Δευτέρα, 26 Ιουνίου 2017

BRCA CANCER RISK ESTIMATES

While it has been well established that carriers of the BRCA1 and BRCA2 mutations face a higher risk for breast and ovarian cancer, most studies to date have been retrospective.
A new prospective study on several assessment variables, published online June 20 in JAMA, has further clarified which women face the highest risks.
"This large prospective cohort of women with BRCA1 and BRCA2 mutations has enabled us to obtain the most precise estimates of age-specific breast and ovarian cancer risks to date," said lead study author, Antonis Antoniou, PhD, from the Centre for Cancer Genetic Epidemiology, University of Cambridge, United Kingdom. "These should provide more confidence in the counseling and clinical management of women with faults in the BRCA1 and BRCA2 genes."
The ideal epidemiologic study for estimating cancer risks is a prospective study, he explained. In that model, healthy women with genetic faults are followed over time and overcome potential biases. However, to date, published prospective studies have been very small.
The present study used data from a prospective cohort of women with BRCA1 and BRCA2 mutations who were recruited from 1997 to 2011 and were followed over time. The study included almost 10,000 women and was made possible through collaborations among scientists from Europe, North America, and Australia. 
"The prospective study design explains why it has taken 20 years of hard work to get these results," Dr Antoniou told Medscape Medical News. "Most importantly, it took an enormous long-term contribution and commitment from the women themselves to allow the scientists to be able to assemble this dataset."

Family History Implications Differ by Cancer Type

A novel finding in this study is that breast cancer risk for women with faults in BRCA1 and BRCA2 increases rapidly at a young age then remains at a constant high level for the rest of their lives.
"It peaks in the 40s for BRCA1 mutation carriers and in the 50s for BRCA2 carriers, but carriers of mutations in both genes are at about the same high risk in later life," Dr Antoniou explained. "This is important information to inform the clinical management also of women with mutations over the age of 60 years old."
Some clinics, he noted, have discharged women with mutations when they reached older ages, but the "current study suggests that this may not be appropriate."
The researchers found that the cumulative risk for breast cancer risk up to age 80 years was 72% for BRCA1 mutation carriers and 69% for BRCA2 carriers.
For ovarian cancer, the cumulative risk to age 80 years was 44% for BRCA1 and 17% for BRCA2 carriers.
Another important finding was the role of family history in estimating risk.
This has only been studied indirectly in the past and, again, only in retrospective studies. "The results from the current study show clearly and for the first time in a prospective study, that the cancer risks for women with BRCA1 and BRCA2mutations depend on the extent of the woman's family history of cancer," Dr Antoniou explained.
Advances in genetic technologies have opened up the potential of screening all women for BRCA1 and BRCA2 mutations, and currently there is considerable debate as to whether to offer universal mutation screening.
"The cancer risk estimates from our study will provide critical information for informing such policies," he said.  "For example, our results show clearly that women without family history of cancer are likely to be at lower breast cancer risk than women with strong cancer family history who had been typically seen in clinical genetics centers."
The results showed that the risk for breast cancer for both BRCA1 and BRCA2carriers increased along with the number of first- and second-degree relatives who had been diagnosed with the disease.
However, a similar association was not observed for ovarian cancer.
A third key point was that a significantly higher breast cancer risk when the mutations were located in certain regions for both BRCA1 and BRCA2, but mutation position did not appear to affect ovarian cancer risk.
Dr Antoniou pointed out that only a small number of retrospective studies have shown that cancer risks vary by mutation location within BRCA1 and BRCA2. However, a major limitation of those studies was that researchers could not estimate the cancer risks associated with mutations at different locations, mainly because of the retrospective nature of the studies and the inherent biases in the study designs.
"Therefore, it has been unclear how to apply those findings in clinical practice and how to incorporate those in the risk assessment of women with mutations," he said. "The results from this study show clearly, and again for the first time in a prospective study, that the cancer risks for women with BRCA1 and BRCA2 mutations depend on the  position of the specific fault within the gene."
"Moreover, the study provides for the first time cancer risk estimates for mutations at different locations," he added. "Therefore, mutation location can now be confidently incorporated in the risk assessment of women with BRCA1 and BRCA2  mutations."

Adding to Knowledge Base

Commenting on the study, Charles Shapiro, MD, from the Tisch Cancer Institute at Mount Sinai Medical Center in New York City, agreed that a very important aspect of this study is that it was prospective.
"Most previous studies have been retrospective, so this is really an important point," he told Medscape Medical News.
And one of the key points is that this is an example of data sharing. "Patients often think that everyone shares data, but that's not the case," Dr Shapiro said. "One institution may not be able to get enough numbers, but if 3 get together, then they have enough for the study."
That is essentially what they did in this paper in order to be able to draw data from such a large cohort, he noted. "This is something that we really need to do more of."
The findings from this study are already known, in that certain mutations convey risks. "But what we don't know yet is why," Dr Shapiro said. "And that is where more investigation is needed."
The study also found that carriers with a family history of cancer have a higher risk, but that wasn't anything new, he noted.
"What is important is that we need to refer every patient who needs to be referred for screening," Dr Shapiro said. "And we need to get a family history on all patients, as that is a recommendation from guidelines."

Study Details

The cohort comprised 6036 women who were BRCA1 carriers and 3820 with BRCA2, who were recruited through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry, and the Kathleen Cuningham Foundation Consortium for Research Into Familial Breast Cancer.
During the follow-up period, 426 participants were diagnosed with breast cancer, 109 with ovarian cancer, and 45 with asynchronous contralateral breast cancer.
The incidence of breast cancer for BRCA1 carriers increased between 21 to 30 years and 31 to 40 years but then remained stable at 23.5 to 28.3 per 1000 person-years for ages 31 to 70 years (P = .97 for trend). Peak incidence occurred in carriers aged 31 to 50 years (28.3 per 1000 person-years).
BRCA2 carriers showed a similar pattern, with peak incidence among those aged 51 to 60 years and incidence of 21.9 to 30.6 per 1000 person-years across ages 41 to 80 years (P = .57 for trend).
For contralateral breast cancer, the risk for a second breast cancer up to 20 years after the first cancer was 40% for BRCA1 carriers and 26% for BRCA2 carriers (hazard ratio [HR], comparing BRCA2 vs BRCA1 carriers, 0.62; = .001), with the risk for a second breast cancer higher among women whose first breast cancer was at a young age (<40 p="" years="">
The incidence of ovarian cancer increased with age up to 61 to 70 years for both mutations but was higher for BRCA1 carriers (HR comparing BRCA1 vs BRCA2, 3.6; P < .001). The cumulative risk for ovarian cancer to age 80 years was 44% for BRCA1and 17% for BRCA2.
A family history boosted the risk for breast cancer. The risk increased as the number of first- and second-degree relatives with breast cancer increased for both BRCA1(HR for 2 vs 0 affected relatives, 1.99; P < .001 for trend) and BRCA2 carriers (HR, 1.91; P = .02 for trend).
The risk for breast cancer was also higher if the mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 carriers (HR, 1.46; P = .007) and c.2831-c.6401 in BRCA2 (HR, 1.93; P < .001).
Conversely, risk for ovarian cancer was not associated with a family history of ovarian cancer or position of the mutation.
This work was supported by Cancer Research–UK grants. Dr Antoniou has disclosed no relevant financial relationships. Several coauthors have disclosed relationships with industry. 

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