Survival After Breast Cancer 'Unaffected by BRCA Status'

Liam Davenport

January 19, 2018

Young women diagnosed with primary breast cancer who have a BRCA mutation are as likely to survive the primary cancer as women without such mutations, concludes a new study from the United Kingdom.

The findings should be reassuring to women contemplating their initial treatment choices, the UK researchers comment. They suggest that the decision about risk-reducing surgery in BRCA mutation carriers need not be made at the time of initial treatment for the primary cancer. But a Canadian expert disagrees, arguing that such preventive surgery is lifesaving.

The study, which included more than 2700 women younger than 40 years, found that among the more than 330 women with a pathogenic BRCA1 or BRCA2 gene mutation, the 10-year survival rate was approximately 73%, which was similar to that seen in patients without the mutations.

The research was published online January 11 in the Lancet Oncology.

"Our findings suggest that younger women with breast cancer who have a BRCA mutation have similar survival to women who do not carry the mutation after receiving treatment," said lead researcher Diana Eccles, MD, from the Cancer Sciences Academic Unit at the University of Southampton, United Kingdom.

She told the charity Cancer Research UK that the findings should give women "more confidence and control" and provide "some reassurance" that women with a BRCA mutation "can complete and recover from their breast cancer treatment."

Dr Eccles added: "It can be difficult for some patients to decide whether or not to have risk-reducing surgery, typically double mastectomies and removal of ovaries.

"And our data suggest that this decision can be made, if preferred, once a woman has physically and psychologically recovered from her cancer treatment."

In an accompanying editorial, Peter A. Fasching, MD, Comprehensive Cancer Center Erlangen–EMN, University Hospital Erlangen, Bavaria, Germany, described the study as "surely only the beginning of a better understanding of young patients with breast cancer."

He pointed out that patients with BRCA mutations are known to be at increased risk for ovarian cancers, contralateral breast cancers, and de novo breast cancers in the same breast, as well as other conditions, and that these risks "determine treatment."

"Knowing that BRCA1 or BRCA2 mutations do not result in a different prognosis might change the therapeutic approach for these risks," Dr Fasching writes.

Preventive surgical measures might have an effect on what might be a very long life. Dr Peter Fasching

"This important topic needs more prospective research as preventive surgical measures might have an effect on what might be a very long life after a diagnosis of breast cancer at a young age," he adds.

Sporadic vs Hereditary Breast Cancer

Previous studies that compared outcomes between women with BRCA mutations and those with sporadic breast cancer have yielded mixed results; some have shown better, others worse, and yet others similar outcomes.

The researchers therefore conducted the Prospective Outcomes in Sporadic vs Hereditary Breast Cancer (POSH) study, which involved women aged 18 to 40 years who had been diagnosed with primary breast cancer. The patients were recruited at 127 hospitals in the United Kingdom within 12 months of diagnosis.

Information on personal characteristics, tumor pathology, disease stage, and surgical and cytotoxic treatment was collated from medical records, and a questionnaire on family history was administered.

The team used local routine pathology reports to determine the estrogen-receptor (ER), progesterone-receptor (PR), and HER2 receptor status of the women. In addition, whole blood samples were genotyped to determine BRCA mutation status.

The participants were not informed of their BRCA status as a matter of course, although they could receive a clinical genetic referral on the basis of local protocols.

Patients were treated in accordance with local protocols. They underwent clinical follow-up at 6 and 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival.

The team reports that from 2000 to 2008, they recruited 3021 eligible women, of whom 2733 were included in the analysis. The average age of the final cohort was 36 years.

The majority of women (60%) had histologic grade 3 disease; 67% had ER-positive disease; 73% had HER2-negative breast cancer; and 57% had PR-positive disease. Twenty percent had triple-negative breast cancer.

In all, 338 (12%) of the final cohort had either a BRCA1 or BRCA2 mutation, of whom 75 (22%) did not meet current guidelines on genetic testing with respect to family history and pathology status.

During a median follow-up of 8.2 years, 151 (6%) women were diagnosed with a contralateral breast tumor, representing 18% of BRCA1 carriers, 12% of BRCA2 carriers, and 4% of BRCA-negative women.

In addition, 752 (28%) women developed a distant recurrence, and 678 (25%) women died; 651 (96%) deaths were due to breast cancer.

Overall survival at 2 years was 97.0% among BRCA-positive patients and 96.6% in BRCA-negative women. Overall survival at 5 years was 83.8% and 85.0%, respectively; and at 10 years, it was 73.4% and 70.1%, respectively.

After adjusting for known prognostic factors, there was no significant difference in overall survival between BRCA-positive and BRCA-negative participants, at a hazard ratio of 0.96 on multivariate analysis (P = .76).

Among the 558 women with triple-negative breast cancer, 159 (28%) developed a distant recurrence, and 153 (27%) died. All deaths were due to breast cancer.

In this group, 2-year survival was significantly better among BRCA-positive than BRCA-negative women, at 95% vs 91% (multivariate hazard ratio, 0.59; P = .047). However, the difference in survival was no longer significant at 5 and 10 years (P = .62 and P = .12, respectively).

In a post hoc analysis, these results were not affected by excluding the 21 BRCA-positive and the 10 BRCA-negative women who underwent bilateral mastectomy within the first year of diagnosis.

Dr Eccles said that this finding suggests that risk-reducing surgery "does not have to be immediately undertaken along with the other treatment."

She added: "In the longer term, risk-reducing surgery should be discussed as an option for BRCA1 mutation carriers in particular to minimize their future risk of developing a new breast or ovarian cancer."

"Decisions about timing of additional surgery to reduce future cancer risks should take into account patient prognosis after their first cancer, and their personal preferences," she commented in a press statement.

