective endocrine-based therapies has led to significantly improved survival in women with hormonally sensitive breast cancer, endocrine resistance eventually develops, fueling progression, the authors wrote.

In other advanced cancer settings, strategies to re-profile the molecular landscape of the tumor to identify new treatment targets for patients who are developing resistance to their current therapy are becoming more frequent.  Emerging resistance mutations in EGFR in lung cancer, for example, can help identify patients who need to switch to a second- or third-generation drug.

But according to the study authors, on-treatment tumor sampling in hormone receptor-positive breast cancer has been limited because patients usually harbor metastases that are difficult or impossible to access. Added to that, molecular pathways that drive therapeutic resistance in metastatic breast cancer are seldom druggable, at least thus far.

Emerging liquid biopsy techniques not only offer a solution for the former problem but also open new opportunities to conduct efficacy studies for new treatments, the MGH group proposed.

While liquid biopsy testing can identify a variety of potentially actionable biomarkers — as demonstrated in the team's study — the investigators chose to focus on HER2 alterations, which they saw in about 8 percent of the cohort.

"With the advent of TKIs such as neratinib that can target HER2 mutant breast cancer, there is increasing interest in this topic as it is an actionable finding," Aditya Bardia, the study's senior author and a medical oncologist at MGH, said in an email this week.

One challenge in trying to bring liquid biopsy findings to bear on patient treatment, though, is that mutations are often present in only some of a patient's cancer cells. As such, they may or may not be functioning as enough of a driver of the disease that targeting them will be effective.

Of the 11 unique HER2 mutations the team saw in their study, eight had been previously reported in cancer, while three were novel. Besides the HER2 mutations, there were also multiple coexisting mutations, including in ESR1, TP53, and PIK3CA.

The investigators decided that functional validation could help glean whether a patient with a blood-borne mutation, even one appearing subclonally, might be treatable. Taking HER2 as their test case, the researchers isolated circulating tumor cells from one of the study patients with a microfluidic technology called the CTC-iChip, created an ex vivo cell culture, and tested therapies against it.

In the dish, the patient's cancer cells showed resistance to multiple targeted drugs, including endocrine and CDK 4/6 inhibitors, but high sensitivity to the anti-HER2 therapy neratinib (Puma Biotechnology's Nerlynx).

Based on this evidence, the researchers decided to look at the treatment outcome of other patients from the cohort with HER2 mutations. In one index patient who was treated with neratinib, the investigators saw "significant clinical response, with complete molecular resolution of two distinct clonal HER2 mutations."

The patient remained in prolonged partial remission for more than a year.

Drug efficacy data was only available for this one study subject with a HER-2 mutation, even though others received the drug. A second individual got neratinib but deteriorated too quickly to have more than a few doses, while a third had started treatment but hasn't been followed long enough to analyze the results. The authors wrote that the positive response seen in that one individual still makes a strong case for the clinical potential of this type of blood-based testing, both in the context of anti-HER2 therapy and across the expanding menu of molecularly targeted drugs.

"When patients progress, we can learn a lot from taking blood samples and re-sequencing them to look for new driving mutations," Bardia wrote. "As we demonstrated in this paper, we may identify mutations which confer a new vulnerability and an actionable target."

The index patient that the MGH team reported on was treated with neratinib as part of an IRB-approved basket clinical trial. The drug isn't currently approved for use in HER2-mutated metastatic breast cancer, only for adjuvant treatment of patients with early-stage disease with overexpressed or amplified HER2.

Puma Biotechnology said this July, though, that it was submitting a supplemental new drug application to the US Food and Drug Administration for neratinib in combination with capecitabine for the treatment of patients with HER2-positive metastatic breast cancer who have progressed on at least two prior HER2-targeted treatments.

The drug is also being used in tumor-agnostic basket trials to treat patients with advanced solid tumors, regardless of where they occur in the body, with the potential to garner a pan-cancer indication if these studies bear fruit.

Bardia wrote that this ongoing work will hopefully provide confirmation for what the team saw in their analysis. In the meantime, he added, the team's report provides strong evidence that blood-based DNA testing may help identify otherwise inaccessible actionable mutations — whether in HER2 or other targets — and be a useful tool for triaging patients for genotype-directed clinical trials.

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