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Polygenic Risk Scores Could Help Predict Second Primary Breast Cancer

Goodwin, Peter M.

doi: 10.1097/01.COT.0000533703.22314.d7
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BARCELONA—Patients treated for BRCA-associated breast cancers could be given more accurate estimates of their risk for developing second primaries of the contralateral breast by combining polygenic risk scores (PRS) with standard risk factors if findings from a study with over 10,000 patients reported at the 2018 European Breast Cancer Conference are validated (Abstract 7).

“Polygenic risk scores combine all the effects of several low-risk variants together, so you get a score with more impact,” said lead author Alexandra van den Broek, PhD, a genetic epidemiologist from the Netherlands Cancer Institute in Amsterdam. “It's already known that it is predictive for a first primary breast cancer in the general population and for BRCA1 and 2 mutation carriers.”

This new study was able to take the prediction further. “We assessed the effect of polygenic risk scores—already published in the case of risk for first primary breast cancer—and looked if it could predict risk for a contralateral second primary breast cancer specifically in the high-risk BRCA1 and 2 mutation carriers,” she explained.

“We found that several of the polygenic risk scores were indeed predictive of contralateral breast cancer risk in both BRCA1 and BRCA2 mutation carriers.”

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Study Details

In patients with either a BRCA1 or BRCA2 mutation, the study found PRS could identify additional risk of up to around 10 percent for a tumor arising in the contralateral breast within 10 years of the initial primary cancer and 20 percent extra risk within 20 years. Potentially this will be significant additional information to inform clinical choice.

The Netherlands researchers were part of the international Consortium of Investigators of Modifiers of BRCA 1/2 (CIMBA) coordinated through the University of Cambridge, England.

Genotyping was done using the iCOGS array and could potentially help women make difficult decisions such as whether to opt for additional prophylactic surgery, said van den Broek.

“We know women with a BRCA mutation are at a higher risk, but it has also been shown that individual risks may vary widely, so we wanted to see if there was any way to better identify patients at lower and higher risks,” she noted.

“By better identifying those at lower and at higher risk, we can better provide counseling for intensified screening or even consider preventive measures. It will give women better-informed options to reduce risk.”

The study genotyped patients from countries around the world including the Netherlands, Spain, U.K., U.S., Australia, and Canada using the iCOGS array (based on over 200,000 single nucleotide polymorphisms from the Collaborative Oncological Gene-Environment Study originally set up to improve understanding of genetic susceptibility to three hormone-related cancers: breast, ovarian, and prostate cancers)—and the OncoArray (with around 260,000 single nucleotide polymorphisms that include “markers of interest” for each of five diseases: breast, ovarian, prostate, colorectal, and lung cancers).

Study patients totaling 6,612 carried the BRCA1 mutation and 4,220 patients had BRCA2. In the cohort with BRCA1, the hazard ratio of risk for contralateral second primary breast cancer among those in the highest quartile of PRS was 1.54 (p<0.001) compared with those in the lowest—equivalent to an increased risk of 10 percent after 10 years.

For the women who had mutated BRCA2, the hazard ratio of the highest risk scoring women compared to the lowest was 1.47 (p<0.001)—a 7 percent increased risk of contralateral breast cancer after 10 years.

While more than 150 common low-risk variants had already been identified as markers for a first breast cancer in the general population—and in women specifically with BRCA1/2 mutation—each one individually conferred only a small additional risk. But when combined to include many variants, however, they had already collectively emerged as highly predictive for the risk of a first breast cancer.

“These polygenic risk scores were originally developed to try to better predict the risk of developing a first breast cancer,” Van den Broek noted. “Our research suggests that they can also be used to help patients who have survived their first breast cancer to better understand their level of risk for a second breast cancer. We hope these findings will add to the existing knowledge about predicting risk for a second breast cancer in these survivors.”

By detecting as much as a 10 percent increased risk of a second primary—in combination with standard risk-assessment—PRSs could make an important practical difference, though Van den Broek said they still need to look at interactions with additional risk factors such as age, type of treatment, and family history.

“Polygenic risk scores might in the future be incorporated in risk prediction models, which are helpful to counsel and help women to make shared decisions,” she said.

Isabel T. Rubio, MD, PhD, co-chair of the European Breast Cancer Conference and Director of the Breast Surgical Unit at Clinica Universidad de Navarra in Spain, who was not involved in the research, shared her thoughts. “Facing a diagnosis of breast cancer and carrying a BRCA mutation are overwhelming for many women. New information on the individual risks of developing a contralateral breast cancer in this population will help in the decision-making process on preventive surgery or intensive follow-up. Research like this brings new information to help with these difficult decisions.”

Peter M. Goodwin is a contributing writer.

Wolters Kluwer Health, Inc. All rights reserved.
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