Survival after bilateral breast cancer: results from a population-based study

Background Controversy exists on the impact of bilaterality of breast cancer on survival. We used population-based data to compare survival of women with unilateral versus bilateral breast cancer. Patients and methods At the Geneva cancer registry, we identified all 7,912 women diagnosed with invasive breast cancer between 1970 and 2002. Breast cancers were categorized as unilateral, synchronous bilateral (contralateral tumour diagnosed within six months after the first tumour) and metachronous bilateral (contralateral tumour diagnosed over six months after the first tumour). With multivariate modelling we compared characteristics and survival between women with unilateral and bilateral disease. Results Patients with synchronous bilateral tumours (n = 155, 2.0%) had more often lobular histology and less frequently stage I disease than women with unilateral disease. Women with metachronous breast cancer (n = 219, 2.8%) received less often chemotherapy or hormone therapy for their first tumours. Ten-year disease-specific survival was similar (66%) after unilateral and metachronous bilateral breast cancer, but worse after synchronous bilateral cancer (51%). After adjustment, breast cancer mortality risks were not significantly increased for women with either synchronous or metachronous bilateral disease (Hazard ratios 1.1 (0.8–1.5) and 0.8 (0.5–1.4), respectively). Conclusion This large population-based study indicates that bilaterality of breast cancer is not associated with impaired survival.     

Effects of obesity and race on prognosis in lymph node-negative, estrogen receptor-negative breast cancer

SummaryBackground Several factors may contribute to poorer prognosis for obese breast cancer patients, including unfavorable disease features, the influence of fat on estrogen availability, co-morbidity, and socio-demographic factors. Both obesity and estrogen receptor negative (ER-) tumors are more prevalent in black women than in whites in North America. We evaluated obesity and race in relation to outcomes in women with ER-breast cancer.Methods Among 4077 women from National Surgical Adjuvant Breast and Bowel Project clinical trials for node-negative, ER-breast cancer, we evaluated disease-free survival (DFS) and its constituents (tumor recurrence, contralateral breast cancer (CBC), second primary cancers, deaths prior to these events) and mortality in relation to body mass index (BMI) and race, using statistical modeling to account for other prognostic factors.Results Compared to those of normal weight (BMI≤24.9), DFS hazard was greater for obese (BMI ≥ 30) women [hazard ratio (HR)=1.16, 95% confidence interval (CI)=1.01–1.33]. Obesity did not increase recurrence hazard, but did influence CBC (HR=2.08, 95% CI=1.22–3.55 in postmenopausal women) and second cancers (HR=1.49, 95% CI=1.06–2.10). Mortality increased with obesity; when partitioned by likely cause, those with BMI ≥ 35.0 had greater risk of non-breast cancer mortality (HR=1.86, 95% CI=1.21–2.84). Relative to whites and adjusted for BMI, black women had greater hazard for DFS (HR=1.17, 95% CI=1.00–1.38), CBC (HR=1.37, 95% CI=0.94–1.99), and non-breast cancer deaths (HR=2.10, 95% CI=1.45–3.03); risk for deaths likely due to breast cancer was closer to that in whites (HR=1.18; 95% CI=0.93–1.50).Conclusions For women with node-negative, ER-breast cancer from clinical trials, obesity did not increase recurrence risk, but was associated with greater risk for second cancers, CBC, and mortality, particularly non-breast cancer deaths. Less favorable prognosis for black women persists in clinical trials, and is in part attributable to non-breast cancer outcomes.     

