CANCER RISKS IN WOMEN WITH 2 BREAST OR OVARIAN CANCERS: CLUESTO GENETIC CANCER SUSCEPTIBILITYHelen S. EVANS1*, Cathryn M. LEWIS2, David ROBINSON1, C.M. Janine BELL1, Henrik MLLER1 and Shirley V. HODGSON21Thames Cancer Registry, Division of Medicine, Guys, Kings and St. Thomas School of Medicine, London, United Kingdom2Division of Medical and Molecular Genetics, Guys, Kings and St. Thomas School of Medicine, London, United Kingdom
Women diagnosed with 2 cancers of the breast and/orovary are at higher risk of developing subsequent cancers.Using registrations from the Thames Cancer Registry, wequantified the risks at different cancer sites. Increased riskswere found for cancers that are part of the BRCA1 and BRCA2tumour spectrum: oropharyngeal cancer, malignant mela-noma of the skin (BRCA2) and colon cancer (BRCA1). We alsofound significantly increased risks of myeloid leukaemia(probably due to radiotherapy) and of cancer of the corpusuteri (which may be due to hormonal factors). 2001 Wiley-Liss, Inc.
Key words: breast cancer; ovarian cancer; BRCA1; BRCA2; geneticsusceptibility
Individuals who develop more than 1 cancer may do so as aresult of exposure to carcinogens predisposing to several differentcancer types, chemotherapy or radiotherapy for previous cancersor inherited susceptibility to several forms of cancer. Inheritedmutations in BRCA1 and BRCA2 cause a substantially increasedlifetime risk of both breast and ovarian cancers. Thus, women whodevelop 2 of these cancers may be expected to have a constitu-tionally increased risk of developing subsequent cancers to whichthe mutations in these genes predispose. Cancers for which anincreased relative risk (RR) has been found in BRCA1 and BRCA2mutation carriers include colon cancer, pancreatic cancer, gallblad-der cancer and melanoma.1,2 We used the Thames Cancer Registrydatabase to identify women with 2 separate breast and/or ovariancancers in order to determine whether other specific subsequentcancers were diagnosed more frequently than expected.
The present report is complementary to that from a Swedishrecord linkage study, which investigated cancer incidence in theoffspring of women with bilateral breast cancer.3 Apart fromincreased incidence of breast and ovarian cancers, that study foundan excess of squamous-cell carcinomas at several sites.
MATERIAL AND METHODS
The Thames Cancer Registry is a population-based registry thatstarted in 1960 and now covers a population of 14 million insoutheast England. The database currently contains details of over1.5 million cancers. An analysis of cases diagnosed during 1987reported that completeness 5 years after the end of the year was92%, with variation between 80% and 100% depending on the siteof cancer and the age of the patient.4 Patients registered at theThames Cancer Registry represent a cohort of individuals followedfrom diagnosis to death. The numbers of observed third andsubsequent primary cancers can be compared with the expectednumbers using age- and sex-specific cancer rates observed in thecorresponding region during the same period.
Once a patient has been diagnosed with 1 primary cancer, it isimportant that metastases or recurrences are not misclassified asnew primary tumours. The rules for accepting a second tumour arewell defined and nationally agreed among the UK registries. As ageneral rule, a new primary tumour needs to be at a differentanatomic site and of a different histologic type from the firsttumour or to be stated explicitly as being a new primary tumour bythe treating clinician.
An index cohort was created by extracting all registrations ofwomen with 2 breast cancers, 2 ovarian cancers or 1 ovariancancer and 1 breast cancer. Person-years at risk were calculatedfrom the date of diagnosis of the second of these cancers to thedate of diagnosis of a subsequent cancer at a specified site or to theexit date (date of death, loss to follow-up or 85th birthday, which-ever was earlier). Patients diagnosed prior to 1 January 1971 werefollowed up actively, obtaining information on cause of death,until 31 December 1982. These patients were censored at this date.Patients diagnosed after 31 December 1970 were followed uppassively through the National Health Service Central Registry,which provides notifications of all deaths routinely to the registry.These patients were censored at 31 December 1996. Age-, sex- andperiod-specific cancer incidence rates for the region covered by theThames Cancer Registry were then applied to the cohort, to cal-culate the number of subsequent tumours that would be expectedfor each site. The observed number was divided by the expectednumber to obtain a standardised incidence ratio (SIR) estimate and95% confidence intervals (CIs) were calculated assuming a Pois-son distribution. Nonmelanoma skin cancers and nonmalignanttumours were excluded.
