update on hereditary breast cancer

Update on Hereditary Breast CancerKaren Lisa Smith, MD, MPH and Mark E. Robson, MD

Corresponding authorMark E. Robson, MD Memorial Sloan-Kettering Cancer Center, Clinical Genetics and Breast Cancer Medicine Services, Department of Medicine, 1275 York Avenue, New York, NY 10021, USA. E-mail: [email protected]

Current Oncology Reports 2006, 8:14–21Current Science Inc. ISSN 1523-3790Copyright © 2006 by Current Science Inc.

Women with BRCA1 or BRCA2 mutations are at substantial risk for breast and ovarian cancer. This review describes recent developments in the approach to hereditary breast cancer. Risk-reducing surgeries remain the most effective means of preventing breast cancer in mutation carriers. For women with breast tissue at risk, magnetic resonance imaging is rapidly becoming incorporated into screening programs. For affected women, management does not currently differ from that of women with sporadic breast cancer, although women may choose to undergo bilateral mastectomy. Preclinical data suggest that BRCA muta-tion–associated breast cancers may benefit from specific targeted therapeutic approaches.

IntroductionBetween 5% and 10% of breast cancer cases are caused by germline mutations in highly penetrant cancer suscepti-bility genes that are inherited in an autosomal dominant manner [1]. Although breast cancer is a component of several hereditary cancer syndromes, approximately 85% of hereditary breast cancer cases are linked to mutations in the BRCA1 or BRCA2 genes [2]. The products of these genes are involved in multiple cellular processes, includ-ing DNA repair and transcriptional regulation in response to DNA damage. Although the prevalence of BRCA muta-tions in the general population is thought to be quite low, founder mutations present in certain ethnic groups lead to a comparatively high prevalence of mutation carriers. For example, one in 40 Ashkenazi Jews carries one of three founder mutations in BRCA1 or BRCA2 [3].

Carriers of BRCA1 and BRCA2 mutations are at increased risk for multiple malignancies, but risks are highest for breast cancer and ovary cancer. Cancer risk esti-mates vary, but a recent comprehensive review estimated cumulative risks of breast cancer by age 70 of 65% and 45% in BRCA1 and BRCA2 mutation carriers, respectively

[4••]. For ovary cancer, risks are lower, with estimated cumulative risks by age 70 of 39% and 11% in BRCA1 and BRCA2 mutation carriers, respectively. For breast cancer, much of the risk occurs at young ages, with women aged 30 to 49 years with BRCA1 mutations at a greater than 30-fold higher risk of breast cancer than women of the same age in the general population and women aged 30 to 49 years with BRCA2 mutations at between 10- and 16-fold higher risk than the general population. Some studies have suggested that the outcome of breast cancer associated with BRCA1 mutations is inferior to that of sporadic breast cancer, although this has not been confirmed in other studies. There are no data to suggest that the outcome of breast cancer associated with BRCA2 mutations is different from that of sporadic breast cancer [5].

Given the substantial breast cancer risk faced by mutation carriers, their frequent young age at diagno-sis, and possible inferior breast cancer outcome, special strategies are required for physicians caring for mutation carriers. This paper reviews current knowledge and recent advances in the approach to unaffected and affected BRCA mutation carriers.

Management of Unaffected Carriers of BRCA1 or BRCA2 MutationsIn light of the significant breast cancer risks faced by carriers of BRCA1 and BRCA2 mutations, it is generally recommended that such women undergo breast cancer risk–reducing interventions and/or intensive breast cancer surveillance. In addition, retrospective studies have sug-gested that breast cancer risk in BRCA mutation carriers may be modulated by reproductive and lifestyle factors.

Risk-reducing interventions in unaffected mutation carriersBreast cancer risk–reducing interventions for unaffected BRCA1 or BRCA2 mutation carriers include surgical options (prophylactic bilateral mastectomy or prophy-lactic oophorectomy) and chemoprevention (tamoxifen). Hartmann et al. [6] previously calculated that prophy-lactic bilateral mastectomy reduces breast cancer risk by greater than 90% in mutation carriers. This finding was confirmed by Meijers-Heijboer et al. [7], who observed a 100% reduction in the risk of breast cancer in muta-tion carriers who underwent bilateral prophylactic mastectomy. However, more women in the mastectomy

Update on Hereditary Breast Cancer Smith and Robson 15

group in their study had also undergone prophylactic oophorectomy, potentially biasing the results in favor of enhanced benefit of prophylactic bilateral mastectomy. The ultimate risk reduction may be slightly lower than 100%, as at least one woman in the Netherlands cohort has developed metastatic breast cancer after preventive mastectomy. More recently, in a retrospective cohort study of 105 clinically ascertained BRCA mutation carri-ers who underwent prophylactic bilateral mastectomies and 378 BRCA mutation carriers who did not, Rebbeck et al. [8•] confirmed the benefit of prophylactic bilateral mastectomy, demonstrating a breast cancer risk reduction of 91% to 95%.