Conservative surgery in patients with multifocal/multicentric breast cancer

Purpose Many physicians recommend mastectomy in case of multifocal (MF) or multicentric (MC) breast cancer due to a theoretical risk of poor local control with less extensive surgery. We retrospectively evaluate outcome of patients with MF/MC cancers who had breast conservation with specific attention on local control and predictive factors of recurrence. Patients and methods Four hundred and seventy six patients with either MF (n = 421) or MC (n = 55) breast cancer, underwent breast-conserving surgery between 1997 and 2002 in a single institution. Median follow up was 73 months (range 11–118). Results Median age was 53 years (range 23–86). Invasive lobular carcinoma was found in 88 patients (18.5%) and mixed ductal-lobular cancer in 27 (5.7%) patients. Two hundred and sixty-seven patients (76.7%) had two identified tumor foci, 55 patients (15.3%) had three and 29 patients (8.0%) had four or more. Two hundred and sixty-one patients (55.3%) had nodal involvement. The 5-year cumulative incidence of local relapse was 5.1%. At the multivariate analysis, over-expression of HER2/neu and lack of both estrogen and progesterone receptors (HR: 3.2, 95% C.I. 1.01–10.0, and HR: 2.7, 95% C.I. 1.06–7.7, respectively) were associated with a higher ipsilateral breast cancer reappearance rate. Involvement of four or more lymph nodes and lack of estrogen and progesterone receptors (HR: 2.7, 95% C.I. 1.06–6.7, and HR: 4.7, 95% C.I. 2.1–10.4, respectively) were associated with poorer overall survival. Conclusions In selected patients with MF/MC breast cancer, wide conservative surgery is not associated with poor local disease control and can be considered whenever acceptable cosmetic results can be achieved.     

Breast cancer risk factors and second primary malignancies among women with breast cancer

Purpose To examine the association between breast cancer risk factors and second primary cancers (independent diagnoses occurring at least 12 months after the initial breast cancer diagnosis) among breast cancer survivors. Methods In this population-based study, cancer outcomes among breast cancer survivors first diagnosed during 1987–2000 were investigated. Invasive breast cancer cases were identified from the statewide tumor registry and interviewed regarding their pre-diagnosis risk factors, including reproductive and lifestyle characteristics, approximately 1 year after diagnosis. Data on second primary cancers (not recurrences) and deaths were obtained by linkage with tumor registry reports and death certificates through December 31, 2002. Hazard ratios (HR) were estimated using proportional hazards regression stratified by age and adjusted for stage and other factors. Results Among the 10,953 breast cancer cases, 10.8% experienced a second cancer diagnosis within an average of 7 years (including 488 breast, 132 colorectal, 113 endometrial, and 36 ovarian cancers). Risk of a second primary breast cancer increased according to low parity (P = 0.002), older age at menopause (P = 0.08), greater body mass index (P = 0.003) and adult weight gain (P = 0.02), and a family history of breast cancer-particularly among women with 2 or more first-degree affected relatives (HR = 1.8, 95% CI: 1.1–2.9). Reduced risk of colorectal cancer after breast cancer was observed in relation to older ages at menarche (P = 0.05), younger age at menopause (P = 0.04), postmenopausal hormone use (HR = 0.4, 95% CI: 0.3–0.7), normal body mass index (P = 0.07), and infrequent alcohol consumption (P = 0.01). Second endometrial cancer risk was associated with increasing body mass index (P < 0.01) and adult weight gain (P = 0.03). Risk of second ovarian cancer appeared related to recent alcohol intake and family history of breast cancer. Women who reported consuming any alcohol appeared to have a 55% reduction in ovarian cancer risk (95% CI: 0.2–1.0) compared to non-drinkers, while having 2 or more first-degree relatives with breast cancer was associated with an increased risk of ovarian cancer (HR = 4.3, 95% CI: 1.3–14.6). Conclusion This study suggests that family history of breast cancer as well as potentially modifiable characteristics including body weight, alcohol intake, and postmenopausal hormone use may be associated with risk of a second cancer diagnosis among breast cancer cases.     