We identified 2,813 women with at least 2 primary cancers, thefirst 2 being breast or ovary: 2 breast (n 5 2,274), 2 ovary (n 5 25)or 1 of each (n 5 514). One hundred twenty-eight women had athird cancer diagnosed and 6 had a fourth cancer. We omitted fromthe analysis further cases of breast cancer (11 cases), ovariancancer (11 cases) and cancer at nonspecific sites (6 cases). Themean follow-up period was 4.9 years in the breastbreast group,2.7 years in the breastovarian group and 2.7 years in the ovarianovarian group.
Four cancer sites showed statistically significant increases (Ta-ble I): oropharynx (SIR 14.7, 95% CI 1.7351.6), malignant mel-anoma of skin (SIR 4.68, 95% CI 2.029.22), corpus uteri (SIR3.07, 95% CI 1.725.06) and myeloid leukaemia (SIR 5.04, 95%CI 1.8511.0). Colon cancer had an SIR of 1.60 but did not quitereach statistical significance (95% CI 0.932.54).
The strategy of analysis in our study has previously been littleexploited. We studied a small cohort of women who already had 2
Grant sponsor: Special Trustees of Guys Hospital; Grant sponsor:Dunhill Medical Trust.
*Correspondence to: Thames Cancer Registry, 1st Floor, Capital House,42 Weston Street, London SE1 3Q, UK. Fax: 144-20-7378-9510.E-mail: firstname.lastname@example.org
Received 23 May 2001; Revised 24 July 2001; Accepted 30 July 2001
Int. J. Cancer: 94, 758759 (2001) 2001 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
cancers (breast, ovarian), to measure the incidence of third andsubsequent cancers. The small cohort size is balanced by theexpectation of high RRs of subsequent cancers that are geneticallyassociated with breast and/or ovarian cancer. The study of multiplecancers within the same individual leads to higher RRs and, hence,increased statistical power compared to a study of cancer occur-rence in relatives. However, the measured associations may beconfounded by nongenetic effects that influence the risks of dif-ferent cancers.
As with all studies of multiple primary cancers, there are po-tential sources of bias which need to be taken into consideration.Patients with 1 primary cancer are likely to be subject to moreadvanced medical surveillance than the general population, socancers may be diagnosed that would otherwise remain undetec-ted. It is possible that some metastases will be misdiagnosed asnew primary cancers. Conversely, a genuine primary cancer maybe misdiagnosed as a metastasis and excluded.
Our study confirms many of the increased cancer risks that werepreviously identified in BRCA1 and BRCA2 mutation carriers1,2 orin the Swedish study of the offspring of women with bilateralbreast cancer.3
Some of the increased risks for cancer of the oropharynx andmelanoma that we detected are likely to be due to BRCA2. The
Breast Cancer Linkage Consortium2 studied BRCA2 mutation car-riers and found statistically increased RRs of cancer of the buccalcavity and pharynx (RR 5 2.26) and malignant melanoma (RR 52.58). They also found increased risks of stomach (RR 5 2.59),gallbladder (RR 5 4.97) and pancreatic (RR 5 3.51) cancers; therisks of these cancers were increased in our study but were notstatistically significant due to small numbers.
The increased colon cancer risk is likely to be mostly due toBRCA1 mutation carriers, who have previously been reported tohave an RR for colon cancer of 4.11.1 The only other cancer siteat increased risk in BRCA1 mutation carriers was the prostate,which would not be observed in our study. No increased risk ofcolon cancer has been found in BRCA2 mutation carriers.2
The Swedish study showed that there was a significant in-crease in melanoma diagnosed at ages 15 to 34 in daughters ofwomen with 2 breast cancers (SIR 5 2.26, 95% CI 1.04 4.34),suggesting a common genetic predisposition.3 Our finding of a5-fold increased risk of melanoma is strongly supportive of thishypothesis. The main novel finding in the Swedish study was anincreased risk of squamous-cell carcinoma and our finding of anexcess in cancers of the oropharynx and hypopharynx is con-sistent with this. The lack of an excess of cervical cancer wasnot unexpected as the median age of the women in our cohortwas 56 years, which is above the age at which peak incidenceof cervical cancer occurs.5
The increased risk we detected for cancer of the corpus utericould be due to common predisposing hormonal factors, particu-larly high oestrogens.6 Treatment for breast cancer with tamoxifenmay play a contributory role in the observed excess of endometrialcancer.7 No increase in endometrial cancer has been noted inBRCA1 or BRCA2 mutation carriers1,2 or in the Swedish study.3The increase in myeloid leukaemia is likely to be treatment-related.