Despite its efficacy, many BRCA mutation carriers are reluctant to undergo prophylactic bilateral mastectomy. Prophylactic oophorectomy is another surgical option that reduces breast cancer risk while simultaneously reducing the ovary cancer risk also faced by BRCA mutation car-riers. Rebbeck et al. [9] demonstrated that prophylactic oophorectomy reduces the risk of breast cancer by 47% in BRCA1 mutation carriers. This risk reduction was not demonstrated in the subset of subjects older than 50, however, raising a question about the efficacy of this procedure in postmenopausal mutation carriers and sug-gesting that the risk reduction resulted from the induction of premature menopause. In a subsequent retrospective cohort study, Rebbeck et al. [10•] confirmed their initial findings by observing a 53% breast cancer risk reduction and a greater than 90% ovary cancer risk reduction with prophylactic oophorectomy in women with either BRCA1 or BRCA2 mutations. In this study also, breast cancer risk was not reduced by prophylactic oophorectomy in women older than 50. In a prospective nonrandomized cohort study, Kauff et al. [11] demonstrated that prophy-lactic oophorectomy reduced the risk of the combined endpoint of breast cancer and BRCA-related gynecologic cancer by 75%, compared with women who chose to undergo radiographic surveillance. Because of these stud-ies, it is generally recommended that women with BRCA mutations consider prophylactic oophorectomy at the completion of childbearing.

The value of chemoprevention in reducing the risk of breast cancer in BRCA mutation carriers is currently uncertain. The P1 trial of 13,388 women at high risk for breast cancer (defined as at least 1.66% 5-year pre-dicted breast cancer risk) demonstrated a 49% reduction in breast cancer risk with tamoxifen [12]. However, a substudy focusing on BRCA mutation carriers alone found an insignificant trend toward a protective effect of tamoxifen in BRCA2 mutation carriers (OR=0.38, 95% CI 0.06–1.56), but no protection, and actually a trend toward increased risk in BRCA1 mutation carriers (OR=1.67, 95% CI 0.32–10.7) [13•]. The number of BRCA mutation carriers in this substudy, however, was small, and thus the potential value of tamoxifen in breast cancer risk reduction for BRCA mutation carriers has not been

fully explored. No data are available with regard to the use of newer antiestrogen agents, such as other selective estrogen receptor modulators or aromatase inhibitors in the prevention of breast cancer in mutation carriers.

Breast cancer surveillance in unaffected mutation carriersFor unaffected BRCA mutation carriers who choose not to undergo prophylactic bilateral mastectomy, breast cancer surveillance with the aim of diagnosing cancer at an early, curable stage is indicated. Until recently, the rec-ommendations for breast cancer screening in unaffected mutation carriers were similar to those for the general population and involved clinical breast examination and mammography but initiated at a younger age than in the general population. The sensitivity of mammography for breast cancer screening in mutation carriers, however, is significantly lower than that for the general population [14]. Potential reasons for this limited utility of screening mammography in women with BRCA mutations include its relative insensitivity in dense breasts and young women [15], the frequent benign appearance of BRCA mutation–associated cancers on mammography, and the occurrence of rapidly growing breast cancers in BRCA mutation carriers, leading to the development of cancers between regularly scheduled mammographic screening intervals and advanced cancers at diagnosis [14,16,17].