Reproductive factors and histologic subtype in relation to mortality after a breast cancer diagnosis

Evidence suggests that certain reproductive factors are more strongly associated with the incidence of lobular than of ductal breast cancer. The mechanisms influencing breast cancer incidence histology may also affect survival. Women with invasive breast cancer (N = 22,302) diagnosed during 1986–2005 were enrolled in a series of population-based studies in three US states. Participants completed telephone interviews regarding reproductive exposures and other breast cancer risk factors. Histologic subtype was obtained from state cancer registries. Vital status and cause of death were determined through December 2006 using the National Death Index. Women were followed for 9.8 years on average with 3,050 breast cancer deaths documented. Adjusted hazard rate ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazards regression models for breast cancer-specific and all-cause mortality. Parity was inversely associated with breast cancer-specific mortality (P _Trend = 0.002). Associations were similar though attenuated for all-cause mortality. In women diagnosed with ductal breast cancer, a 15% reduction in breast cancer-specific mortality was observed in women with five or more children when compared to those with no children (HR = 0.85, 95% CI: 0.73–1.00). A similar inverse though non-significant association was observed in women with lobular subtype (HR = 0.70, 95% CI: 0.43–1.14). The trend did not extend to mixed ductal–lobular breast cancer. Age at first birth had no consistent relationship with breast cancer-specific or all-cause mortality. We found increasing parity reduced mortality in ductal and lobular breast cancer. The number of full-term births, rather than age at first birth, has an effect on both breast cancer-specific and overall mortality.     

Inflammatory breast cancer: high risk of contralateral breast cancer compared to comparably staged non-inflammatory breast cancer

Inflammatory breast cancer (IBC), the most lethal form of breast cancer, has characteristics linked to higher risk of contralateral breast cancer. However, no large studies have examined risk of contralateral breast cancer following IBC. We calculated absolute risk of invasive contralateral breast cancer among 5,631 IBC and 174,634 comparably staged non-IBC first breast cancer cases who survived at least 2 months following diagnosis and were reported to 13 Surveillance, Epidemiology, and End Results (SEER) registries between January 1, 1973 and December 31, 2006. We considered that contralateral cancers occurring within 2–23 months of first cancer diagnosis may more likely be metastatic/recurrent disease and those occurring 2 or more years after diagnosis independent primaries. Absolute risk of contralateral breast cancer was generally greater following IBC than regional/distant non-IBC, regardless of age and hormone receptor status of first cancer diagnosis. Much of the increase in absolute risk following IBC occurred within 2–23 months of first cancer diagnosis, while the risk for non-IBC occurred more gradually over time since diagnosis. For instance, among women first diagnosed before age 50, absolute risks following IBC and non-IBC were 4.9 vs. 1.1% at 2 years, 6.0 vs. 2.2% at 5 years, and 7.7 vs. 6.1% at 20 years after diagnosis. However, patterns of higher risk following IBC than non-IBC were also evident for at least 10–15 years in the subcohort of women who survived at least 24 months without a contralateral cancer. In conclusion, our results suggest that IBC has higher risk of cancer in the contralateral breast than comparably staged non-IBC, possibly due to both metastatic/recurrent disease and independent primaries.     

Patient and tumor characteristics of bilateral breast cancer at screening mammography in the Netherlands, a population-based study

Few data are available on bilateral breast cancer in the screening population. The aim of this study was to determine patient and tumor characteristics of women with bilateral breast cancer at screening mammography. We included all 350,637 screening mammography examinations of women participating in a biennial screening program in a southern screening region of the Netherlands between May 1998 and January 2010. For referred women, all breast imaging reports, biopsy results, and surgery reports during one year after referral were collected. We compared patient and tumor characteristics of referred women with a diagnosis of bilateral breast cancer or unilateral breast cancer at workup. Bilateral or unilateral breast cancer had been diagnosed in respectively 40 (2.2%) and 1766 (97.8%) of 1806 referred women. Women with bilateral or unilateral breast cancer did not differ significantly in mean age, mammographic breast density, family history of breast cancer, or use of hormone replacement therapy. Compared with index cancers, contralateral cancers comprised significantly more lobular cancers (P = 0.02). Tumor size, mitotic activity, and estrogen receptor status were comparable for both groups, but contralateral cancers had a significantly lower risk of lymph node metastases (P = 0.03). Compared to unilateral breast cancer, contralateral malignancies in women with bilateral breast cancer comprised significantly more lobular cancers (P = 0.004) and lymph node negative cancers (P = 0.01). Contralateral breast cancers detected at screening comprise more lobular cancers and show less nodal involvement than index cancers or unilateral cancers. No differences are observed with respect to other patient and tumor characteristics.     

