Bilateral Breast Cancer

Age

Prior to the advent of genetic testing, large studies from England and Connecticut (along with the large personal experience of Haagensen) demonstrated that family history and young age at first cancer were strongly related to the risk of bilateral breast cancer. More recent reports allow greater nuance in risk assessment. The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study demonstrated that for noncarriers of BRCA1 and BRCA2 mutations with no family history, the 10-year cumulative risk of CBC was approximately 4.6% in women aged 25 to 54 years at first diagnosis. For the same age group this risk increased to 15.6% for noncarriers with a bilaterally affected first-degree relative, and to 18.4% for BRCA1/2 mutation carriers. In a more recent and definitive prospective cohort study from Kuchenbaeker and colleagues the 20-year cumulative risk of CBC for BRCA1 and BRCA2 mutation carriers was 40% (95% CI 35–45%) and 26% (95% CI 20–33%), respectively; the risk of CBC was higher with younger age at first cancer, and with a history of breast cancer in a first- or second-degree relative. Tumor subtype is also related to the risk of CBC; Nichols and colleagues using SEER data found that age-specific CBC rates for women diagnosed before age 30 were 0.45%/year for ER-positive breast cancer versus 1.26%/year for ER-negative disease. Although young age at diagnosis is a strong indication for genetic testing, in younger women with ER-positive cancers and who are noncarriers the risk for CBC is modest and closer to that of breast cancer population overall.

Hereditary Breast Cancer

Approximately 5% to 10% of breast cancers are hereditary and associated with an inherited germline mutation. Mutations in the genes BRCA1 and BRCA2 account for most hereditary breast cancers and across an extensive literature the most recent estimates suggest a lifetime breast cancer risk of 72% and 69%, respectively. The risks of CBC—as above—are higher as well, and highest for women who develop their first breast cancer at a young age. This substantial risk of CBC among the youngest BRCA1 and BRCA2 carriers, particularly those women <40 years of age, should be considered when counseling them on surgical options at the time of their first cancer.

Multigene panel testing has led to the identification of additional non- BRCA gene mutations for which the risk of breast cancer appears to be lower than for BRCA1/2 , but is statistically significant for PALB2 , CHEK 2 , and ATM . Risk appears to be the highest for PALB2 but is highly dependent on family history, with risk by age 70 years ranging from 33% (for PALB2 carriers with no family history) to 58% (for those with premenopausal breast cancer in two or more first-degree relatives). There are to date no reliable risk estimates for CBC in women with non- BRCA mutations, so treatment decisions must be based on patients’ other risk factors—especially age and family history—and not on their gene mutation per se.

Multigene panel testing also identifies “variants of uncertain significance” (VUS), in which it is unclear whether the altered amino acid sequence impairs the protein function. Until sufficient evidence of increased risk emerges for a particular mutation, VUS are not clinically actionable and should not be used to counsel patients on the risk of breast cancer, and especially the risk of CBC.

Family History

Family history of breast cancer is a well-established risk for breast cancer, even in the absence of a known genetic mutation. Seventy-four studies from the pre- BRCA era relate family history to the risk of breast cancer and are the subject of a comprehensive meta-analysis. Taken together, they confirm that an affected family member increases the relative risk (RR) for developing breast cancer: 1.9 for any relative, 2.0 for a mother, 2.3 for a sister, 1.8 for a daughter, 3.6 for mother and sister, and 1.5 for a second-degree relative.

The WECARE study assessed the risk for CBC among affected non- BRCA women with a family history of breast cancer. Those with an affected first-degree relative had an almost twofold greater risk of developing CBC (RR 1.9) compared with women with no family history. Risk of CBC was also related to the age at diagnosis of the affected patient, the age at diagnosis of the family member, and the extent of the family history ( Fig. 66.1 ). Bilateral breast cancer in an affected relative was a strong predictor of CBC risk, with a 10-year cumulative risk comparable to that of BRCA mutation carriers (15.6% vs. 18.4%, respectively), suggesting that family history should always be part of counseling regarding the risk of CBC.

Radiation Exposure

Increasing use of breast-conserving surgery plus radiotherapy (RT) for early-stage breast cancer has raised concern about the possibility of CBC induced by low-dose radiation scatter. This has not been observed. Two major trials of breast conservation versus mastectomy, the National Surgical Adjuvant Bowel and Breast Project (NSABP) B-06 and the Milan trial, each with 20-year follow-up, did not find any differences in the frequency of CBC with or without RT. These data do not absolutely rule out a relationship between RT and the risk of CBC. In the 2005 EBCTCG overview (a meta-analysis of 46 randomized trials of RT vs. no RT and 17 trials of RT vs. more surgery, in 32,800 patients) the incidence of CBC at 15 years was significantly higher with RT versus none, but the absolute difference was small (9.3% vs. 7.5%, P = 0.002). These data do not take into consideration the increased precision of contemporary RT techniques, the trend toward smaller treatment fields and—for women over the age of 70 years—the option of no RT at all.

A striking exception to the preceding findings is the increased risk of breast cancer in young women treated with mantle RT for Hodgkin’s lymphoma. Early reports suggested very high risks of breast cancer and even of CBC, with a study of childhood cancer survivors suggesting cumulative breast cancer risk comparable to the of BRCA1 mutation carriers, 30% by 50 years of age. A more recent study from the Netherlands of 3905 patients treated for Hodgkins between the ages of 15 and 50, surviving at least 5 years and followed a median of 19 years, is more encouraging. Although breast cancer was the most frequent second cancer, the cumulative risk of breast cancer at 30 years was 16.6% (95% confidence interval [CI] 14.1%–19.2%), lower than previously observed. The evidence for an increased rate of synchronous or metachronous CBC following RT for Hodgkins is limited by very small patient numbers and is to date inadequate to counsel patients. The increased risk for a first breast cancer is clear, mainly for women treated at younger ages. This risk appears to be higher than for the general population, but lower than initially thought.