Controversially, Dr Eccles suggested in an article published in the Southern Daily Echo that the risk for secondary cancers among BRCA carriers is not as high as previously thought and that, consequently, the vast majority of women with these mutations do not need to undergo bilateral mastectomy.

She was quoted as saying: "Hypothetically, if all the BRCA carriers did have the preventative surgery, then for 20 percent it was the right decision.

"But the other side of it is that there would be 80 percent who didn't need to."

Speaking to Medscape Medical News, Dr Eccles was quick to point out that this study was "not about people who have never had cancer and were making a decision to have bilateral mastectomy," such as in the famous case of Angelina Jolie.

Rather, it was about women who had already been diagnosed with breast cancer. The aim of the study was to determine whether having a BRCA mutation had an impact on long-term survival of primary breast cancer.

Dr Eccles said: "All this study is saying is that, at the point of cancer diagnosis, the priority is to treat the cancer right, to get the highest possibility that you're going to survive from that cancer, before you have to make a decision about whether you're going to have bilateral mastectomy."

She continued: "You can make [the decision] at the time if you're all geared up and ready and waiting, but for some patients, that is just too much.

"They don't know they're BRCA carriers, they've suddenly got this diagnosis, and they feel that just being a BRCA carrier means they have to choose to have bilateral mastectomy," she said.

Although the impact on outcomes of targeted treatments for BRCA carriers is "a different question again," Dr Eccles added that the current study "is showing, in some ways, that it doesn't matter what your BRCA status is.

"You treat the cancer based on what you've got. It might matter if you're offering a different therapeutic option to see whether it's better in BRCA carriers, but that's not what we looked at," she said. "Conventional breast cancer treatment is as good for BRCA carriers as for anyone else."

The researchers note that there are a number of limitations to their study, including that the treatment of BRCA carriers has changed substantially since the study was undertaken and that triple-negative breast cancer is now much better understood

Does Mutation Change Management?

Approached for comment, Steven A. Narod, MD, Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada, pointed out that among the patients in the study, too few bilateral mastectomies were performed to enable researchers to determine the impact of that procedure on outcomes in BRCA carriers.

Moreover, the follow-up period was too short, given what is known about the natural history of contralateral breast cancers in BRCA carriers and the impact on overall survival.

In an interview with Medscape Medical News, Dr Narod said that the question he deals with every day when seeing a breast cancer patient with a BRCA mutation is that of how to treat the cancer: "Does the presence of a mutation alter my management?"

He explained that at the Toronto teaching hospitals, they have been undertaking a study in which all women younger than 50 years who are diagnosed with breast cancer undergo BRCA mutation testing. More than 1000 women have undergone such testing so far.

Dr Narod said that although the findings have not yet been published, it is clear that the result of the genetic test has "a very profound effect on how they are treated.

"That is, they tend to get bilateral mastectomies, they tend to get oopherectomy, they tend to get chemotherapy," he said.

He continued: "The critical question is: Is that good? That would be good if it was in the interests of the patients."

Dr Narod pointed to a study by his team that was published in 2014 in the BMJ. That study involved 390 breast cancer patients, all of whom were BRCA mutation carriers, who were seen at 12 cancer genetics clinics.

Bilateral mastectomy was performed in 181 women. During 20 years of follow-up, 79 women died. The 20-year survival rate was 88% among women who underwent bilateral mastectomy and 66% anong those who underwent unilateral surgery.

On multivariate analysis, which took into account prognostic factors, this equated to a 48% reduction in death from breast cancer among women who underwent bilateral mastectomy in comparison with those who did not (P = .03).

That 2014 study shows that undergoing a bilateral mastectomy does improve survival.

Regarding the current study, Dr Narod noted that although there were 54 contralateral breast cancers in BRCA carriers during follow-up, only 21 BRCA-positive women underwent bilateral mastectomy.

He suggested that had Dr Eccles and colleagues performed bilateral mastectomy as a matter of course in BRCA carriers, they "would have prevented 54 contralateral breast cancers."

Dr Narod also noted that, because it takes an average of 6 years after the primary diagnosis to be diagnosed with a contralateral breast cancer and another 5 to 6 years to die from the contralateral disease, "it takes 10 years to save a life from a contralateral breast cancer.

"If you look at our 2014 BMJ paper, it's very clear: the curves don't separate for 10 years," he said.

In other words, if a woman with a BRCA mutation dies of breast cancer in the first 10 years after diagnosis, she dies of the first breast cancer. "If you die from breast cancer from year 10 to 20, you're dying of the second breast cancer," he added.

The question of whether the follow-up period in the current study was long enough to determine the impact of BRCA mutations on survival is made more relevant by the fact that the average age of the women in the study was only 36 years.

"These are young women," Dr Narod said. "You don't want them to live to 46. If the goal is to make them live to 46, you don't treat them with bilateral mastectomy.

"If you want to make them live until 70 without bilateral breast cancer, you'd better do a bilateral mastectomy."

Dr Narod said that it is "very strange" that the article does not present a conclusion based on the survival outcomes with respect to whether genetic testing for BRCA mutations should be carried out at all.

"At the end of the day, do you recommend genetic testing during the diagnosis of a 36-year-old woman with breast cancer or do you not? We recommend it. There's no question. I recommend it," he said.

This study was funded by Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant. Dr Eccles has received honoraria from AstraZeneca and Pierre Fabre. One coauthor has received honoraria from Roche, and one coauthor has received honoraria from GlaxoSmithKline and Pfizer. Other authors have disclosed no relevant financial relationships. Dr Fasching has received grants from Novartis and personal fees from Novartis, Pfizer, Roche, Amgen, and Teva.

Lancet Oncol. Published online January 11, 2018. Full text, Editorial

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