Most Breast-Ovarian Cancer Patients Miss Genetic Tests

Most Breast-Ovarian Cancer Patients Miss Genetic TestsDespite the existence of evidence-based guidelines supporting genetic testing for women with a history of breast and/or ovarian cancer, most of these women didn’t get tested, according to researchers.

Based on an analysis of pooled data from three cancer control modules, fewer than one in five women with a history of breast or ovarian cancer meeting National Cancer Comprehensive Network (NCCN) criteria underwent testing, reported Christopher P. Childers, MD, of the David Geffen School of Medicine at UCLA in Los Angeles, and colleagues.

Up to 10% of breast and 15% of ovarian cancers can be linked to heritable gene mutations — most commonly mutations in the BRCA1 and BRCA2 — which suggests that the identification of women with these mutations can direct both cancer treatment and surgical decision-making, they wrote in the Journal of Clinical Oncology.

While the rates of genetic testing in newly diagnosed patients meeting NCCN criteria have been increasing, “there is likely a large cohort of breast and ovarian cancer survivors for whom testing was not offered, pursued, or even available,” Childers’ group wrote.

They used nationally representative samples from the 2005, 2010, and 2015 National Health Interview Surveys (NHIS). Eligible patients included women with a history of breast cancer and/or ovarian cancer who met certain NCCN eligibility criteria based on age of diagnosis and family history:

  • Diagnosis of breast cancer at ages ≤45
  • Diagnosis at ages ≤50 with one or more first-degree relatives (FDRs) with breast cancer
  • Diagnosis at any age with one or more FDRs with breast cancer ages ≤50
  • Diagnosis at any age with one or more FDRs with ovarian cancer
  • Women who themselves had ovarian cancer

Outcomes included the percentage of eligible individuals who either discussed genetic testing with a health professional, were advised to undergo such testing, or actually underwent testing.

Of 47,218 women identified from the three surveys, 2.7% had breast cancer. Of those women, about 36% met one or more of the eligibility criteria, and of those, 29% discussed testing with a healthcare professional, 20.2% were advised to undergo testing, and 15.3% underwent testing.

Approximately 0.4% of the women in the survey had ovarian cancer. Of those, 15.1% discussed testing, 13.1% percent were advised to undergo testing, and just 10.5% underwent testing.

Based on the pooled sample, an estimated 1,471,279 women with a history of breast and/or ovarian cancer meet one or more of the eligibility criteria. The authors determined that within this population, the rate of genetic testing was 13.8% (95% CI 10.8% to 17%).

“Using only these five criteria, this generates a population-based estimate of unmet need of genetic testing for breast and ovarian cancer survivors between 1,212,334 and 1,312,381,” they noted.

Furthermore over 70% of eligible patients with breast cancer and 80% of those with ovarian cancer haven’t even discussed genetic testing with a health professional.

“Given the low testing rate and large impact of identifying a heritable mutation, aggressive solutions should be considered,” Childers’ group suggested. “These may include universal testing for women with breast and/or ovarian cancer or other select populations, directed patient education for self-referral, or modified direct-to-consumer testing.”

The study had some limitations, including the fact that NHIS collects self-reported data only, and is not validated against the medical record. Also, recall bias in terms of “advising, discussing, and testing are all possible and are likely magnified as patients become more removed from their treatment,” the authors noted.

In an accompanying editorial, Kevin S. Hughes, MD, of the Avon Comprehensive Breast Evaluation Center at Massachusetts General Hospital in Boston, lamented that while many new strategies involving genetic testing have been adopted and save lives, “we have yet to apply these strategies at the population level where their effect can be generalized beyond a small number of selected patients.”

Hughes wrote that while some reports of the underutilization of genetic testing have been met by calls for more genetic counselors, “there is nowhere near the number of genetic counselors needed to take on population-level testing.”

The problem is that too many mutation carriers are unaware of their status and could develop cancers that could have been prevented or discovered earlier, he stated, adding that healthcare professionals need to take certain steps that will increase the rate of detection of these mutations.