Coffee and tea intake and risk of breast cancer

Known risk factors account for about 10–15% of breast cancer incidence suggesting that lifestyle exposures are crucial in its etiology. Previous epidemiological studies on the association between coffee and tea consumption and breast cancer risk have been inconsistent. We investigated the association of coffee and tea consumption with the risk of breast cancer among women in EPIC-NL cohort, a population-based prospective cohort in Netherlands with 27,323 participants. Exposure was measured by a validated food frequency questionnaire, and the outcome was verified by direct linkage with the Netherlands Cancer Registry. A total of 681 invasive primary breast cancers were diagnosed in 9.6 years of follow-up. Coffee intake increased the risk of breast cancer by more than twofold as compared to non-consumers (HR; 2.25, 95% CI; 1.30–3.90). This association did not hold after multivariate adjustment which resulted in a HR of 1.17, 95% CI; 0.65–2.12. After adjustment to breast cancer risk factors and lifestyle, no association was observed between intake of coffee or tea and risk of breast cancer across all categories of intake. These results were also not altered by body mass index (BMI). Coffee and tea consumption does not seem to be related to the risk of breast cancer in women.     

Second cancers in patients with male breast cancer: a literature review

Purpose  The risk of second malignancies among female breast cancer patients has been studied for decades. In contrast, very little is known about second primary tumors in men. Risk factors for breast cancer in men, including genetic, hormonal and environmental factors, provide parallels to the etiology of breast cancer in women. This review considers the literature related to the risk of developing a second cancer in patients with male breast cancer. Materials and methods  A systematic review of the literature between 1966 and 2007 was conducted and acceptable articles used for analysis. All retrieved articles were screened to identify any papers that had been missed. Studies were included if they discussed the risk of subsequent malignancy in patients with male breast cancer. Results  Patients with history of male breast cancer have an increased risk of a second ipsilateral, or contralateral breast cancer (standardized incidence ratio 30–110). The risk of subsequent contralateral breast cancer was highest in men under 50 years of age at the time of the diagnosis of the initial cancer. The data on non-breast second primary cancers is diverse. One study has suggested an increased incidence of cancers of the small intestine, prostate, rectum and pancreas, and of non-melanoma skin cancer and myeloid leukaemia. Other investigators did not find an increase in the overall risk of subsequent cancer development in men diagnosed initially with primary breast cancer. Although sarcoma, lung and esophageal cancers are well recognized complications of radiation therapy for female breast cancer, there is no evidence for the association of these cancers following radiation therapy in male breast cancer. Conclusions  Although the incidence of second primary cancer in patients with primary male breast cancer requires further study, male breast cancer survivors should probably undergo periodic screening for the early detection of second breast cancers and other adverse health effects.     

Post-diagnosis weight gain and breast cancer recurrence in women with early stage breast cancer

