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Genetic Testing in TNBC

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    Posted: Sep 08 2014 at 8:12pm

Mary-Claire King Urges Wider Genetic Screening For Breast Cancer

A prominent scientist has started a big new debate about breast cancer. GeneticistMary-Claire King of the University of Washington, who identified the first breast cancer gene, is recommending that all women get tested for genetic mutations that can cause breast cancer.

"My colleagues and I are are taking a really bold step," King said. "We're recommending that all adult women in America, regardless of their personal history and regardless of their family history, be offered genetic testing for the breast cancer genes."

But others say that one study is far from enough evidence to know if these women face a higher risk of getting cancer, and that universal testing could lead women to undergo unnecessary surgery, doing more harm than good.

The breast cancer genes are called BRCA1 and BRCA2. Women who have mutations in these genes are much likely to get breast cancer and ovarian cancer. From 5 to 10 percent of breast cancer is caused by BRCA mutations, according to the National Cancer Institute.

Doctors usually recommend women get tested only if one of those cancers runs in their families.

"The difficulty with that approach is that it misses identifying some women who have mutations in these genes," says King, who laid out her arguments in an articlepublished Monday in JAMA, the journal of the American Medical Association. King was awarded a Lasker-Koshland prize Monday for her work on BRCA.

In fact, about half of the women who carry mutations in BRCA1 or BRCA2 have no family history of breast or ovarian cancer, she says.

But no one has recommended screening all women for a very good reason: No one knew how dangerous the mutations were for the average woman.

"There was a big piece of the puzzle missing," King says.

So King and her colleagues decided to try to find that missing piece. They identified more than 400 women who were carrying the mutations even though they had no family history.

"The women turned out to have the same high risks of developing either breast or ovarian cancer that we see among those who are identified by virtue of their family history," says King, who reported the findings in a paper published last week in theProceedings of the National Academy of Science.

King thinks that's the tipping point — it's time to recommend all women get screened.

"People who are positive can do something about it. Some women, for instance Angelina Jolie, wrote elegantly about her decision to have a double mastectomy," she says. They could also have their ovaries removed to make sure they never get ovarian cancer.

But that's exactly what has a lot of breast cancer advocates worried.

"We are far, far from being ready to recommend that all women be screened for genetic predisposition to breast cancer," says Fran Visco, president of the National Breast Cancer Coalition.

Visco and others aren't convinced the new data are strong enough to know anything for sure. Just because a woman has one of these mutations doesn't mean she'll definitely get cancer. Thus a woman could undergo radical surgery for no good reason.

"These are very serious surgeries that women have to undergo. Removing their breasts. Removing their ovaries. We're talking about surgery to remove healthy body parts. If we give women this message, we may very well end up doing more harm than good," Visco says.

In addition, screening tests can cost hundreds to thousands of dollars depending on insurance coverage.

"Having the genetic mutation doesn't mean you're definitely going to get cancer," saysDr. Olufunmilayo Olopade, a geneticist at the University of Chicago.

Women who find out they are carrying the mutations could get regular MRIs to try to catch any cancer early, when it's most treatable, Olopade says. They could also do things to try to minimize their chances of getting cancer in the first place. "If you have children, breast-feed children, don't gain weight and eat right — exercise. All those things modify the risk for mutation carriers."

Copyright 2014 NPR. To see more, visit http://www.npr.org/.


Edited by 123Donna - Dec 04 2014 at 8:12pm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Nov 18 2014 at 8:31am
Breast cancer prevention could be improved by genetic testing

But the great majority of breast cancers occur in women without a known family history of the disease. The new study shows additional genetic testing and risk factor assessment could help more accurately identify women, with and without family history, who are at elevated risk and could benefit most from preventive strategies.

Study leader Professor Monserrat Garcia-Closas, Professor of Epidemiology at The Institute of Cancer Research, London, said:

"Our study shows that genetic testing has the potential to improve strategies for preventing breast cancer, and suggests that multiple, small-effect genetic risk factors could be included alongside the major breast cancer genes to assess risk. We hope it helps to start a wider discussion about how to add more accurate risk prediction tools to future prevention programmes.

To read the entire article:

http://www.medicalnewstoday.com/releases/285442.php?tw


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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Dec 04 2014 at 8:15pm

Gene Testing in Triple-Negative Breast Cancer Patients

A study of nearly 2000 patients with triple-negative breast cancer has found that nearly 15% carry deleterious genetic mutations, lending support to current guidelines that recommend genetic testing in this patient population, say the researchers.

The study was published online December 1 in the Journal of Clinical Oncology.

The findings support current practice guidelines in the United States for genetic testing for triple-negative breast cancer. This form of breast cancer, which has little or no expression of estrogen receptor, progesterone receptor, and human epidermal growth-factor 2 receptor, is associated with a worse prognosis than other types of breast cancer.

