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Targeted NGS Identifies 'Potentially Treatable' Alterations in 90 Percent of Residual Breast Cancers

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Using targeted next-gen sequencing, a team led by researchers from Vanderbilt University has identified targetable molecular lesions in 90 percent of chemotherapy-resistant triple-negative breast cancers, but they caution the results don't mean most patients will see immediate benefits from such testing going forward.

"At this point, this information is not for use in a practice setting; however, as an extension of this [study], we now profile all our [triple-negative breast cancer] patients that have residual disease," said Carlos Arteaga, senior author of the study and a professor of medicine and cancer biology and director of the breast cancer program at the Vanderbilt-Ingram Cancer Center.

The results of the study, which used Foundation Medicine's targeted NGS test, were published online in Cancer Discovery last month.

For their study, which analyzed tumor samples from women who were treated in the early 2000s and had since died, the researchers used targeted NGS and digital RNA expression to profile more than 70 chemotherapy-resistant triple-negative breast cancers that were surgically removed after neoadjuvant chemotherapy. In addition, they profiled matched pre-treatment biopsies of 20 tumors by NGS to see how the tumors had changed during therapy.

Triple-negative breast cancers – tumors that do not express estrogen receptor, progesterone receptor, or human epidermal growth factor 2 – are often treated with neoadjuvant chemotherapy before surgery in order to make the surgery less invasive and to kill silent micro-metastases.

About 30 percent of patients have what is called a "pathological complete response," along with a good prognosis in terms of recurrence and survival. The other 70 percent retain residual disease in their breast or lymph node, are likely to develop metastases, and have poorer survival.

The standard of care for these patients is observation because doctors don't know what treatment might kill the micro-metastases they are likely to carry.

The researchers hoped to find genetic lesions in their residual tumors — which they assume are also present in their micro-metastases — that could be targeted by therapies.

"The idea is to gain intelligence on the cancer by interrogating that residual disease and to start thinking about adjuvant trials with a targeted therapy in the immediate post-operative setting, based on the information from these cancers," Arteaga told Clinical Sequencing News.

Using Foundation Medicine's NGS test, which the company offers as a service, the Vanderbilt team sequenced 182 oncogenes and tumor suppressor genes as well as 37 introns in 14 genes frequently rearranged in cancer in 81 formalin-fixed paraffin-embedded cancers, at a mean depth of coverage of 609x. After excluding several samples for lack of coverage or because they had amplified HER2 genes, they analyzed the data from 74 tumors.

They classified their molecular alterations into a number of clinically targetable pathways or functional groups: those associated with cell cycle alterations, PI3K/mTOR alterations, growth factor receptor amplifications, Ras/MAPK alterations, or DNA repair alterations.

Ninety percent of the tumors had a genetic alteration that is "potentially treatable with a currently available targeted therapy," they wrote, and could be exploited as targets in adjuvant trials after surgery, instead of just observing the patients.

Arteaga cautioned, though, that this does not necessarily mean there will be new treatment options for most patients immediately. "They have an alteration for which, based on our knowledge of the basic science of that alteration, we can make a good inference that it may generate dependence of that cancer on that target, against which we have a drug," he explained. "That drug, more than likely, is not approved but is in development."

"There are going to be different shades of 'targetable'," with different meanings, he explained. Targetable could mean the alteration is an indication for an approved therapy, but it may only be approved for another type of cancer. For example, antibodies targeting the EGF receptor are approved for colon but not breast cancer. It could also mean that a patient is eligible for enrollment into a clinical trial for a drug that is still in development.

"It's something that requires some careful explanation because most patients are going to say, 'Oh, you can treat me and can cure me now.' Well, that's not it," he said.

Following the results of the study, Vanderbilt has been offering molecular profiling by Foundation's test to all triple-negative breast cancer patients with residual disease. So far, "very few" have undergone testing, and it's too early to say for how many it has made a difference in their treatment, Arteaga said.

For some patients, the information may not be relevant until several years after their surgery because therapies that can target their tumor's lesion are still in development, for example drugs targeting the FGF receptor. "We say, 'Look, this is like a life insurance policy you're buying. You're buying information that you may need in the future, because some of these alterations are going to have an approved drug down the road," he said.

Other patients are already enrolled in a clinical trial for a new compound, and their treatment after surgery is determined by that. For them, the molecular profile will not make a difference, at least not in the short term. "Our plan is, if those patients recur … to interrogate that recurrence, which you are going to have to biopsy anyway, and look for concordance," he said.

For a small number of patients, the test could have an immediate impact, though. In their study, the researchers found a few chemotherapy-resistant tumors with amplifications in the HER2 gene that were not present in the primary tumor. Patients like that could receive HER2 therapies after surgery. "Even though they have no clinical disease, we're assuming they have micrometastatic disease," Arteaga said. "When we treat it when it's micro, we are going to have a much bigger impact than when it's macro."

While Foundation Medicine has been a good partner for now, offering "what I think is one of the most advanced next-gen seq methods out there," Arteaga said, Vanderbilt is currently setting up its own laboratory to offer similar targeted NGS testing in-house. This, he said, will be "more practical" and might reduce costs.

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