Three specialists discuss the different approaches to managing breast cancer patients with a family history of BRCA mutations.
For women with hereditary breast cancer, deciding on the best treatment option can be challenging. Should they opt for surgical removal of the contralateral breast to forestall another breast cancer down the road? Are they candidates for breast-conservation therapy? Is their prognosis the same as that of women with sporadic cancer? Are there any definitive answers to these questions?
Yes and no, depending on which specialist is treating patients in this unique population. Data on surgical options are limited, said Marian B.E. Menke-Pluymers, MD, PhD, a breast cancer surgeon at Erasmus University Medical Centre–Daniel den Hoed Cancer Centre in Rotterdam, the Netherlands.
For the radiation oncologist, local failure after breast-conservation treatment is a serious concern, according to Abram Recht, MD, professor of radiation oncology at Harvard Medical School and deputy chief of the department of radiation oncology at Beth Israel Deaconess Medical Center, both in Boston.
Finally, for the medical oncologist, despite nearly two decades’ worth of advances in the management of BRCA1 and BRCA2 mutation carriers, data specific to the management of such patients are only now becoming available, explained Susan M. Domchek, MD, an associate professor at Abramson Cancer Center, University of Pennsylvania School of Medicine in Philadelphia. Dr. Domcheck will give a talk at SABCS 2010 on the management of women with a significant predisposition to breast cancer (December 8, Ballroom C-2).
"Guidance of these patients is complex and demands a multidisciplinary approach, preferably within the setting of a family cancer clinic," Dr. Menke-Pluymers said. "There are no data in the literature on the optimal treatment for breast cancer in gene mutation carriers so far."
Surgery and recurrence
A discussion of surgical treatment strategies requires the following:
• An awareness of the risks of systemic and local recurrence
• An understanding of the risk of a second primary or contralateral breast cancer
• An understanding of the value of risk-reducing strategies such as prophylactic contralateral mastectomy, adjuvant systemic therapy, and prophylactic oophorectomy
Asymptomatic BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 50% to 85%. Those with unilateral breast cancer have a 3% to 4% annual risk of developing a breast cancer in the contralateral breast, compared with 0.3% to 0.5% for patients with sporadic breast cancer, Dr. Menke-Pluymers said (Ann Oncol 17:391-400, 2009; J Clin Oncol 24:2437-2443, 2006).
It also appears that the cumulative risk of developing a contralateral breast cancer is higher for BRCA1 mutation carriers than it is for BRCA2 carriers, and that the risk increases with younger age at diagnosis of the primary tumor, she noted (J Clin Oncol 35:5887-5892, 2009; SABCS 2009 abstract 903).
There are also differences in risk between BRCA-associated breast cancer and familial, non-BRCA disease, she said. Distinguishing between these two groups before choosing a surgical treatment strategy is vital. "For patients with a family history, but without a proven mutation, it is most difficult to estimate the risk of contralateral breast cancer. The risk will depend on the pedigree of that particular family. It is important to confer with a geneticist," she stressed.
Breast-conservation treatment is an option if the tumor size is favorable in relation to the size of the breast. But before offering this choice, it is imperative to know the risk of ipsilateral breast tumor recurrence. Ipsilateral breast tumor recurrence rates of 20% to 40% following breast-conserving therapy have been reported after a follow up ranging from six to 10 years, Dr. Menke-Pluymers said (Lancet 359:1471-1477, 2002; Eur J Cancer 40:1150-1158, 2004; J Natl Cancer Inst 91:2112-2117, 1999; Eur J Cancer 41:2304-2311, 2005; SABCS 2009 abstract 959).
Given the high risk of ipsilateral breast cancer recurrence, patients may opt for ipsilateral mastectomy. But patients with a BRCA1 or 2 mutation also have a high risk of contralateral breast cancer, and they may therefore opt for prophylactic contralateral mastectomy. This significantly reduces the risk of contralateral breast cancer development but is not associated with improvement of breast cancer-related survival and overall survival (J Clin Oncol 22:2328-2335, 2004; N Engl J Med 345:159-164, 2001).
Prophylactic bilateral oophorectomy and tamoxifen have also been shown to reduce the risk of contralateral breast cancer, and there may also be a role for adjuvant chemotherapy in reducing this risk, particularly in patients treated before the age of 45, she said.
For hereditary breast cancer patients who are considering radiation and breast-conservation therapy, issues that need to be addressed include the following:
• Local failure after breast-conservation therapy
• Breast cancer-specific survival rates after breast conservation therapy vs ipsilateral mastectomy
• Complications in BRCA1 and BRCA2 mutation carriers
• Radiation carcinogenesis, particularly for cancers in the contralateral breast
With regard to local failure, "the long and short of it is, there is really no impact of family history per se on the risk," Dr. Recht said. No link has been found in studies of patients with any family history or patients with a first-degree relative with breast cancer (Int J Radiat Oncol Biol Phys 31:295-303, 1995; Breast J 1:202-209, 1995; Ann Surg Oncol 9:912-919, 2002; Breast J 2:238-245, 1996; J Clin Oncol 16:2045-2051, 1998).
However, in patients with BRCA1 or BRCA2 mutations, some studies show no or minimal differences between such patients and those with sporadic cancers (J Clin Oncol 24:2437-2443, 2006; Ann Oncol 17:391-400, 2006) while others show a substantial difference between these groups of patients, he noted (Ann Surg Oncol 11:157-64, 2004; J Clin Oncol 91:2112-2117, 1999; Lancet 359:1471-1477, 2002).