Given the relative insensitivity of screening mam-mography in BRCA mutation carriers, the significant breast cancer risk they face, the low uptake of prophylac-tic bilateral mastectomy, and the incomplete protection from prophylactic oophorectomy, improved screening methods are obviously needed. Recent advances in gado-linium-enhanced breast magnetic resonance imaging (MRI) have led to several prospective nonrandomized trials evaluating breast MRI in combination with other modalities for breast cancer screening in high-risk women (Table 1). These studies have consistently demonstrated superior sensitivity of MRI in comparison with other screening modalities at the expense of slightly reduced specificity and an increased false-positive rate. Reported sensitivities, specificities, and positive predictive values for MRI have ranged from 71% to 100%, 81% to 95%, and 7% to 57%, respectively. Importantly, most cancers detected by MRI have been small and node negative [18–20,21••,22,23]. However, although MRI has offered consistent advantages across studies in the detection of invasive breast cancer, mammography may still be supe-rior to MRI for the detection of ductal carcinoma in situ presenting with microcalcifications [20,23].

Although these studies are not directly comparable due to differences in the components and schedules of the screening programs, differences in patient populations, and differences in definitions of positive MRI studies, in aggregate they support the use of screening breast MRI. However, many issues remain to be resolved with regard

16 Breast Cancer

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and

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19]

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]W

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[23]

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55.2


to the appropriate use of screening MRI in BRCA muta-tion carriers. Although breast cancers diagnosed with MRI are of lower stage than breast cancers diagnosed by other screening modalities, there are not yet data indicating that breast MRI reduces breast cancer–related mortality, nor have there been any randomized trials comparing MRI with other screening modalities, although such trials would be unlikely to accrue participants at this point [24–26]. In addition, the imperfect specificity of MRI results in a certain number of false-positive studies, which require follow-up imaging or biopsies, potentially yielding sig-nificant patient anxiety and possibly impeding compliance [24,25]. Additional limitations of MRI include variations in technique and interpretation between centers, the require-ment for radiologist expertise and MRI-guided biopsy, patient claustrophobia, variations in breast parenchymal enhancement during different phases of the menstrual cycle, and the inability of patients with pacemakers or other prohibited devices to undergo MRI screening [25].

Although there is an emerging consensus that MRI screening should be a part of surveillance programs for mutation carriers, the optimal combination of screening modalities (MRI, mammography, clinical breast exami-nation, and ultrasound) and their frequency and timing (performed annually together or staggered throughout the year) remain uncertain [24,26]. Given the reduced sensitivity of MRI for the diagnosis of ductal carcinoma in situ (DCIS) and the substantial data supporting the use of screening mammography, it is unlikely that MRI will completely replace screening mammography. However, concerns about the potential for radiation-induced carci-nogenesis and the reduced sensitivity of mammography in very young women may lead to the development of age-specific screening protocols, in which mammogram screening is incorporated into the program after a period of screening with MRI alone.

Factors that modulate the risk of breast cancer in unaffected mutation carriersReproductive factors influence the risk of sporadic breast cancer and have therefore also been investigated as potential modulating factors in the risk of breast cancer in BRCA mutation carriers. The findings of vari-ous studies have been conflicting. Recently, however, Cullinane et al. [27] demonstrated a protective effect of higher parity in BRCA1 mutation carriers but a deleteri-ous effect among BRCA2 mutation carriers in a matched case–control study of 1260 unaffected and 1260 affected BRCA mutation carriers. For BRCA1 mutation carriers, having four or more children in comparison with hav-ing no children was associated with a 38% reduction in breast cancer. In contrast, for BRCA2 mutation carriers, breast cancer was increased 1.5-fold in those with two or more children compared with those with no children. For the BRCA2 mutation carriers who were under age 50, the risk of breast cancer increased by 17% for each

additional birth and was particularly high in the 2 years after delivery [27]. The opposing influence of parity on breast cancer risk in BRCA1 and BRCA2 mutation carriers demonstrated in this study may explain the conflicting results seen in prior studies that grouped carriers of the two mutations together.

In BRCA1 mutation carriers, breast feeding has been shown to be protective against breast cancer. A recent case–control study of 965 BRCA1 or BRCA2 mutation carriers who developed breast cancer and 965 unaffected mutation carriers demonstrated a 45% reduction in breast cancer in BRCA1 mutation carriers who breast fed for longer than 1 year in comparison with those who did not breast feed. This association was not seen for BRCA2 mutation carriers [28].