SummaryPurpose To examine whether weight gain after diagnosis of breast cancer affects the risk of breast cancer recurrence.Patient and methods Patients included 3215 women diagnosed with early stage breast cancer (Stage I >1 cm., II, and IIIA) who were enrolled either in an observational cohort of breast cancer survivors or were part of the comparison group of a dietary intervention trial to prevent breast cancer recurrence. We computed weight change from 1 year prior to diagnosis to study enrollment. Delayed entry Cox proportional hazards models were used to evaluate associations of categories of weight change with time to recurrence, controlling for known prognostic factors.Results Neither moderate (5–10%) nor large (> 10%) weight gain (HR 0.8, 95% CI, 0.6–1.1; HR 0.9, 95% CI, 0.7–1.2, respectively) after breast cancer diagnosis was associated with an increased risk of breast cancer recurrence in the early years post-diagnosis (median time of 73.7 months from diagnosis).Conclusion Our research provides evidence that weight gain commonly seen in the first several years following a breast cancer diagnosis does not increase a woman’s risk for breast cancer recurrence in the first 5–7 years post-diagnosis. However, this research does not address the effects of weight gain on overall survival or on the risk of other new cancers, other prognostic outcomes of concern to the breast cancer survivor.For the Life After Cancer Epidemiology (LACE) Study group (Bette J. Caan, Adrienne Castillo, Erica P. Gunderson, Laurel Habel, Martha L. Slattery, Barbara Sternfeld), For the Women’s Healthy Eating and Living (WHEL) Study Group (Jennifer A. Emond, Loki Natarajan, Lovell Jones, Vicky A. Newman, Cheryl L. Rock, Marcia L. Stefanick, Cynthia A. Thomson, John P. Pierce)     

Risk of second primary breast cancers among women with ductal carcinoma in situ of the breast

Background The diagnosis of ductal carcinoma in situ (DCIS) has become increasingly common, but it is not clear which factors predict the development of subsequent breast cancers in these women. The risk of second primary breast tumors was examined in a large, ethnically diverse population-based cohort of women with DCIS. Methods California Cancer Registry data on 23,547 women with first DCIS diagnosed in 1988–1999 were examined to estimate the incidence of second DCIS and invasive breast cancer relative to women in the general population. Relative risks were calculated using Poisson regression to estimate which women with DCIS were likely to develop a second DCIS or invasive breast cancer. Results Compared to the general population, women with DCIS had significantly increased risk of contralateral DCIS (standardized incidence ratio [SIR] 4.2, 95% confidence interval [CI] 3.7–4.7), contralateral invasive cancer (SIR 1.4, 95% CI 1.2–1.5), ipsilateral DCIS (SIR 4.2, 95% CI 3.5–5.0), and ipsilateral invasive cancer (SIR 1.7, 95% CI 1.4–2.1). Variation by race/ethnicity, age, time, and tumor and treatment characteristics were observed. Black women were 1.9-fold more likely to develop ipsilateral invasive cancer than white women. Young age at onset, comedo histology and having received partial mastectomy only or having neither surgical nor radiation treatment for first DCIS were predictive of ipsilateral cancers. Conclusions Close follow-up of women with DCIS is warranted, particularly those who are Black or diagnosed at young age. Investigations should continue to clarify the underlying mechanisms of racial, age, and other differences in second cancer risk.     

Pattern of metastatic spread in triple-negative breast cancer

Purpose The prognosis of women with triple-negative breast cancers (defined as cancers that are estrogen receptor-negative, progesterone receptor-negative and HER2/neu negative) is poor, compared to women with other subtypes of breast cancer. It is proposed that the underlying difference in recurrence rates may be explained in part by different routes of metastatic spread. Experimental design We studied a cohort of 1608 patients diagnosed with breast cancer, diagnosed between January 1987 and December 1997 at Women’s College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor-negative, progesterone receptor-negative and HER2/neu-negative. We compared the incidence rates of metastatic spread to bone and to other (non-bone) organs in women with triple-negative and other forms of breast cancer. Results Of the 1,608 patients, 180 (11.2%) had triple-negative breast cancer. The 1608 women were followed for a median of 9.0 years (range 0.1–19 years). Compared to other patients, those with triple-negative breast cancer had an increased likelihood of distant recurrence over the study period (adjusted hazard ratio (HR) 1.9; 95% CI: 1.5–2.5, P < 0.0001). The relatively poor prognosis was apparent in the five years after diagnosis (HR 2.9; 95% CI: 2.1–3.9; P = 0.0001) but not thereafter (HR 0.5; 95% CI: 0.2–1.1; P = 0.07). In particular, women with triple-negative breast cancer were four times more likely to experience a visceral metastasis within five years of diagnosis than those with other types of cancer (HR 4.0; 95% CI: 2.7–5.9; P < 0.0001). The rates of bone metastases were comparable for triple-negative and for other forms of cancer in this time period (HR 0.8; 95% CI: 0.4–1.6 P = 0.5). Conclusions The excess risk of distant recurrence in triple-negative breast cancers, versus other forms of cancer, is attributable in large part to an excess of visceral metastases in the first five years following diagnosis.     