A multicenter international study of breast-conservation therapy vs mastectomy in BRCA1 and BRCA2 mutation carriers found that the risk of local failure was low in individuals treated with mastectomy, but continued to increase in women treated with breast-conservation therapy (Breast Cancer Res Treat 121:389-398, 2010).
These results were not surprising, he said. But what was striking was the dramatic difference in the long-term risk for local failure after breast-conservation therapy between patients who underwent chemotherapy and those who did not.
"In patients who had chemotherapy, the local failure rate at five years was 3%, at 10 years it was 8%, and at 15 years it was 11%. But in the minority who did not have chemotherapy, for whatever reason, the failure rate at five years was 8%," Dr. Recht said. "At 10 years it was 17% and at 15 years it was a whopping 44%. We know from other studies, which did not [categorize between] patients according to family history of BRCA status, that treating with systemic therapies substantially reduces the risk of local failure in patients treated with breast conservation. That is likely the case here." Systemic therapies also reduce the risk of developing new primary cancers, he added.
Complications after radiation therapy have been a concern in patients with BRCA mutations, but recent data may minimize those concerns, Dr. Recht said.
A retrospective UK study looked at 37 BRCA1 and 18 BRCA2 patients treated between 1983 and 2002 and found no difference in the risk of complications in those patients treated with breast-conserving therapy and those treated with mastectomy. After a median follow up of 81 months in the BRCA group and 94 months in the non-BRCA controls, the rate of complications—including rib fractures, lung fibrosis, soft tissue and bone necrosis, breast fibrosis, telangectasias, and severe changes in size and shape of the breast—was similar in the two groups (Clin Cancer Res 12:7025-7032, 2006).
However, other genes may contribute to the risk of complications. For example, polymorphisms in the ATM gene have been shown to be associated with an increased risk of fibrosis in patients undergoing breast-conservation therapy, Dr. Recht said (Int J Radiat Oncol Biol Phys 64:776-783, 2006; Int J Radiat Oncol Biol Phys 69: 677-684, 2007).
In addition, patients with p53 mutations or Li-Fraumeni syndrome may be at increased risk of developing in-field radiation therapy-related cancers, he noted (Clin Oncol 19:490-493, 2007; Int J Cancer 96:238-242, 2001).
"It’s clear that we are just beginning to understand the impact that mutations and polymorphisms and other genes have on the risk of complications," Dr. Recht said. "I would encourage you, if you have data on these patients, to investigate and publish it. And I would also encourage you not to assume that we really know how best to manage these patients.
Promise of PARP
BRCA mutation carriers with early-stage disease should receive standard adjuvant systemic therapy based on the features of their primary tumors, Dr. Domchek said.
Early studies in BRCA mutation carriers suggested a worse prognosis compared with patients with sporadic breast cancer, but recent research offers more promising news, she noted. For instance, treatment-related toxicity does not appear to be any worse in mutation carriers (N Engl J Med 357:115-123, 2007; Breast Cancer Res 6:R8-R17, 2004; Int J Cancer 121:1017-1020, 2007; Eur J Cancer 43:867-876, 2007).
"Because of the role of [BRCA] in homologous DNA repair, an excess of toxicity to chemotherapy is possible in these patients," she said. "Limited data from a retrospective study of 62 BRCA1 and BRCA2 mutation carriers who were matched with sporadic controls [showed] no excess toxicity with the chemotherapy regimens that were used" (Clin Cancer Res 12:7033-7038, 2006).
In the metastatic setting, BRCA carriers demonstrated high response rates to anthracycline or chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil, suggesting that the tumors of BRCA1 and BRCA2 mutation carriers might actually be more sensitive to chemotherapy than those of sporadic cancer patients, Dr. Domchek said (J Clin Oncol 27:3764-3771, 2009).
In addition, preclinical and early clinical data suggest that BRCA-associated breast cancers may have enhanced susceptibility to platinum agents. Dr. Domchek cautioned that the total published experience on cisplatin in BRCA1 carriers with early-stage breast cancer is only 14 patients. "Although a lot of people are enthusiastic about this, we really do need to wait, especially since the overall prognosis in mutation carriers is similar to that of sporadics," she said.
Poly (ADP-ribose) polymerase (PARP) inhibitors are generating a great deal of excitement as a possible treatment for BRCA1 and 2 mutation tumors, Dr. Domchek said. In vitro studies have shown that PARP inhibition kills BRCA1- and BRCA2-deficient cells, but does not kill cells with one normal and one mutated copy of BRCA1 or BRCA2.
PARP inhibitors quickly entered clinical trials, Dr. Domchek said. In a recent phase I study, the oral PARP inhibitor olaparib (AZD-2281) demonstrated activity in BRCA carriers and exhibited low toxicity. In 19 BRCA1 and BRCA2 mutation carriers with breast, ovarian, and prostate cancers, nine had objective responses (response rate = 47%) and three had extended stable disease (N Engl J Med 361:123-134, 2009).
There are several PARP studies now ongoing, and there will be many more, Dr. Domchek said. "I encourage everyone to try to get your BRCA1 and BRCA2 mutation carriers on PARP inhibitor studies," she said. "These trials are critical to understanding the optimal systemic regimens in BRCA1 and BRCA2 mutation carriers. It may sometimes feel like a bit of a puzzle to figure out how to get people on these trials, but it is worth the effort."
Source: ASCO 2010 education session.