Oophorectomy plus chemotherapy should now be considered a standard of care for women with breast cancer and BRCA1 mutation. That is the conclusion of researchers in a study published in the September 10 issue of the Journal of Clinical Oncology (2013;31:3191-3196). The study followed 3,345 women in Poland who were age 50 and under who had stages I-III breast cancer in Poland.
The prevalence of BRCA1 mutation in that country is one of the highest in the world, noted the study's senior author, Steven A. Narod, MD, Professor of Medicine at the University of Toronto and Director and Senior Scientist at the Familial Breast Cancer Research Unit of the Women's College Research Institute.
Among the 233 women in the study with the BRCA1 mutation, those who had oophorectomy had a 70 percent reduction in mortality compared with women with intact ovaries.
Chemotherapy also had a profound effect on reducing mortality, the research showed, confirming another recent report by Narod and colleagues (Breast Cancer Res Treat 2013;138:273-279).
In the new study, the 10-year survival rate among breast cancer patients with BRCA1 mutation was similar to that of patients without the mutation—80.9 vs 82.2 percent, respectively.
“The take-home message is that we should consider testing every newly diagnosed patient with breast cancer, especially women under age 50, because if they have a BRCA1 mutation we can implement these recommendations right away,” Narod said.
He said that based on these data, he would recommend treating all women with BRCA1-positive breast cancer with chemotherapy and oophorectomy, especially those with tumors one cm or larger.
“We should think about instituting wide-scale genetic testing for women under age 50 at diagnosis,” Narod said in a telephone interview. “Most women who have BRCA1 mutation in the U.S. probably don't know it. It's no use having these findings unless people know their mutation status.”
He said that in a research program at Women's College Hospital, all women with breast cancer under age 50 are being offered genetic testing for BRCA1.
In this study, the researchers' first aim was to study outcomes in women with small node-negative breast cancers—important because it directly reflects on screening vs. preventive oophorectomies. “We found that a percentage of women with 1 cm tumors were node positive, and that worries me about screening,” he said.
“We also found that 10 percent of women with small node-negative cancers died. From that point of view it suggests we are not where we want to be in cancer prevention relying on screening, because a lot of them will be node positive—a very bad prognostic feature. So the first message is that we should be thinking of preventive surgery and not relying on screening.”
The second question was about the optimum treatment—the options being chemotherapy, mastectomy, tamoxifen, or oophorectomy.
Far and away the most important treatment is oophorectomy, Narod said.
“That's going to be a hard pill for medical oncologists to swallow, since they generally think chemotherapy should take precedence and the important thing is to get the chemo done, then have surgery, and then think about oophorectomy,” he said. “I suggest that's probably the wrong order—oophorectomy is probably a bigger life-saver than the chemotherapy.”
Narod said he didn't expect one paper on that to be sufficient to change medical practice, but it is an important question because there is growing evidence that the risk of death can be reduced by 70 percent with oophorectomy if done immediately after breast surgery. Oophorectomy is generally not used as a treatment for breast cancer in North America as much as in Europe, he noted.
The study's first author is Tomasz Huzarski, MD, PhD, of the International Hereditary Cancer Center of Pomeranian Medical University in Szczecin, Poland. The women in the study were tested in 17 clinics in the Polish Hereditary Breast Cancer Consortium.
Narod said that about six percent of women in Poland have the BRCA1 mutation. That is high, but the prevalence is even higher in the Bahamas, at 28 percent, and the prevalence is also high in Iceland.
For this prospective study, genetic testing for the three most common mutations in BRCA1—5382insC, C61G, and 4153delA—had been offered to unselected women with newly diagnosed breast cancer in Poland since 1996.
The researchers cautioned that these data may not apply to women with other BRCA1 mutations or ethnicities: “We know that in the U.S. and Poland the mutations are the same, although we can't say if the tumors are the same,” Narod said.
Debu Tripathy: U.S. and Poland Differ on Timing
Asked for his opinion for this article, Debu Tripathy, MD, Professor of Medicine and Co-Leader of the Women's Cancer Program at USC/Norris Comprehensive Cancer Center, said that oophorectomy is generally the recommendation that oncologists give to breast cancer patients in the U.S. who have BRCA1 or BRCA2 mutations, compared with the situation in Europe, where it is a much more standard recommendation and women are advised to have oophorectomy sooner.
“Here we tell patients to have the oophorectomy at some point—maybe after child bearing, but not immediately,” he said.
It is known that oophorectomy lowers the risk of breast cancer and breast cancer mortality, especially if done well below menopause, he said, noting that the procedure also lowers the rates of both ovarian cancer and the mortality from the disease.
Tripathy said he tells patients that if they are planning on having children, they should have an oophorectomy soon afterward, and to try to complete child-bearing by their mid-30s. “I think this study will lead medical oncologists and genetic counselors and surgical oncologists [in the U.S.] to look at the data and consider whether it is time to have the guidelines a little more clearly written,” he said.
Other Pathways Possible
Narod said it is a puzzle why oophorectomy appears to affect survival in women with predominantly ER-negative tumor—suggesting that the hormone-responsive cells may not be the cancer cells themselves but rather other cells in the breast matrix, and that the estrogen receptor is not the only relevant pathway.
It may also be that latent metastatic lesions are hormone responsive, he said: “The relationship between BRCA1 and estrogen receptor and progesterone receptor is complicated. BRCA1 regulates progesterone and estrogen, but there are also cells in the breast tissue other than cancer cells that respond to these receptors and transmit other signals into cancer cells through pathways other than estrogen receptors.”
Tripathy said it is known that oophorectomy and also tamoxifen are effective as prevention and appear to lower mortality risk, but mostly in ER-positive cancers. But there is also evidence that tamoxifen lowers the risk of a second, contralateral breast cancer in women who carry the BRCA1 gene.
“It could be that early precursors of breast cancer, even the ones that are destined to be ER negative, go through some period where they do require estrogen,” Tripathy said. “So even by the time they are diagnosed and the tumor does not have estrogen receptors and at that point we know that they do not benefit from adjuvant tamoxifen, they still might benefit from some hormonal intervention in the pre-cancer period.”