With regard to oral contraceptives, previous studies have suggested an increased risk of breast cancer asso-ciated with the use of oral contraceptives in mutation carriers. In particular, this association was demonstrated in BRCA1 mutation carriers, and especially for those who took the pill prior to 1975 [29]. In contrast, in a recent population-based case–control study among BRCA muta-tion carriers, Milne et al. [30•] demonstrated a protective effect of modern-day oral contraceptives against breast cancer for BRCA1 mutation carriers. In this study, oral contraceptive use for at least 12 months was associated with a 78% reduction in the risk of breast cancer among BRCA1 mutation carriers. This protective effect was not observed for BRCA2 mutation carriers. The remarkably strong protective effect of oral contraceptives in this study remains to be explained.

Overall, with the exception of the protective effect of breast feeding, data regarding the influence of reproduc-tive factors on breast cancer risk in BRCA mutation carriers are conflicting. Because prospective studies in this area are unlikely to be performed, one must rely on retrospective data, which is subject to bias. Given the conflicting data, specific recommendations regarding parity and contracep-tion are generally not made for BRCA mutation carriers.

Other factors with a potential impact on breast can-cer risk in BRCA mutation carriers include smoking and coffee intake. Smoking was previously thought to be pro-tective against breast cancer in BRCA mutation carriers; however, a recent study demonstrated no significant asso-ciation between smoking and breast cancer risk in BRCA mutation carriers [31]. With regard to the impact of coffee intake on breast cancer risk in BRCA mutation carriers, a recent case–control study demonstrated that coffee intake is unlikely to be harmful and may be protective [32].

Management of Affected Carriers of BRCA1 or BRCA2 MutationsBased on current data, the management of BRCA muta-tion–associated and sporadic breast cancers need not differ, although surgical decisions often do.

18 Breast Cancer

Characteristics of BRCA mutation–associated breast cancersIn comparison with sporadic breast cancers, BRCA1 mutation–associated breast cancers are more likely to be hormone receptor and HER2-neu negative and to have higher grade. In addition, DCIS is less frequent in BRCA1 mutation–associated breast cancers than in sporadic breast cancers. In contrast, BRCA2 mutation–associated breast cancers tend to have similar features to sporadic breast cancers [33].

Breast cancers have recently been classified into several subtypes based on gene expression, with the basal epithe-lial subtype associated with worse prognosis. It has recently been shown that BRCA1 mutation–associated breast cancer is often of the basal epithelial subtype, a finding that may explain the inferior prognosis observed in some studies of BRCA1 mutation–associated breast cancers [34•].

Surgical options for BRCA mutation–associated breast cancersAs with women with sporadic breast cancer, surgical options for the management of breast cancer in women with BRCA mutations include breast-conserving therapy (BCT) or mastectomy. However, women may also choose to undergo bilateral mastectomy for contralateral risk reduction. Issues relevant to surgical decisions for BRCA mutation carriers with breast cancer include the risks of ipsilateral breast tumor recurrence (IBTR) and contralat-eral breast cancer.

Prior studies have suggested that rates of IBTR after BCT in BRCA mutation carriers exceed those observed in women with sporadic breast cancer [35,36•]. For exam-ple, Haffty et al. [36•] demonstrated that after 12 years of follow-up, rates of IBTR were 49% in the BRCA group and 21% in the sporadic cancer group. In BRCA mutation carriers, IBTR often occurs late, suggesting that it may reflect a new primary breast cancer rather than a recur-rence [36•]. With regard to contralateral risk, women with BRCA mutations have shown a greater than three-fold higher risk than women with sporadic breast cancers [35]. In the study by Haffty et al. [36•], rates of contralat-eral breast cancer in mutation carriers and women with sporadic cancer at 12 years of follow-up were observed to be 42% and 9%, respectively.

More recent data, however, have been conflicting with regard to the issue of risk of IBTR in BRCA mutation carriers. As in prior studies, a recent case–control study suggested that IBTR risk is higher in women with muta-tions than in women with sporadic breast cancer (21.8% vs 12.1%) [37]. In contrast, the recent retrospective cohort study by Robson et al. [38] suggested that there is no dif-ference in the risk of IBTR after BCT between mutation carriers and women with sporadic breast cancer. Although it lacked a comparison arm, a recent case series of a pro-spectively followed cohort of 87 affected women with BRCA mutations also demonstrated lower rates of IBTR

than those observed in some previous studies (5- and 10-year risks of 11.2% and 13.6%, respectively). Given the level of these risks, which are similar to those reported in young breast cancer patients without a known hereditary predisposition, the authors concluded that BCT is a rea-sonable option in affected BRCA mutation carriers [39]. Finally, the substantial risk of contralateral breast cancer in BRCA mutation carriers was confirmed by Metcalfe et al. [40] in a large prospective cohort study, which demon-strated that for BRCA1 and BRCA2 mutation carriers with breast cancer, the contralateral breast cancer risks at 10 years of follow-up are 43.4% and 34.6%, respectively.