He suggested some steps that can be taken, such as abbreviating pretest counseling sessions to enable more patients to be seen by genetic counselors or educated clinics. “It is time to move to population-level screening for hereditary cancer susceptibility mutations. We have thought about this for 20 years. It might be time to take action,” he wrote.

To read this entire article on MedPageToday.com, please click here.

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Retaining One Normal BRCA Gene in Breast, Ovarian Cancers Influences Patient Survival

Retaining One Normal BRCA Gene in Breast, Ovarian Cancers Influences Patient SurvivalDetermining which cancer patients are likely to be resistant to initial treatment is a major research effort of oncologists and laboratory scientists. Now, ascertaining who might fall into that category may become a little easier for physicians taking care of people with BRCA1/2 mutations. Researchers in the Perelman School of Medicine at the University of Pennsylvania found a relationship between the genetics of tumors with germline BRCA1/2 mutations and whether the tumor retains the normal copy of the BRCA1/2 gene, and risk for primary resistance to a common chemotherapy that works by destroying cancer cells’ DNA. The team published their study this week in Nature Communications.

Researchers estimate that 5 percent of breast cancers and 20 percent of ovarian cancers are attributable to germline mutations in BRCA1 and BRCA2, the focus of the current study. Overall, 252,710 people will be diagnosed with breast cancer this year and 40,610 will die of the disease, according to the National Cancer Institute. For ovarian cancer, NCI projects 22,440 new cases and 14,080 deaths.

There are many reasons patients may be resistant to treatment—the immune system, the complex landscape of a tumor, or a patient’s own genes can all play a role. Without explicitly looking for it, the Penn team found another mechanism of resistance to a standard treatment for patients with BRCA-associated cancers. “Our primary question was not aimed at evaluating resistance to therapy, but we did end up there,” said senior author Katherine Nathanson, MD, deputy director of the Abramson Cancer Center, and director of Genetics at the Basser Center for BRCA.

Her group evaluated the genetic profiles of 160 breast and ovarian cancers associated with germline mutationsin BRCA1 and BRCA2, in the largest study of these tumors to date. They were interested in determining what types of secondary, additional changes occur in primary BRCA1/2 germline mutation-associated cancers that might act in concert with mutant BRCA1 and BRCA2 to drive the cancers.

The team evaluated how frequently the non-mutated version of the gene lost its function in concert with the original BRCA1/2 germline mutation-associated cancers. In oncology terms, this double-hit status is called “loss of heterozygosity,” or LOH, to signify that both versions (one inherited from mother, one from father) of the normal BRCA gene have been hobbled.

Historically, it had been thought that all tumors associated with germline BRCA1/2 mutations lose the second version of the gene, or LOH. The investigators were surprised to find that was not the case in a surprisingly large percentage of patients. In addition, they found that other genetic and clinical features of patients whose tumors did not undergo LOH (LOH-negative) were significantly different from those that did undergo LOH (LOH-positive).

Notably, they evaluated the overall survival of patients with ovarian tumors with and without loss of heterozygosity. LOH-negative status was associated with worse overall survival in ovarian cancer patients treated with platinum chemotherapy, with a median of 39 months, compared to 71 months in the LOH-positive group who received the same treatment.

The researchers believe the patients with LOH-negative tumors (those with one working copy of BRCA1 or BRCA2 and the other copy carrying the germline mutation) had tumor cells that could still repair the chemotherapy-induced DNA damage in order to survive. In contrast, the investigators surmise that the LOH-positive group (with both gene copies disabled) responded better to the same therapy because their tumor cells died more readily.

“Identifying the LOH status of BRCA1/2 carriers may be useful to predict who might be at risk for primary resistance to DNA-damaging agents such as platinum, which has important implications for treatment of patients with these mutations,” said the study’s first author Kara N. Maxwell, MD, PhD, an instructor of Hematology/Oncology. “We only need to determine the LOH at a specific gene’s location, which is more cost effective than sequencing a patient’s whole genome, for example, and compatible with standard testing.”

By looking at a person’s individual genetics and type of cancer, the Penn team hopes to be able to better tailor care soon after an initial diagnosis to improve survival. Nathanson surmises that knowing a person’s LOH status could guide treatment decisions. She suggests that certain drugs already in today’s cancer treatment arsenal will likely work for patients who are at risk for resistance due to their LOH genetics; however, it’s a matter of choosing the right one.

