SCREENING AND PROPHYLAXIS FOR BREAST CANCER
Screening for breast cancer is based upon the detection of early cancer and not of a premalignant lesion (Smith et al. 2000). Despite a meta-analysis that concluded that there is a reduction up to 18 % of the breast cancer mortality among 40–49 years old women following regular mammographic screening, the effectiveness of this tool for the surveillance of premenopausal women remains debatable. Indeed, after decades of research, the “mammography debate” continues with much vitriolic comment (Rogers 2003), and it seems unlikely that new data will help to resolve the issues easily (Goodman 2002).
The efficiency of screening should be higher if the women screened are at increased risk because of a family history of breast cancer, but as yearly mammography seems to be rather ineffective in BRCA1/2 carriers (Brekelmans et al. 2001; Goffin et al. 2001; Tilanus-Linthorst et al. 2002), other screening modalities such as MRI have been found to be superior at detecting breast cancers.
Magnetic resonance imaging (MRI) is a non-ionizing imaging technique that has already been demonstrated to be sensitive for invasive breast cancer. Its sensitivity is less impaired than mammography by dense parenchyma.
Preliminary results of a German prospective nonrandomized pilot project (including 192 asymptomatic women proved or suspected to be BRCA1/2 mutation carriers) demonstrated that the sensitivity and specificity of breast MRI was superior to conventional mammography and high-frequency breast ultrasound (Kuhl et al. 2000). Much larger studies in North America and Europe have confirmed that MRI is superior to mammography for the detection of breast cancers in BRCA1/2 carriers (Kriege et al. 2004; Warner et al. 2004, 2011). It is not known if this will translate to a better long-term outcome but the data on medium-term survival are encouraging (Rijnsburger et al. 2010; Passaperuma et al. 2012). Interestingly, among those who develop an MRI-detected breast cancer, the survival for BRCA1 mutation carriers may be inferior to BRCA2 mutation carriers, and different screening regimens may be required for younger BRCA mutation carriers (Heijnsdijk et al. 2012).
For some women at very high risk of breast cancer (e.g., BRCA1 or BRCA2 mutation carriers, those with Cowden syndrome, Li–Fraumeni syndrome, or occasionally an undiagnosed dominant breast/ovarian cancer pedigree), preventive bilateral mastectomies may be the preferred option, but the women require careful counseling and a discussion of the residual risk of breast cancer following different types of surgical procedure (a subcutaneous mastectomy, leaving the nipple, may have a measurable residual risk, and a total mastectomy, with or without nipple-sparing, is probably the preferred option). Information is still accumulating about the efficacy of such prophylactic surgery, but so far, invasive breast cancers appear to be very rare after total mastectomy in BRCA1/2 mutation carriers (Meijers-Heijboer et al. 2001; Rebbeck et al. 2004); by contrast, there are several reports of invasive breast cancer following subcutaneous mastectomy in BRCA1 (Rebbeck et al. 2004) and BRCA2 (Kasprzak et al. 2005) mutation carriers. Contralateral mastectomy should also be considered for women likely to be BRCA1/2 mutation carriers who have had breast cancer because their risk of contralateral breast cancer is substantially increased to approximately 40 % at 10-year follow-up. Notably, the risk is reduced by tamoxifen and oophorectomy (Metcalfe et al. 2004). Testing at time of breast cancer diagnosis is likely to increase the frequency of initial contralateral mastectomy (Schwartz et al. 2004).
At present, many screening protocols for BRCA1/2 carriers include ovarian cancer surveillance, but the true value, if any, of regular assessment with CA-125 and transvaginal ultrasound is unknown, and both case reports (e.g., Hebert-Blouin et al. 2002) and recent biological data (Berns and Bowtell 2012), combined with modeling (Brown and Palmer 2009), suggest that these cancers arise very quickly and are probably not amenable to any currently available form of screening.
The role of chemoprophylaxis is still unclear in women with a family history of breast cancer, but drugs such as tamoxifen may be considered for such at-risk women; the data are conflicting, but point towards a benefit even for women who are destined to develop an ER-negative breast cancer.
Although tamoxifen was rarely prescribed for this purpose by US oncologists (Robson 2002), it has now been recommended that either tamoxifen or raloxifene should be offered for 5 years to postmenopausal women with a uterus and at high risk of breast cancer, unless they have a past history or may be at increased risk of thromboembolic disease or endometrial cancer, in the updated NICE guidelines, which also provide guidance on risk assessment and surveillance, at http://www.nice.org.uk/CG164.
Use of the oral contraceptive pill (OCP), even for relatively short periods, is protective against ovarian cancer in BRCA1/2 mutation carriers (Narod et al. 1998). The situation for breast cancer risk is less clear. There have been four major studies. A large case-control study showed that early use, use before 1975, and prolonged use (>5 years) was associated with significantly increased risks of breast cancer among BRCA1, but not BRCA2 mutation carriers (Narod et al. 2002). By contrast, a population-based study found no evidence for increased risk and even some suggestion of a decreased risk for BRCA1 carriers (Milne et al. 2005). A third study found no excess risk for women diagnosed with breast cancer under 50 for women using the OCP for one year; for BRCA2, there was a slightly increased risk for women who used the OCP for more than 5 years (Haile et al. 2006). The most recent, a retrospective cohort study of 1,593 BRCA1/2 mutation carriers, found an increased risk of breast cancer for BRCA1/2 mutation carriers who ever used oral contraceptives (adjusted hazard ratio [HR] = 1.47; 95 % CI, 1.16–1.87). HRs did not change when considering time since stopping use, age at start, or year of starting. Longer use was associated with an increased risk of breast cancer for both BRCA1 and BRCA2 mutation carriers, most notably among young women who used the OCP before their first full-term pregnancy (4 or more years of use before first full-term pregnancy was associated with a HR of 1.49 [95 % CI, 1.05–2.11] for BRCA1 mutation carriers and HR = 2.58 [95 % CI, 1.21–5.49] for BRCA2 mutation carriers) (Brohet et al. 2007). Thus, there is no consensus between the four studies. Perhaps, until larger prospective studies are completed, it might be prudent to avoid OCP use in young BRCA1/2 mutation carriers (i.e., less than 25 years old) who have not had a full-term pregnancy. On the other hand, a decision to pursue genetic testing prior to considering OCP use in a young woman at known genetic risk who is not otherwise inclined to learn of her mutation status would need to be carefully considered.