Has monitoring of the contralateral breast improved the prognosis in patients treated for primary breast cancer?

Bilateral breast cancer has a cumulative incidence of about 7% in patients with primary operable breast cancer, and most of these lesions are metachronous. Most retrospective studies have shown that a majority of these patients have invasive cancer in the second breast, and varying percentages have nodal metastases, which may be of a higher stage than the first cancer. Physicians are now more aware of the importance of careful monitoring of the second breast after ipsilateral mastectomy, and improvements have been made in mammographic surveillance. A retrospective, comparative analysis of two separate breast cancer populations at risk for bilateral breast cancer was done on patients who entered into the system before effective mammographic monitoring (BEM) and after effective mammographic monitoring (AEM). The first group of patients consisted of 500 consecutive patients with primary breast cancer diagnosed during the years 1969 through 1975, of whom 37 (7.4%) had bilateral breast cancer. The second group consisted of 557 consecutive patients diagnosed during the years 1977 through 1984, of whom 36 (6.5%) had bilateral breast cancer. The staging percentages of the second breast cancer in the BEM group were Stage 0, 5.4%; Stage I, 48.6%; Stage II, 10.8%; Stage III, 21.6%; and Stage IV, 13.5%. The second group had an improvement in stage, with 33.3% being Stage 0, 22.2% Stage I, 29.6% Stage II, 3.7% Stage III, and 3.7% Stage IV (P less than 0.05). The median interval between primary lesions was 39 months in the first group and 19 months in the second group (in part, this difference may represent increased identification of synchronous cancers). The second breast cancer was undetected by mammography in 9 of 34 (26%) patients. Six were detected by contralateral biopsy (all were lobular carcinomas in situ), and three were found by clinical examination (all were invasive cancers). It was concluded that more aggressive monitoring of the second breast by frequent clinical examination, mammography, and selected contralateral biopsy appears to have increased the early detection rate of second breast cancers in patients under observation.     

Relationship between diabetes and risk of second primary contralateral breast cancer

Breast cancer survivors have a substantially higher risk of developing a second primary contralateral breast cancer (CBC) compared to the risk of breast cancer among women in the general population. While data regarding the relationship between diabetes and breast cancer incidence are inconsistent, diabetes is more clearly linked to an elevated risk of all-cause mortality among breast cancer survivors. However, no prior studies have assessed its impact on CBC risk. We assessed the relationship between diabetes, and CBC risk in a population-based nested case–control study consisting of women 40–79 years of age diagnosed with a first primary ER-positive invasive breast cancer. It included 322 women who developed a second primary CBC and 616-matched control women diagnosed only with a first breast cancer. We used conditional logistic regression to quantify associations between diabetes and CBC risk. Compared to women without a history of diabetes, diabetics had a 2.2-fold [95% confidence interval (CI) 1.3–3.6] increased risk of CBC. This risk was more pronounced among women diagnosed with their first breast cancer before age 60 years (odds ratio, OR = 11.5, 95% CI 2.4–54.5), compared to those diagnosed at age 60 years or older (OR = 1.5, 95% CI 0.8–2.7, P for interaction = 0.011). Diabetics diagnosed with breast cancer appear to have an elevated risk of CBC. This is the first study to report this relationship, but if confirmed efforts to insure that diabetic breast cancer survivors are carefully screened for second breast cancers may be warranted.     