To read this entire article on MedicalXpress.com, please click here.

Mastectomy Likely Not Effective for Ovarian Cancer Survivors with BRCA Mutation

Mastectomy Likely Not Effective for Ovarian Cancer Survivors with BRCA MutationPatients with BRCA gene mutations have a significantly higher risk of developing breast and ovarian cancers. As a preventive measure, many patients undergo mastectomy or removal of the ovaries and fallopian tubes.

However, these surgeries may not be worth the cost for some patients with BRCA mutations who have previously had ovarian cancer, according to a new study published by the Annals of Surgical Oncology.

The study suggests that prophylactic mastectomy among ovarian cancer survivors with a BRCA mutation may not increase survival and is not cost-effective.

The authors said that their findings are significant because the National Comprehensive Cancer Network recently recommended that women with ovarian cancer receive genetic testing, regardless of familial history. Due to these guidelines, more patients are learning they have a BRCA mutation and may seek prophylactic treatment.

“Risk-reducing mastectomy is costly and can require many months of follow-up and recovery,” said lead author Charlotte Gamble, MD. “Our results emphasize that prophylactic mastectomy should be used selectively in women with both a BRCA mutation and a history of ovarian cancer.”

In the study, the authors created a statistical model that compared mastectomy to breast cancer screening, including mammogram and MRI. Included in the model were age at ovarian cancer diagnosis, time between diagnosis and mastectomy, BRCA mutation status, cancer survival rates, and treatment costs, according to the study.

The authors compared risk-reducing mastectomy with breast cancer screening every 6 months after ovarian cancer diagnosis.

The investigators also assessed the treatments through the incremental cost-effectiveness ratio. Interventions where the ratio is less than $100,000 per year of life saved were considered cost-effective.

The benefit of mastectomy over screening alone was observed to depend on the patient’s age at time of diagnosis and time to mastectomy.

For patients diagnosed at any age with BRCA 1 and 2 mutations, prophylactic mastectomy within 4 years of diagnosis was not found to be cost-effective due to limited gains in survival, according to the study.

For patients diagnosed at 60 years and older, survival gain was also limited with prophylactic mastectomy. The authors concluded that the procedure was not cost-effective in these patients, regardless of time since diagnosis.

For patients with the BRCA mutations who were diagnosed at age 40 to 50 years, prophylactic mastectomy at least 5 years after ovarian cancer diagnosis was linked to a survival benefit of 2 to 5 months compared with screening, according to the study. This treatment was found to be cost-effective, the authors noted.

“Our study provides clarity on how a woman’s age and timing of a risk-reducing mastectomy after an ovarian cancer diagnosis impact the benefit of this procedure,” Dr Gamble said. “Within the first 5 years, nobody benefitted from risk-reducing mastectomy and after that threshold, survival gains were seen mostly in the youngest, healthiest ovarian cancer patients.”

These results suggest that prophylactic mastectomy may not be the best treatment route for a majority of ovarian cancer survivors with BRCA mutations.

“There is no right or wrong answer on how to manage breast cancer risk in this unique population,” said senior author Rachel Greenup, MD. “However, we hope that our findings provide guidance to women and their doctors deciding if and when prophylactic mastectomy is beneficial following ovarian cancer treatment.”

To read this entire article on Speciality Pharmacy Times, please click here.

Loss of Heterozygosity in BRCA Gene May Influence Survival in Breast and Ovarian Cancers

Loss of Heterozygosity in BRCA Gene May Influence Survival in Breast and Ovarian CancersResearchers in the Perelman School of Medicine at the University of Pennsylvania have found a relationship between the genetics of tumors with germline BRCA1/2mutations—and whether the tumor retains the normal copy of the BRCA1/2 gene—and risk for primary resistance to a common chemotherapy that works by destroying cancer cells’ DNA.  The team published their findings in a paper by Maxwell et al in Nature Communications.

Researchers estimate that 5% of breast cancers and 20% of ovarian cancers are attributable to germline mutations in BRCA1 and BRCA2.

