1. DiGiulio, Sarah

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Identifying inherited genetic mutations known to predispose an individual to a higher risk of certain cancers has opened up vast new opportunities for screening patients for cancer risk earlier and advising them on steps and actions that can be taken to lower cancer risk. The implications for preventive cancer care are immense.

Kenneth Offit, MD. K... - Click to enlarge in new windowKenneth Offit, MD. Kenneth Offit, MD

And now, as genetic testing for such mutations becomes part of standard practice, a recent study investigated how well current guidelines in this area are working. The data suggests that in some patients with advanced cancer broader sequencing of germline and tumor DNA for cancer-related genes may detect more potentially clinically significant heritable mutations than the approach recommended in current guidelines: using family history, age, and features of tumor pathology associated with cancer syndromes..


In a sample of 1,040 patients with advanced cancer, 182 (17.5%) had clinically actionable inherited mutations (as identified via tumor DNA and germline DNA testing). Yet, 55.5 percent of the patients in that subset (101) would not have found out about those mutations if they had undergone DNA sequencing recommended in current guidelines. The study was published in the Journal of the American Medical Association (2017;318:806-815).


"The high proportion of findings that were unanticipated by the guidelines-based testing was certainly striking," Kenneth Offit, MD, Chief of the Clinical Genetics Service and Robert and Kate Niehaus Chair in Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center, New York City, told Oncology Times.


Offit noted that the research presented a logistical challenge, as patients had to be provided with increased genetic counseling services to understand the options they had to learn about potential genetic mutations in their tumors and in their normal non-cancerous DNA. Nevertheless, these findings are significant-and have implications for practice, including how to potentially update future guidelines.


Here's what else he shared about this research and why it's important.


1 What was the goal of your research when you set out to do this study?

"Oncologists are increasingly performing sequencing of tumors to identify targeted therapies [that might help a certain patient]. To be most accurate, this also involves sequencing 'normal' DNA at the same time. The goal of this project was to determine the prevalence of inherited cancer predisposing mutations in patients with advanced cancer tested 'agnostically,' regardless of family history. The pressing question we sought to answer was to determine what proportion of inherited genetic mutations we would have 'missed' if we had used standard family history and 'phenotypic' criteria for testing instead of the 'agnostic' approach.


"This study was important to do now because some academic and commercial companies either do not test normal DNA at the time of tumor testing, or do not return these results. We were seeking an evidence base to learn the advantages of returning this information."


2 You found that, indeed, you would have "missed" a significant number of those inherited mutations. What are the implications of that?

"We found a relatively high burden of clinically actionable inherited mutations-17.5 percent-in patients with advanced disease. We broke the data down by ancestry-as individuals descended from those of Ashkenazi Jewish (non-Jewish European) ancestries have certain 'founder' mutations at higher frequency.


"We then found that between a third and half of mutations detected would not have been predicted by our guidelines-based rules. We also found that a subset of patients had clinically actionable inherited mutations that impacted discussion of targeted treatment. For example, PARP inhibitors or checkpoint blockade drugs were discussed in 38 of the 182 patients with inherited mutations.


"These findings will need to be confirmed by other groups doing this same type of tumor-normal sequencing. We need to prove, using laboratory-based or epidemiology approaches, that some of the unusual mutations detected using this 'agnostic' approach are indeed linked to the cancers in these families. Until this is done, we should not change guidelines.


"But it is fair to say that guidelines are already allowing broader 'panel'-based approaches for those with certain types of cancer. How broad, or how focused, these panels should be remains to be determined."


3 What is the most important takeaway for practicing oncologists and cancer care providers to know about this research?

"To guide practice, all of these new genetic data need to be used in a decision-analysis type model that weighs cost as well as benefit. I think it is fair to say that this type of broad genetic screening is the most sensitive. But for the clinician in practice now, using family history information has been the accepted and cost-efficient way to go.


"For large cancer centers committed to precision medicine and tumor-sequencing approaches, and for patients seeking this type of 'cutting-edge' approach, I think this study makes a strong argument to return genetic results to patients to target their cancer treatment and to guide their families to take preventive action."