Penetrance of breast cancer,ovarian cancer and contralateral breast cancer in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> families: high cancer incidence at older age

Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the general population in this region. We identified 1188 female mutation carriers and first-degree female relatives in 185 families with a pathogenic BRCA1 or BRCA2 mutation. The occurrence of breast cancer, contralateral breast cancer and ovarian cancer was recorded. The cumulative incidence of breast cancer by age 70 was 71.4% (95% CI 67.2–82.4%) in BRCA1 and 87.5% (82.4–92.6%) in BRCA2 mutation carriers. For ovarian cancer at age 70, it was 58.9% (53.5–64.3%) in BRCA1 and 34.5% (25.0–44.0%) in BRCA2 mutation carriers. For breast cancer we saw a rise of 24.2% in the cumulative incidence in the seventh decade for BRCA2 mutation carriers versus 6.3% for BRCA1. For ovarian cancer the rise in the seventh decade was 17.3% for BRCA1 mutation carriers and 15.1% for BRCA2. The 10-year risk for contralateral breast cancer was 34.2% (29.4–39.0%) in BRCA1 families and 29.2% (22.9–35.5%) in BRCA2. We show that the incidence of breast and ovarian cancer in BRCA2 mutation carriers and of ovarian cancer in BRCA1 mutation carriers is still high after 60 years. This may justify intensive breast screening as well as oophorectomy even after age 60. The risk of contralateral breast cancer rises approximately 3% per year, which may affect preventive choices.     

Epidemiology of contralateral breast cancer.

Two to 11% of women diagnosed with breast cancer will develop contralateral breast cancer in their lifetime. Women with a first primary are at a 2-6-fold increased risk of developing contralateral breast cancer compared with the risk in the general population of women developing a first primary cancer. The incidence rate of contralateral breast cancer varies from four to eight per 1000 person-years. To assess the risk factors associated with the development of contralateral breast cancer among women with a first primary breast cancer, the epidemiological literature concerning these factors was reviewed and summarized. Studies have shown that a family history of breast cancer, an early age at initial diagnosis, and a lobular histology of the first primary breast cancer increase the risk of developing contralateral breast cancer. Although chemotherapy and tamoxifen therapy may reduce this risk, there are inconsistent results regarding the effects of radiotherapy and the effects of reproductive, environmental and other factors. Additional analytical studies addressing all potential risk factors associated with the development of contralateral breast cancer are necessary in view of the increasing incidence and survival of women with a first primary.     

Margin status and the risk of local recurrence after breast-conserving treatment of lobular breast cancer

Background Invasive lobular breast carcinoma is known for its multicentricity and is associated with a higher incidence of incomplete excision after breast-conserving therapy. The aim of the study was to examine the influence of positive surgical margins on the local recurrence rate in patients diagnosed with invasive lobular cancer and treated with breast-conserving therapy. Methods All 416 women diagnosed with invasive lobular breast cancer and undergoing breast-conserving treatment between 1995 and 2002 were selected from the population-based Eindhoven Cancer Registry. Their medical charts were reviewed and detailed information was collected. Results The risk of margin involvement was 29% after the first operation and 17% when taking into account the final margin status of the patients undergoing re-excision. During follow-up, 18 patients developed a local recurrence. The 5 year actuarial risk of developing a local recurrence was 3.5% (95% confidence interval 2.5–4.5) and the 8 year risk was 6.4% (95% confidence interval 4.7–8.0). There was no influence of positive surgical margins on the risk of local recurrence, neither in the univariate analysis nor after adjustment for age, tumour size, nodal status and adjuvant systemic treatment. Conclusion Patients with invasive lobular cancer, treated with breast-conservation, have a low risk of local recurrence, despite their high risk of having a microscopically incomplete excision of the tumour.     