There are many reasons patients may be resistant to treatment: the immune system, the complex landscape of a tumor, or a patient’s own genes can all play a role. Without explicitly looking for it, the Penn team found another mechanism of resistance to a standard treatment for patients with BRCA-associated cancers. “Our primary question was not aimed at evaluating resistance to therapy, but we did end up there,” said senior author Katherine Nathanson, MD, Deputy Director of the Abramson Cancer Center and Director of Geneticsat the Basser Center for BRCA.

Her group evaluated the genetic profiles of 160 breast and ovarian cancers associated with germline mutations in BRCA1 and BRCA2, in the largest study of these tumors to date. They were interested in determining what types of secondary, additional changes occur in primary BRCA1/2 germline mutation-associated cancers that might act in concert with mutant BRCA1 and BRCA2 to drive the cancers.

Study Findings

The team evaluated how frequently the nonmutated version of the gene lost its function in concert with the original BRCA1/2 germline mutation-associated cancers. This double-hit status is called “loss of heterozygosity,” or LOH, to signify that both versions of the normal BRCA gene have been hobbled.

Historically, it had been thought that all tumors associated with germline BRCA1/2 mutations experience LOH. The investigators were surprised to find that was not the case in a surprisingly large percentage of patients. In addition, they found that other genetic and clinical features of patients whose tumors did not undergo LOH (LOH–negative) were significantly different from those that did undergo LOH (LOH–positive).

Notably, they evaluated the overall survival of patients with ovarian tumors with and without loss of heterozygosity. LOH–negative status was associated with worse overall survival in ovarian cancer patients treated with platinum chemotherapy, with a median of 39 months compared to 71 months in the LOH–positive group who received the same treatment.

The researchers believe the patients with LOH–negative tumors (those with one working copy of BRCA1 or BRCA2 and the other copy carrying the germline mutation) had tumor cells that could still repair the chemotherapy-induced DNA damage in order to survive. In contrast, the investigators surmise that the LOH–positive group (with both gene copies disabled) responded better to the same therapy because their tumor cells died more readily.

“Identifying the LOH status of BRCA1/2 carriers may be useful to predict who might be at risk for primary resistance to DNA-damaging agents such as platinum, which has important implications for treatment of patients with these mutations,” said the study’s first author Kara N. Maxwell, MD, PhD, Instructor of Hematology/Oncology at Penn. “We only need to determine the LOH at a specific gene’s location, which is more cost-effective than sequencing a patient’s whole genome, for example, and compatible with standard testing.”

Dr. Nathanson surmised that knowing a person’s LOH status could guide treatment decisions. She suggests that certain drugs already in today’s cancer treatment arsenal will likely work for patients who are at risk for resistance due to their LOH genetics; however, it’s a matter of choosing the right one.

To read this entire article on The ASCO Post, please click here.

Does Talcum Powder Cause Ovarian Cancer?

Does talcum powder cause ovarian cancer?Does talcum powder cause ovarian cancer?

A Los Angeles jury thinks so. This week it ordered Johnson & Johnson to pay $417 million to 63-year-old Eva Echeverria. She blamed her terminal illness on Johnson’s Baby Powder, which she used for decades starting at age 11. The company should have warned consumers about the risk, she argued.

The jury award is the biggest yet against Johnson & Johnson, which has lost most of a half-dozen trials involving claims its baby powder and Shower to Shower powder cause ovarian cancer. The company denies there’s a connection between its products and the disease and quickly said it would appeal the Los Angeles verdict. Lawsuits involving thousands more plaintiffs are pending.

Medical and cancer experts divide sharply on talc’s role. Some are convinced the powder is linked to an increased risk of ovarian cancer. Others, including government health experts, say the evidence is lacking.

“The scientific body of literature is not compelling at this time to support a strong association between talcum powder and ovarian cancer, let alone to say any one specific case was associated with powder,” said Amanda Fader, a gynecologic oncologist at Johns Hopkins University who was not involved in the studies.