Given the substantial risks of contralateral cancers, it is not surprising that some BRCA mutation carriers opt to undergo bilateral mastectomies at the time of breast cancer diagnosis. This procedure reduces the risk of contralateral breast cancer by approximately 95% in both pre- and post-menopausal women [41•]. Because the decision to proceed with bilateral mastectomy is often difficult, there has been a recent trend toward rapid genetic counseling and testing at the time of diagnosis of breast cancer in women thought to potentially carry BRCA mutations. Test results can then be incorporated into surgical decision making. In one series, 65% of BRCA mutation carriers counseled about contralateral breast cancer risks at the time of diagnosis of breast cancer chose to undergo bilateral mastectomy [42]. Although logistically difficult to accomplish in many cen-ters, uptake of rapid genetic counseling and testing is high, and most women choose to wait for the results before pro-ceeding with surgery [43].

Systemic therapy for BRCA mutation–associated breast cancersAs with sporadic breast cancers, systemic therapy has been shown to improve outcome in early-stage BRCA mutation–associated breast cancers. In a retrospective cohort of Ashkenazi Jewish women who underwent BCT, 10-year breast cancer–specific survival in BRCA1 muta-tion carriers was inferior to that of BRCA2 mutation carriers and of women with sporadic breast cancer (62%, 84%, and 86% respectively). However, BRCA1 status pre-dicted breast cancer mortality only among women who did not receive adjuvant chemotherapy, suggesting that adjuvant systemic chemotherapy can mitigate the worse prognosis in BRCA1 mutation carriers [38]. Systemic hor-monal therapy has also been studied in affected BRCA mutation carriers and found to be beneficial, particularly with regard to contralateral risk reduction. For example, Metcalfe et al. [40] and Narod et al. [44] observed an approximately 50% contralateral breast cancer risk reduction in affected carriers treated with tamoxifen. With regard to BRCA1 mutation carriers in particular, this finding is curious, given that most BRCA1 muta-tion–associated breast cancers do not express estrogen receptors. Thus, similar to the lack of effect of tamoxi-fen observed for primary prevention in this population,


tamoxifen would not be expected to reduce contralateral risk in affected mutation carriers. However, a high con-cordance rate with regard to estrogen receptor status has been observed between first and second breast cancers in BRCA mutation carriers [45]. It is possible that most of the women in whom tamoxifen reduced contralateral risk in the studies by Metcalf et al. [40] and Narod et al. [44] received tamoxifen as adjuvant therapy for an index estrogen receptor–positive breast cancer and would have been more likely to develop estrogen receptor–positive second breast cancers also, which would thus be more susceptible to hormone receptor modulation.

Future DirectionsAt present, no clinical data support the use of different systemic therapies in the management of BRCA muta-tion–associated and sporadic breast cancers. However, preclinical studies suggest that BRCA mutation–associ-ated breast cancers may have enhanced sensitivity to agents such as mitomycin and cisplatin, and very pre-liminary work suggests the basis for a reduced sensitivity to spindle poisoning agents such as taxanes [46•]. Clini-cal studies in this realm have been proposed, raising the exciting possibility of genetically directed therapy.

Another exciting potentially targeted approach to the management of BRCA mutation–associated breast cancers is the use of a new class of drugs called poly(ADP-ribsose) polymerase-1 (PARP-1) inhibitors. PARP-1 is an enzyme involved in the repair of DNA single-strand breaks. In the absence of PARP-1 activity, single-strand breaks may become double-strand breaks. If this occurs, repair is generally accomplished through homologous recombination, a process that requires BRCA1 and BRCA2 activity. Based on their inability to perform homologous repair, preclinical evidence has suggested that PARP-inhi-bition in BRCA-deficient cells results in accumulation of DNA damage and, ultimately, in apoptosis. Thus, BRCA-deficient cells are particularly sensitive to the effects of PARP-1 inhibitors, offering another option for genetically targeted therapy [47,48].