Our study identified women at high risk of carrying BRCA1 andBRCA2 mutations because of their diagnosis of 2 breast or ovariancancers. The risk of ovarian cancer is higher in BRCA1 thanBRCA2 mutation carriers and the survival after ovarian cancer issubstantially lower than for breast cancer. Our sample will there-fore contain more cancers from BRCA2 mutations, despite theirsimilar contribution to breast cancer.8 Also, we considered onlycancers diagnosed after study entry through 2 cases of breastand/or ovarian cancers; therefore, we would not detect any in-creased risk of childhood sarcoma, as found by the Swedish study.3We conclude that the majority of the risk increase is due to carriersof germline BRCA1 and BRCA2 mutations, though there may alsobe other predisposing genes. The excess of endometrial cancermay have a hormonal basis and myeloid leukaemias may be due toradiotherapy.
1. Ford D, Easton DF, Bishop DT, et al. Risks of cancer in BRCA1-mutation carriers. Lancet 1994;343:6925.
2. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutationcarriers. J Natl Cancer Inst 1999;91:13106.
3. Hemminki K, Vaittinen P, Easton D. Familial cancer risks to offspringfrom mothers with 2 primary breast cancers: leads to cancer syn-dromes. Int J Cancer 2000;88:8791.
4. Bullard J, Coleman MP, Robinson D, et al. Completeness of cancerregistration: a new method for routine use. Br J Cancer 2000;82:11116.
5. Herbert A, Smith JAE. Cervical intraepithelial neoplasia grade III
(CIN III) and invasive cervical carcinoma: the yawning gap revisitedand the treatment of risk. Cytopathology 1999;10:16170.
6. Henderson BE, Ross R, Bernstein L. Estrogens as a cause of humancancer. Cancer Res 1988;48:24653.
7. Bergman L, Beelen ML, Gallee MP, et al. Risk and prognosis ofendometrial cancer after tamoxifen for breast cancer. Lancet 2000;356:8817.
8. Peto J, Collins N, Barfood R, et al. Prevalence of BRCA1 and BRCA2gene mutations in patients with early-onset breast cancer. J NatlCancer Inst 1999;91:9439.
TABLE I STANDARDISED INCIDENCE RATIOS (SIR) OF SUBSEQUENTPRIMARY CANCERS AFTER INITIAL DIAGNOSIS OF 2 BREAST CANCERS,
2 OVARIAN CANCERS OR 1 BREAST AND 1 OVARIAN CANCER
Subsequent site Observed Expected SIR 95% CI
Oropharynx 2 0.14 14.7 1.7351.6Hypopharynx 1 0.18 5.44 0.1430.9Oesophagus 2 2.37 0.84 0.103.05Stomach 7 4.56 1.53 0.623.16Colon 17 10.7 1.60 0.932.54Rectum 6 5.21 1.15 0.422.51Liver 1 0.54 1.84 0.0510.3Gallbladder 3 0.82 3.67 0.7610.7Pancreas 6 4.04 1.49 0.543.23Larynx 1 0.40 2.50 0.0613.9Lung, bronchus 20 14.7 1.36 0.832.10Connective tissue 2 0.34 5.94 0.7121.2Skin malignant
melanoma8 1.71 4.68 2.029.22
Cervix uteri 1 2.65 0.38 0.012.10Corpus uteri 15 4.89 3.07 1.725.06Bladder 7 3.68 1.90 0.763.92Kidney 2 1.57 1.27 0.154.60Non-Hodgkins
lymphoma2 3.23 0.62 0.082.24
Multiple myeloma 2 1.66 1.20 0.154.35Lymphoid leukaemia 1 1.04 0.96 0.025.36Myeloid leukaemia 6 1.19 5.04 1.8511.0
759BREAST AND OVARIAN CANCER RISKS
MATERIAL AND METHODSRESULTSDISCUSSIONTABLE I