The American Cancer Society says studies on talcum powder and ovarian cancer “have been mixed, with some studies reporting a slightly increased risk and some reporting no increase … For any individual woman, if there is an increased risk, the overall increase is likely to be very small.”

The National Cancer Institute (NCI) concludes “the weight of evidence does not support an association between perineal talc exposure and an increased risk of ovarian cancer.”

Yet Fader and others aren’t ruling out the possibility that a link might someday be established. The Food and Drug Administration, which says it has found no link, is doing additional research on the topic.

Talc, a mineral composed of magnesium, silicon, oxygen and hydrogen, is used extensively in cosmetics and personal care products. Women sometimes use talcum powder on their genital areas, sanitary napkins or diaphragms to absorb moisture and odor — contrary to the guidance of most physicians. (Asbestos, which has been linked to lung cancer, used to turn up as an impurity in talc, but it has been banned for several decades.) 

Many pediatricians also discourage the use of such powder on babies because the particles can cause breathing problems, according to Jennifer Lowry, a pediatrician and environmental health expert at Children’s Mercy Hospital in Kansas City.   

More than 22,000 women in the United States will be diagnosed with ovarian cancer this year, and 14,000 will die. The biggest risk factors, all well established, include a family history of breast or ovarian cancer, mutations in the BRCA genes and age.

The debate over talc began decades ago. In the early 1970s, scientists discovered talc particles in ovarian tumors. In 1982, Harvard researcher Daniel Cramer reported a link between talcum powder and ovarian cancer. His study was followed by several more finding an increased risk of ovarian cancer among regular users of talcum powder. Cramer, who at one point advised J&J to put a warning on its products, has become a frequent expert witness for women suing the company.

His studies and the many others that found a relationship used a case-control approach: A group of women diagnosed with ovarian cancer and a group without it were asked to recall their past diet and activities, and the results were then compared.

Critics say these kinds of studies have serious drawbacks, particularly “recall bias.” Women may forget what they did or, if diagnosed with cancer, might inadvertently overestimate their use of a suspect substance. People without a serious disease may be less motivated to remember details.

Three other studies — considered cohort studies — did not find any overall link. Unlike the case-control studies, these efforts began with a large group of women who did not have cancer and followed the progress of their health, with participants recording what they were doing in real time. The results of this approach, most scientists say, are stronger because they aren’t subject to the vagaries of memory.

One such study included more than 61,000 women followed for 12 years as part of the National Institutes of Health’s Women’s Health Initiative.

But critics, including Cramer, say the cohort investigations have their own flaws. Because ovarian cancer is so rare, they say, prospective studies don’t always end up with enough cancer cases to detect a potential link between talcum powder and the disease.

And evidence can change as new research becomes available. That explains why the NCI, which uses expert “editorial boards” to vet the voluminous information it puts out for doctors and consumers, has amended its language on talc.

In February 2014, one editorial board reviewed an analysis of several case-control studies that found genital-powder use was associated with a “modest increased risk” of ovarian cancer. The board decided to add the article to the NCI website and noted a weak association between talc and ovarian cancer. It also added a link to the website of the International Agency for Research on Cancer, a World Health Organization agency that had concluded years ago talcum powder was “possibly carcinogenic” when used in the genital area.

But a year later, the same board scrutinized the Women’s Health Initiative study and took another look at previous studies. That’s when it changed the wording on the NCI’s site to say the “weight of evidence” did not support a link. The board also removed the IARC information.

The FDA, too, has wrestled with the issue. In 2014, it denied a citizens’ petition asking the agency to require a warning label on talcum powder; its review of the scientific literature found no link between the product and cancer, officials said.

But because the agency continues to get “adverse event reports” involving talcum powder, it is taking another look at the evidence and launching its own laboratory research. The summary for one study, funded by the FDA’s Office of Women’s Health, says “talc’s effects on female genital system tissues have not been adequately investigated.”

In a statement after the Los Angeles verdict, Johnson & Johnson said “we deeply sympathize with the women and families impacted by this disease.” But, it added, the science “supports the safety of Johnson’s Baby Powder.”