The impact of loco-regional recurrences on metastatic progression in early-stage breast cancer: a multistate model

To study whether the effects of prognostic factors associated with the occurrence of distant metastases (DM) at primary diagnosis change after the incidence of loco-regional recurrences (LRR) among women treated for invasive stage I or II breast cancer. The study population consisted of 3,601 women, enrolled in EORTC trials 10801, 10854, or 10902 treated for early-stage breast cancer. Data were analysed in a multivariate, multistate model by using multivariate Cox regression models, including a state-dependent covariate. The presence of a LRR in itself is a significant prognostic risk factor (HR: 3.64; 95%-CI: 2.02–6.5) for the occurrence of DM. Main prognostic risk factors for a DM are young age at diagnosis (≤40: HR: 1.79; 95%-CI: 1.28–2.51), larger tumour size (HR: 1.58; 95%-CI: 1.35–1.84) and node positivity (HR: 2.00; 95%-CI: 1.74–2.30). Adjuvant chemotherapy is protective for a DM (HR: 0.66; 95%-CI: 0.55–0.80). After the occurrence of a LRR the latter protective effect has disappeared (P = 0.009). The presence of LRR in itself is a significant risk factor for DM. For patients who are at risk of developing LRR, effective local control should be the main target of therapy.     

Genetic implications of bilateral breast cancer: a population based cohort study

BACKGROUND: Women with breast cancer are at high risk of bilateral breast cancer. We aimed to assess the incidence of bilateral breast cancer in relation to age and time since diagnosis of first cancer. METHODS: We analysed a population-based cohort of 123757 women with a first primary breast cancer diagnosed in Sweden from 1970 to 2000 for frequency of bilateral breast cancers and deaths by means of record linkage. Second primary breast cancers were categorised as synchronous bilateral breast cancers if diagnosed within 3 months of the first primary cancer or as metachronous if diagnosed more than 3 months after diagnosis of first primary cancer. FINDINGS: We identified 6550 women who had developed bilateral breast cancer. Age-incidence patterns of synchronous and unilateral breast cancer were similar, although the absolute rates of synchronous bilateral cancer were 50-100 times lower than those of unilateral cancer. A woman aged 80 years or older is at least twice as likely to be diagnosed with synchronous bilateral breast cancer than is a woman younger than 40 years. In the first 20 years after diagnosis of primary breast cancer, incidence of metachronous bilateral cancer decreased from about 800 per 10(5) person-years to 400 per 10(5) person-years in patients diagnosed with primary breast cancer before the age of 45 years, whereas incidence remained at 500-600 per 10(5) person-years in those age 45 years or older at diagnosis. After 30 years' follow-up, cumulative risk of metachronous bilateral breast cancer was about 15% irrespective of age at first primary breast cancer. INTERPRETATION: The higher than expected risk of synchronous bilateral breast cancer could be explained by non-genetic factors. By contrast, incidence of metachronous bilateral cancer fits neither a model of highly penetrant genes nor aggregation of environmental risk factors.     

Risk of second non-hematological malignancies among 376,825 breast cancer survivors

Breast cancer survivors are at increased risk of treatment-related second cancers. This study is the first to examine risk 30 or more years after diagnosis and to present absolute risks of second cancer which accounts for competing mortality. We identified 23,158 second non-hematological malignancies excluding breast in a population-based cohort of 376,825 one-year survivors of breast cancer diagnosed from 1943 to 2002 and reported to four Scandinavian cancer registries. We calculated standardized incidence ratios (SIR) and utilized a competing-risk model to calculate absolute risk of developing second cancers. The overall SIR for second cancers was 1.15 (95% confidence interval [CI] = 1.14–1.17). The SIR for potentially radiotherapy-associated cancers 30 or more years after breast cancer diagnosis was 2.19 (95% CI = 1.87–2.55). However, the largest SIRs were observed for women aged <40 years followed for 1–9 years. At 20 years after breast cancer diagnosis, the absolute risk of developing a second cancer ranged from 0.6 to 10.3%, depending on stage and age; the difference in the absolute risk compared to the background population was greatest for women aged <40 years with localized disease, 2.3%. At 30 years post breast cancer diagnosis, this difference reached 3.2%. These risks were small compared to the corresponding risk of dying from breast cancer. Although the absolute risks were small, we found persistent risks of second non-hematological malignancies excluding breast 30 or more years after breast cancer diagnosis, particularly for women diagnosed at young ages with localized disease.