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CancerTYPE ID Study Underscores Value of Knowing Tissue of Origin Amid Tissue-Agnostic Approvals


NEW YORK – The US Food and Drug Administration's tissue-agnostic approval last month of Novartis' BRAF/MEK inhibitor drug combination has created a fresh dilemma for oncologists treating patients with cancers of unknown primary (CUP).

The FDA's approval means that any refractory patient with a BRAF V600E mutation-positive tumor can now try the Tafinlar (dabrafenib)/Mekinist (trametinib) combo as a last-ditch option. Given there are multiple tissue-agnostic treatments available in the refractory setting, it makes it more likely that these patients will be offered genomic profiling to gauge if they have any therapeutically actionable biomarkers.

The tissue-agnostic approval does not extend to the first-line metastatic cancer setting. However, many doctors may think that even if the tissue of origin is unknown for a CUP patient, as long as they harbor a BRAF V600E mutation, they can also receive Tafinlar/Mekinist. This is particularly problematic, since in CUP cases it is important to not only identify actionable biomarkers but also the primary site of the cancer to determine the most appropriate first-line therapy.

A timely study using Biotheranostics' CancerTYPE ID test combined with next-generation sequencing to identify patients with CUP who are eligible for treatment with BRAF inhibitors provides a roadmap for resolving this treatment dilemma.

CancerTYPE ID is a molecular cancer classifier developed by Biotheranostics, a subsidiary of Massachusetts-based Hologic, to identify the site of origin for metastatic cancers with unknown or uncertain diagnoses. It uses real-time PCR to measure the expression of 92 genes in the patient's tumor and matches the gene expression pattern to a database of known tumor types. According to Kai Treuner, senior director of oncology diagnostics at Biotheranostics, it has been used to analyze more than 32,000 patients to date.

In work presented at the American Society of Clinical Oncology's annual meeting in June, researchers from the Mayo Clinic and Biotheranostics were able to determine the tumor type in 92.5 percent of 3,168 diagnostically ambiguous cases. Of those, BRAF mutations were identified in 87 patients, accounting for 18 different tumor types.

At the time the abstract was submitted, 22 of those 87 cases had a tumor type eligible for an FDA-approved BRAF inhibitor such as melanoma, non-small cell lung cancer, colorectal adenocarcinoma, and thyroid cancer. Another 26 patients were eligible for ongoing clinical trials of BRAF inhibitors. Without identification of the site of origin and tumor biomarkers, those patients would not have been eligible to receive an FDA-approved BRAF inhibitor or enroll in a clinical trial.

Between 1 percent and 2 percent of individuals with metastatic cancer — or around 80,000 patients per year — have CUP. Anthony Greco, a medical adviser for CancerTYPE ID, said that much of what is known about CUP comes from autopsies.

"I've participated in close to 40 [autopsies] in 40 years, plus there are over 800 reported in the literature," said Greco. In about 75 percent of those cases, a small primary tumor is found, and Greco estimates that many of the remaining cases have tumors that are not discoverable on autopsy.

"These patients have a primary [cancer, but] it's just too small to find," he said. "Once you know what the tissue of origin is, for instance, by using CancerTYPE ID, you treat them the same way you would if you knew it from the beginning," Greco said.

This makes it important to evaluate patients' tumors for actionable biomarkers and site of origin, but in Greco's view, CancerTYPE ID is underutilized in CUP patients. For example, he said that about 4 percent of CUP patients end up with a melanoma diagnosis. In the study presented at ASCO, 17 patients turned out to have melanoma, and four out of the 17 also had a BRAF V600E mutation.

BRAF inhibitors are indicated for BRAF-mutated melanoma patients in the first-line setting, so they can receive these drugs. But according to Greco, without identifying these cancers as metastatic melanoma, the patients wouldn't have immunotherapy as a second-line treatment. Moreover, in patients with breast cancer, kidney cancer, or a number of other cancer types, even if they have a BRAF V600E mutation, a BRAF inhibitor may not be the preferred first-line therapy.

"Next-generation sequencing is often used, but CancerTYPE ID is not used," he reflected. "And then, if they find genetic alterations that they think are treatable, such as BRAF V600E mutations, many would go ahead and treat that patient because the FDA has now approved BRAF inhibitors for any solid tumor with metastatic cancer."

Prior to the advent of CancerTYPE ID, patients with ambiguous cancers or CUP would have been treated with empiric chemotherapy, such as taxanes, platinum, gemcitabine, cisplatinum, and carboplatinum. But once the site of origin is identified, these patients are now eligible for targeted drugs or immunotherapy.

"What's happened over the past several years is that many advanced cancers have become much more treatable, not only because of better chemotherapy, but because of targeted drugs which can be used to treat genetic abnormalities like BRAF V600E, for example," said Greco. "And immunotherapies become extremely important for many advanced cancer patients. But you need to know what type of cancer a patient has in order to give them optimal, first-line precision therapy."

While the original purpose of the study presented at ASCO was to enable access to FDA-approved BRAF inhibitors and clinical trials for patients with ambiguous diagnoses and CUP, the subsequent tissue-agnostic approval of the Tafinlar-Mekinist combo has further underscored the benefit of combining cancer type identification with NGS profiling for those patients — especially for ruling out when the BRAF/MEK inhibitor should not be the first choice. For example, BRAF V600E-mutated colorectal cancers are unresponsive to BRAF and MEK inhibitor combination therapy. Patients with V600E-mutated CUP whose disease is determined to be colorectal cancer should be treated with a standard chemotherapy regimen, or, if microsatellite instability (MSI) is present, immune checkpoint inhibitors.

An important part of making this connection for this patient group is the Molecular Synergy to Advance Individualized Cancer Care (MOSAIC) database. MOSAIC is a de-identified database of CUP and diagnostically ambiguous cases with CancerTYPE ID testing plus tumor type-guided multimodal biomarker testing.

"MOSAIC was formed with the goal of building a comprehensive database that includes CancerTYPE ID test results, molecular profiling, patient demographics, and clinicopathological information, all of which could be leveraged by Biotheranostics to conduct research projects that will further advance our understanding of cancers with diagnostic uncertainty," said Treuner.

MOSAIC includes over 3,000 cases and continues to grow as new cases are submitted for testing. Biotheranostics does not allow commercial access to MOSAIC at this time but is using it for research, such as determining the frequency of specific molecular alterations in identified tumor types that originally presented with diagnostic uncertainty. In those studies, biomarker-directed treatment options have been identified based on the patient's tumor type and molecular testing.

Treuner said that the expansion of the MOSAIC database depends on submission of patient samples for CancerTYPE ID testing, which currently is only a fraction of the total number of cases that could benefit. "One challenge that persists is increasing awareness of CancerTYPE ID and adoption into routine clinical care for patients with cancer of unknown origin or diagnostic uncertainty," said Treuner.

Greco reiterated his worry that the trend toward tumor-agnostic approvals in precision oncology could mislead oncologists into a belief that identifying the site of the cancer no longer matters. "That is an error in thinking. We need to know what type of cancer the patient has," he said. "You can just use comprehensive molecular profiling … without knowing what the tissue of origin is in this group of patients. If you do, you can make some major inappropriate first-line therapy decisions because you don't treat everyone with every type of cancer based on genetic abnormalities."