No matter what side they are on, scientists agree more research — through lab studies with animals or human tissue — is needed to understand how talcum powder could potentially cause cancer. One hypothesis is talc applied to the genital area can migrate up the vagina to the ovaries, causing chronic inflammation that eventually results in malignancies. But that is only a hypothesis.

“We need to dig deeper to understand what’s going on,” said Joellen Schildkraut, a professor of public health sciences at the University of Virginia School of Medicine, who says she is uncertain about talc’s effect on the ovaries. “We really need to understand the mechanism, if there is one.”

To read this entire article by The Washington Post, please click here.

Does Baby Powder Cause Cancer? A Jury Says Yes. Scientists Aren’t So Sure

Does Baby Powder Cause Cancer? A Jury Says Yes. Scientists Aren't So SureIf you’re a woman, there’s a good chance you’ve used Johnson’s Baby Powder at some point. It smells good, and it can keep you dry.

But is it dangerous?

Dr. Daniel Cramer says yes. He’s a professor of obstetrics and gynecology at Brigham and Women’s Hospital in Boston. He says talc — the mineral in talcum powder — can cause ovarian cancer.

“Overall, women may increase their risk in general by about 33 percent by using talc in their hygiene,” Cramer says.

On Monday, a California jury awarded Eva Echeverria $417 million in a case against Johnson & Johnson. Echeverria, who is suffering from terminal ovarian cancer, claimed it was caused by Johnson’s Baby Powder, which she used on her perineum for decades.

Hers wasn’t the first jury award against the company. And thousands more cases are pending.

It has opened a long-simmering question about whether talcum powder used in the genital area can cause cancer.

Cramer, who has served as a paid consultant on several ovarian cancer cases against Johnson & Johnson, published one of the first studies noting an association between talc and ovarian cancer in 1982.

“This story goes back a long, long way, back into the ’70s when people noted that ovarian cancer had many similarities to asbestos exposure,” he says. “Meanwhile another group in England found talc that was deeply embedded in ovaries and said there might be a story here.”

In fact, talc is a mineral that is sometimes mined alongside asbestos. And asbestos, a known carcinogen, was found in the past in some talc products.

After his first study on the talc-cancer association, Cramer followed up with an article in 1985 calling on companies like Johnson & Johnson to put warning labels on their talcum powder products.

Johnson & Johnson declined to be interviewed for this story. The company said in a statement that it plans to appeal the California verdict.

“We are guided by the science, which supports the safety of Johnson’s Baby Powder,” wrote company spokeswoman Carol Goodrich in a statement. “In April, the National Cancer Institute’s Physician Data Query Editorial Board wrote, ‘The weight of evidence does not support an association between perineal talc exposure and an increased risk of ovarian cancer.’ We are preparing for additional trials in the U.S., and we will continue to defend the safety of Johnson’s Baby Powder.”

Some researchers agree that the link between talc and ovarian cancer isn’t all that clear.

The International Agency for Research on Cancer, part of the World Health Organization, in 2010 called talc a possible carcinogen.

“It’s not proof positive,” says Joellen Schildkraut, a professor of public health at the University of Virginia. “These studies are suggestive. They support the idea.”

Her research shows there’s a stronger link between talc and ovarian cancer among African-American women than there is among white women. But to her, even that link isn’t proof.

“I would not call this conclusive. It’s consistent with other reports in the past. It’s suggestive of a stronger association, but it is not conclusive,” she says.

There are theories about how talcum powder could cause cancer. If women put it on their underwear or on feminine products, it could get into their reproductive system. Then, talc particles could make their way to the ovaries — research has already shown that can happen, and talc has been found in ovarian tumors. The talc could then cause irritation and inflammation that, over time, could lead to cancer.

“We can say that it is associated with an increased risk [of cancer],” says Shelley Tworoger, a cancer epidemiologist at the Moffitt Cancer Center in Tampa, Fla. “And there are biologic mechanisms by which we think that talc could actually impact ovarian cancer. But I would stop short of saying that it necessarily causes ovarian cancer.”

But she says there’s certainly enough information out there to guide women.

“Why use it?” she says. “I don’t know if I should say this or not, but … why not just be safe and not use it?”

To read this entire article on NPR.org, please click here.