This study has important implications for clinical practice, said lead author Fergus J. Couch, PhD, professor of laboratory medicine and pathology at the Mayo Clinic in Rochester, Minnesota. This is "a confirmatory study so large that it really does give fairly accurate probability estimates for these patients," Dr Couch told Medscape Medical News.

"It ended up actually confirming a lot of what we already had in place, but it's important to do that. Hopefully, going forward, it will strengthen those guidelines and people will actually follow those now for testing of patients," he added. "Where I see the benefit is that it will convince people to follow the guidelines."

Deleterious Mutations Found in Nearly 15%

Dr Couch and colleagues analyzed data on 1824 women with triple-negative breast cancer from 12 studies in the United States and Europe. The average age at diagnosis was 51 years. In this cohort, 34% of patients had at least one first- or second-degree relative with breast cancer, and 4% had a relative with ovarian cancer.

Germline DNA samples were obtained from each women and tested for mutations in 122 DNA repair genes, including 17 known to be predisposing to breast cancer.

In all, 271 deleterious mutations were identified in 267 (14.6%) of the women; 8.5% were in the BRCA1gene, 2.7% were in the BRCA2 gene, and 3.7% were in the remaining 15 genes (the majority of which were in the PALB2BARD1RAD51DRAD51D, and BRIP1 genes).

Patients with deleterious gene mutations were significantly younger at diagnosis than those with no mutations (45 vs 51 years). Nevertheless, 10.0% of mutation carriers were diagnosed when they were 60 years or older, whereas 5.5% of all patients with triple-negative disease were.

Mutation carriers also presented with higher-grade tumors than patients without mutations (P < .001). Associations between the presence of mutations and a family history of breast or ovarian cancer were less consistent, however.

Improvements in Care

Dr Couch said he hopes that the findings will increase genetic testing in patients with triple-negative breast cancer, and believes that this will ultimately improve care for the patient population.

He noted that the National Comprehensive Cancer Network (NCCN) guidelines recommend that all patients younger than 60 years with triple-negative breast cancer, whether or not they have a family history of the disease, undergo genetic testing. "Unfortunately, in the clinics that tends to get ignored, and many people do not get tested," he said.

"As we've shown, there's a fairly large number of mutation carriers embedded in that population," he said.

Knowing that a genetic mutation is involved could lead to a change in therapy, he suggested, noting that drugs acting as poly(ADP-ribose) polymerase (PARP) inhibitors have shown promise in the treatment of BRCA cancers. In fact, the first ever drug in this class, olaparib (Lynparza, AstraZeneca), has just been recommended for approval in ovarian cancer in patients with BRCA mutations in the European Union, although it wasnot recommended for that indication in the United States.

Dr Couch suggested that once patients are known to have aBRCA mutation, they could be enrolled in a clinical trial with PARP inhibitors. "That's a new development that is of benefit to these people," he said.

A further benefit of identifying mutations in triple-negative patients, Dr Couch explained, is that they can inform their family members, who can be tested and learn whether or not they are at risk.

Comparison of American and British Guidelines

As part of their analysis, Dr Couch and colleagues applied the findings to both the NCCN guidelines, which recommend testing all patients diagnosed with triple-negative breast cancer before the age of 60 years, and the National Institute for Health and Care Excellence (NICE) guidelines in the United Kingdom, which do not recommend testing patients diagnosed when they are older than 40 years if they do not have a family history of cancer.

"In the UK, the NICE guidelines select people for testing based on a probability model. You have to have a likelihood greater than 10% of having a BRCA1 or BRCA2 mutation in order to get tested," Dr Couch explained.

"That generally ends up being a cut-point of about 40 years of age for diagnosis, and anyone under 40 years or with a family history ends up getting tested," he added.

"Everybody thought that was a reasonable approach, but in our study we've basically shown that up to 20% of patients are missed by that cut-off, which is a very large proportion," he pointed out. "We looked at the numbers and the ages at diagnosis, and we found that, of those diagnosed between the ages of 40 and 50 without a family history, 8.6% have mutations, and between the ages of 50 and 60, 7.5% have mutations."

"That's not very far off 20%, and perhaps the UK NICE group would want to reconsider their cut-point and, in fact, extend it up to 50 or 60 years of age for testing, just like they do in the United States," he said.

An interesting question remains. Why, in the absence of the findings from this study, was the cutoff of 60 years chosen for the NCCN guidelines? "There really weren't a lot of data to support that," Dr Couch noted.

"I think a lot of it was just a number of genetic counselors or physicians who saw a lot of these types of patients and just had a general feeling that this was the right way to go," he explained. "It was sort of a 'safe zone' where they wouldn't miss very many patients."

