Germline Testing: Variant in 1 in 6 Cases of Advanced Cancer

Pam Harrison

June 22, 2021

For patients with advanced solid tumors, the rate of detection of pathogenic germline variants (PGV) that are therapeutically relevant is high enough to justify a new recommendation — that all such patients should undergo germline testing, the authors of a new study suggest.

"With nearly 1 of every 6 patients in this cohort having a PGV identified, many of which are of therapeutic importance, we conclude that directed germline testing should be considered in all patients with advanced cancer," say the study authors, Erin Cobain, MD, and Arul Chinnaiyan, MD, PHD, University of Michigan, Ann Arbor.

In addition, they argue for next-generation sequencing (NGS) profiling for patients with carcinoma of unknown primary origin (CUP), as this also provides significant clinical benefit. Over half of CUP tumors in the analysis were reclassified to a specific cancer diagnosis and subsequently treated with standard-of-care therapy, the same study indicates.

The study was published online in JAMA Oncology in February, but there have been a number of comments and responses to the findings — not all of them agreeing with the authors conclusions — that were published online in the same journal last week.

Concerns Over Generalizability of the Findings

One of the responses, from a group in Australia, raises "concerns regarding the generalizability" of the findings, and in particular, the expansive recommendation for "directed germline testing in all patients with advanced cancer."

The authors of that response, Catherine Dunn, MBBS, Lucy Gately, MBBS, PhD, and Peter Gibbs, MBBS, MD, all from the Walter and Eliza Hall Research Institute in Melbourne, Australia, question whether this approach is ready for "prime time."

First, they argue, the current analysis should report results for the entire cohort evaluated. "This includes the 10.8% of the cohort where no result was returned but who were exposed to all the costs of testing," Dunn and colleagues observe.

And despite the finding that a potentially targetable mutation was detected in almost 72% of the cohort, "this is far from a home run," they write; only 11.6% of the total cohort ever received a targeted agent, they point out.

Furthermore, 62.9% of patients treated with sequencing-directed therapy (SDT) received no clinical benefit, they add.

Dunn and colleagues also suggest that alternative methods such as simple immunohistochemistry can also detect some clinically relevant biomarkers at a small fraction of the cost associated with NGS.

In addition, the most frequently identified marker for exceptional response to treatment — homologous recombination repair detects — can be detected using limited panels, Dunn and colleagues point out. "We suggest that the approach to personalized oncology must itself be personalized," they comment.  

The study cohort, for example, included many cases of CUP along with other rare cancers, both of which elevate the yield of detectable PGVs over what might be expected in an unselected cancer population.

"Moreover, reflex molecular testing will be of limited benefit for tumors for which effective standard-of-care treatments exist, including a targeted therapy, and of no benefit to those too unwell to receive any targeted therapy," Dunn and colleagues observe.

Targeted therapies in turn are often "prohibitively expensive" and may not be available outside of clinical trials, they argue. Lastly, the only study of NGS testing found that the use of molecularly targeted agents outside their indications failed to improve progression-free survival (PFS) compared with physicians' choice of treatment in heavily pretreated patients with cancer.

In a reply that addresses these arguments, study authors Cobain and Chinnaiyan agree that less costly limited gene panels or immunohistochemical assays can often be used to gain clinically relevant information. "However, it must also be considered that the cost of NGS testing is far less than the cumulative cost of other diagnostic assays used in the routine care of patients with advanced cancer, such as serial computed tomography scans or the cost of therapeutics," Cobain and Chinnaiyan point out.

They also note that other groups have similarly identified high rates of novel PGV detection in unselected populations of patients with advanced cancer, as well as in cohorts of specific cancer types with well-established guidelines for genetic testing.

"As guideline-based testing strategies do not identify all patients at risk and identification of PGVs has significant clinical implications for both patients and their family members, we continue to advocate for germline testing in all patients with advanced cancer," Cobain and Chinnaiyan conclude.

They acknowledge, however, that "more limited gene panels than what was used in our study may be appropriate for this purpose."

Study Details

Cobain and Chinnaiyan explain that patients in this cohort study were participants in the Michigan Oncology Sequencing (Mi-ONCOSEQ) program. They underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing.

NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%).

Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%).

The results were returned to the treating oncologists. This led to 132 patients (16.2%) receiving sequencing-directed therapy, of whom 49 patients (37.1%) had clinical benefit. Exceptional responses were observed in 26 patients (19.7% of treated patients).

Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance.

For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses.

"None of these therapies would have been recommended per standard of care guidelines," the authors comment, "indicating that sequencing information was of significant value."

They also point out that not only did many PGVs identified by NGS have therapeutic relevance for patients themselves, they could have significant implications for patients' family members who, should a similar PGV be detected, can be offered genetic testing, enhanced screening, or risk-reducing interventions.

Cobain declares having received personal fees from AstraZeneca, Athenex, and Ayala Pharmaceuticals. Chinnaiyan reports serving on the advisory board for Tempus, which has licensed the Mi-Oncoseq1700 panel and integrative sequencing approach from the University of Michigan; serving on the scientific advisory board for Ascentage; and being cofounder and serving on the advisory boards for Oncopia, LynxDx, and Esnik.

Study: JAMA Oncol. Published online February 25, 2021. Full text

Comment & Response: JAMA Oncol. Published online June 17, 2021. Comment, Response

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