Retaining One Normal BRCA Gene In Breast, Ovarian Cancers Influences Patient Survival

Retaining One Normal BRCA Gene In Breast, Ovarian Cancers Influences Patient SurvivalDetermining which cancer patients are likely to be resistant to initial treatment is a major research effort of oncologists and laboratory scientists. Now, ascertaining who might fall into that category may become a little easier for physicians taking care of people with BRCA1/2 mutations. Researchers in the Perelman School of Medicine at the University of Pennsylvania found a relationship between the genetics of tumors with germline BRCA1/2 mutations and whether the tumor retains the normal copy of the BRCA1/2 gene, and risk for primary resistance to a common chemotherapy that works by destroying cancer cells’ DNA. The team published their study this week in Nature Communications.

Researchers estimate that 5 percent of breast cancers and 20 percent of ovarian cancers are attributable to germline mutations in BRCA1 and BRCA2, the focus of the current study. Overall, 252,710 people will be diagnosed with breast cancer this year and 40,610 will die of the disease, according to the National Cancer Institute. For ovarian cancer, NCI projects 22,440 new cases and 14,080 deaths.

There are many reasons patients may be resistant to treatment—the immune system, the complex landscape of a tumor, or a patient’s own genes can all play a role. Without explicitly looking for it, the Penn team found another mechanism of resistance to a standard treatment for patients with BRCA-associated cancers. “Our primary question was not aimed at evaluating resistance to therapy, but we did end up there,” said senior author Katherine Nathanson, MD, deputy director of the Abramson Cancer Center, and director of Genetics at the Basser Center for BRCA.

Her group evaluated the genetic profiles of 160 breast and ovarian cancers associated with germline mutations in BRCA1 and BRCA2, in the largest study of these tumors to date. They were interested in determining what types of secondary, additional changes occur in primary BRCA1/2 germline mutation-associated cancers that might act in concert with mutant BRCA1 and BRCA2 to drive the cancers.

The team evaluated how frequently the non-mutated version of the gene lost its function in concert with the original BRCA1/2 germline mutation-associated cancers. In oncology terms, this double-hit status is called “loss of heterozygosity,” or LOH, to signify that both versions (one inherited from mother, one from father) of the normal BRCA gene have been hobbled.

Historically, it had been thought that all tumors associated with germline BRCA1/2 mutations lose the second version of the gene, or LOH. The investigators were surprised to find that was not the case in a surprisingly large percentage of patients. In addition, they found that other genetic and clinical features of patients whose tumors did not undergo LOH (LOH-negative) were significantly different from those that did undergo LOH (LOH-positive).

Notably, they evaluated the overall survival of patients with ovarian tumors with and without loss of heterozygosity. LOH-negative status was associated with worse overall survival in ovarian cancer patients treated with platinum chemotherapy, with a median of 39 months, compared to 71 months in the LOH-positive group who received the same treatment.

The researchers believe the patients with LOH-negative tumors (those with one working copy of BRCA1 or BRCA2 and the other copy carrying the germline mutation) had tumor cells that could still repair the chemotherapy-induced DNA damage in order to survive. In contrast, the investigators surmise that the LOH-positive group (with both gene copies disabled) responded better to the same therapy because their tumor cells died more readily.

“Identifying the LOH status of BRCA1/2 carriers may be useful to predict who might be at risk for primary resistance to DNA-damaging agents such as platinum, which has important implications for treatment of patients with these mutations,” said the study’s first author Kara N. Maxwell, MD, PhD, an instructor of Hematology/Oncology. “We only need to determine the LOH at a specific gene’s location, which is more cost effective than sequencing a patient’s whole genome, for example, and compatible with standard testing.”

By looking at a person’s individual genetics and type of cancer, the Penn team hopes to be able to better tailor care soon after an initial diagnosis to improve survival. Nathanson surmises that knowing a person’s LOH status could guide treatment decisions. She suggests that certain drugs already in today’s cancer treatment arsenal will likely work for patients who are at risk for resistance due to their LOH genetics; however, it’s a matter of choosing the right one.

To read this entire article on MedicalXpress.com, please click here.