"There were really not a lot of data in the literature to support that number prior to our study, so I don't really know how they came up with it. I think there was a lot off guesswork involved," he added.

This study was funded by the National Institutes of Health, the Breast Cancer Research Foundation, and the David F. and Margaret T. Grohne Family Foundation. Dr Couch reports owning a patent with Myriad Genetics.

J Clin Oncol. Published online December 1, 2014. Abstract
http://www.medscape.com/viewarticle/835907#vp_1

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Dec 07 2014 at 11:13pm
High frequency of germline mutations observed in triple negative breast cancers

1. A total of 14.6% of patients with triple negative breast cancers were found to have deleterious mutations in cancer susceptibility genes.

2. Of these patients with mutations, 11.2% were of the BRCA1/2 genes while 3.7% of patients had mutations in 15 other susceptibility genes.

Evidence Rating Level: 3 (Average)

Study Rundown: Triple negative breast cancer (TNBC) are a breast cancer subtype that lack expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. TNBC represents 12-15% of all breast cancers and are associated with worse outcomes compared to other breast cancer subtypes. Previous studies have demonstrated a high frequency of germline mutations in the BRCA1/2 genes in TNBC; however, the prevalence of deleterious mutations in other cancer predisposition genes are not well established. The purpose of this trial was to determine the frequency of germline mutations in a large cohort of TNBC patients. Germline DNA were collected from over 1,800 TNBC patients and analyzed for mutations in 17 cancer predisposition genes. The authors demonstrated that 11.2% of TNBC patients had mutations in BRCA1/2 while 3.7% had mutations in one other cancer susceptibility genes. Patients with deleterious mutations in these genes were statistically more likely to be younger compared to those without mutations. Unlike with BRCA mutations, patients with non-BRCA mutations did not have significant family history of breast or ovarian cancers. The high frequency of BRCA mutations observed in this trial support the use of germline BRCA genetic testing in patients with TNBC, regardless of family history. However, additional information on the penetrance of non-BRCAmutations are required before the clinical utility of these tests can be assessed. A major limitation of this study is that 97% of the included patients were white, while only 1.9% were African American, despite the latter being a risk factor for TNBC.

Click to read the study in the Journal of Clinical Oncology

Relevant reading: Genetic Susceptibility to Triple Negative Breast Cancer

In-Depth [case-control study]: In this study, germline DNA samples from 1824 female patients from 11 centers in the United States, Germany, Finland, Greece, and United Kingdom were collected and sequenced for 17 cancer susceptibility genes. Of these patients, 1762 (97%) were white, 34 (1.9%) were black, 10 (0.6%) were Asian, and 10 (0.6%) were Hispanic. Overall, 271 deleterious mutations were found in 267 patients (14.6%). Of these mutations, BRCA1 was the most frequent with 155 (57%) patients, followed by BRCA2 with 49 (18%) patients, and 67 (25%) with non-BRCA mutations. Patients diagnosed with TNBC at an age younger than 40 years represented 38% of all deleterious mutations. The mean age at diagnosis was younger for deleterious mutations versus wild-type genes (45 vs 52 years, P<0.001). Patients with BRCA1mutations were more likely to have a family history of breast (50%, P<0.001) and ovarian (18%, P<0.001) cancer. Patients with other mutations did not have statistically significant associated family histories.

http://www.2minutemedicine.com/high-frequency-germline-mutations-observed-triple-negative-breast-cancers/
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Linda428 Quote  Post ReplyReply Direct Link To This Post Posted: Dec 08 2014 at 7:08am
I'm wondering how many of you have gone through testing with Foundation One and Caris and actually had your doctors use your specific genetic mutations to find an effective (and the key word being "effective") treatment? I have been to several doctors who specialize in tnbc and they have told me "we don't put much stock in those reports" and then try to put me in trials that have nothing to do with my genetic defects. Two trials have not only failed but left me deathly sick. Eight chemo's have failed. Please give me your experiences and what doctors you've found who will actually look at the report and put together a treatment for you that worked. As you can tell I'm frustrated, my cancer is spreading like crazy so I don't have time to keep wasting. Thanks for any help you can offer.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Oct 16 2019 at 6:46pm

All Women with Breast Cancer Should Undergo Multigene Testing, Study Suggests


Multigene testing for all woman diagnosed with breast cancer can be “extremely cost-effective” compared to testing based on family history or clinical factors in both the United States and the United Kingdom health care systems, according to authors of a new analysis published in JAMA Oncology.

“These findings support changing current policy to expand genetic testing to all women with breast cancer,” concluded senior author Ranjit Manchanda, MD, PhD, of the Barts Cancer Institute, Queen Mary University of London in England, and coauthors.

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