Finally, although BRCA1 and BRCA2 mutations account for the majority of cases of hereditary breast can-cer due to germline mutations, there are many families in whom BRCA mutations are not identified. In these families, mutations in other genes, such as p53, may be at play. Recently, a frameshift mutation in CHK2 (also called CHEK2), a cell-cycle checkpoint kinase, has been identified and is thought to be associated with a twofold increase in breast cancer risk in women and a tenfold increase in breast cancer risk in men [49•]. The prevalence of this mutation, however, is thought to be low in the US population (1% in cases with a personal or family his-tory of breast cancer in comparison with 0.3% in healthy controls), likely limiting the clinical utility of testing for CHK2 mutations in the United States [50].

ConclusionsIt has been just over a decade since the discovery of BRCA1 and BRCA2. The past decade has brought substan-tial advances in surgical risk reduction and screening for mutation carriers. It is hoped that the next decade will bring refinements in screening and risk reduction and advances in genetically directed therapy for affected mutation carriers.

References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance

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33. Narod SA, Offit K: Prevention and management of heredi-tary breast cancer. J Clin Oncol 2005, 23:1656–1663.

34.• Foulkes WD, Stefansson IM, Chappuis PO, et al.: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 2003, 95:1482–1485.

This study describes the association between BRCA1 muta-tion–associated breast cancer and the basal epithelial subtype, a finding that may explain the possibly inferior prognosis of BRCA1 mutation–associated breast cancer.35. Robson M, Levin D, Federici M, et al.: Breast conservation

therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations. J Natl Cancer Inst 1999, 91:2112–2117.

36.• Haffty BG, Harrold E, Khan AJ, et al.: Outcome of conser-vatively managed early-onset breast cancer by BRCA1/2 status. Lancet 2002, 359:1471–1477.

This study describes the risks of ipsilateral breast tumor recurrence and contralateral breast cancer after breast-conserving therapy for BRCA mutation carriers with breast cancer.37. Seynaeve C, Verhoog LC, van de Bosch LM, et al.: Ipsilat-

eral breast tumour recurrence in hereditary breast cancer following breast-conserving therapy. Eur J Cancer 2004, 40:1150–1158.

38. Robson ME, Chappuis PO, Satagopan J, et al.: A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res 2004, 6:R8–R17.

39. Robson M, Svahn T, McCormick B, et al.: Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series. Cancer 2005, 103:44–51.

40. Metcalfe K, Lynch HT, Ghadirian P, et al.: Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004, 22:2328–2335.

41.• McDonnell SK, Schaid DJ, Myers JL, et al.: Efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. J Clin Oncol 2001, 19:3938–3943.

This important article describes the efficacy of contralateral prophylactic mastectomy in affected women with BRCA mutations.42. Evans DG, Lalloo F, Hopwood P, et al.: Surgical decisions

made by 158 women with hereditary breast cancer aged <50 years. Eur J Surg Oncol 2005 Jul 6; [Epub ahead of print].

43. Schwartz MD, Lerman C, Brogan B, et al.: Utilization of BRCA1/BRCA2 mutation testing in newly diagnosed breast cancer patients. Cancer Epidemiol Biomarkers Prev 2005, 14:1003–1007.

44. Narod SA, Brunet JS, Ghadirian P, et al.: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 2000, 356:1876–1881.

45. Weitzel JN, Robson M, Pasini B, et al.: A comparison of bilateral breast cancers in BRCA carriers. Cancer Epidemiol Biomarkers Prev 2005, 14:1534–1538.


46.• Kennedy RD, Quinn JE, Mullan PB, et al.: The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 2004, 96:1659–1668.

This excellent article describes the cellular functions of BRCA1 and preclinical evidence suggesting differential chemosensitivity by BRCA mutation status.47. Bryant HE, Schultz N, Thomas HD, et al.: Specific

killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005, 434:913–917.

48. Farmer H, McCabe N, Lord CJ, et al.: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005, 434:917–921.

49.• Meijers-Heijboer H, van den Ouweland A, Klijn J, et al.: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002, 31:55–59.

This important article describes a newly identified germline muta-tion that may contribute to hereditary breast cancer.50. Offit K, Pierce H, Kirchhoff T, et al.: Frequency of

CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 2003, 4:1.

update on hereditary breast cancer

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