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.     

The impact of adjuvant therapy on contralateral breast cancer risk and the prognostic significance of contralateral breast cancer: a population based study in the Netherlands

BACKGROUND: The impact of age and adjuvant therapy on contralateral breast cancer (CBC) risk and prognostic significance of CBC were evaluated. PATIENTS AND METHODS: In 45,229 surgically treated stage I-IIIA patients diagnosed in the Netherlands between 1989 and 2002 CBC risk was quantified using standardised incidence ratios (SIRs), cumulative incidence and Cox regression analysis, adjusted for competing risks. RESULTS: Median follow-up was 5.8 years, in which 624 CBC occurred <6 months after the index cancer (synchronous) and 1,477 thereafter (metachronous). Older age and lobular histology were associated with increased synchronous CBC risk. Standardised incidence ratio (SIR) of CBC was 2.5 (95% confidence interval (95% CI) 2.4-2.7). The SIR of metachronous CBC decreased with index cancer age, from 11.4 (95% CI 8.6-14.8) when <35 to 1.5 (95% CI 1.4-1.7) for > or =60 years. The absolute excess risk of metachronous CBC was 26.8/10,000 person-years. The cumulative incidence increased with 0.4% per year, reaching 5.9% after 15 years. Adjuvant hormonal (Hazard rate ratio (HR) 0.58; 95% CI 0.48-0.69) and chemotherapy (HR 0.73; 95% CI 0.60-0.90) were associated with a markedly decreased CBC risk. A metachronous CBC worsened survival (HR 1.44; 95% CI 1.33-1.56). CONCLUSION: Young breast cancer patients experience high synchronous and metachronous CBC risk. Adjuvant hormonal or chemotherapy considerably reduced the risk of CBC. CBC occurrence adversely affects prognosis, emphasizing the necessity of long-term surveillance directed at early CBC-detection.     

Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.

BACKGROUND: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. METHODS: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. RESULTS: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). CONCLUSIONS: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.     

Adjuvant radiotherapy and risk of contralateral breast cancer.

BACKGROUND: The risk of contralateral breast cancer is increased twofold to fivefold for breast cancer patients. A registry-based cohort study in Denmark suggested that radiation treatment of the first breast cancer might increase the risk for contralateral breast cancer among 10-year survivors. PURPOSE: Our goal was to assess the role of radiation in the development of contralateral breast cancer. METHODS: A nested case-control study was conducted in a cohort of 56,540 women in Denmark diagnosed with invasive breast cancer from 1943 through 1978. Case patients were 529 women who developed contralateral breast cancer 8 or more years after first diagnosis. Controls were women with breast cancer who did not develop contralateral breast cancer. One control was matched to each case patient on the basis of age, calendar year of initial breast cancer diagnosis, and survival time. Radiation dose to the contralateral breast was estimated for each patient on the basis of radiation measurements and abstracted treatment information. The anatomical position of each breast cancer was also abstracted from medical records. RESULTS: Radiotherapy had been administered to 82.4% of case patients and controls, and the mean radiation dose to the contralateral breast was estimated to be 2.51 Gy. Radiotherapy did not increase the overall risk of contralateral breast cancer (relative risk = 1.04; 95% confidence interval = 0.74-1.46), and there was no evidence that risk varied with radiation dose, time since exposure, or age at exposure. The second tumors in case patients were evenly distributed in the medial, lateral, and central portions of the breast, a finding that argues against a causal role of radiotherapy in tumorigenesis. CONCLUSIONS: The majority of women in our series were perimenopausal or postmenopausal (53% total versus 38% premenopausal and 9% of unknown status) and received radiotherapy at an age when the breast tissue appears least susceptible to the carcinogenic effects of radiation. Based on a dose of 2.51 Gy and estimates of radiation risk from other studies, a relative risk of only 1.18 would have been expected for a population of women exposed at an average age of 51 years. Thus, our data provide additional evidence that there is little if any risk of radiation-induced breast cancer associated with exposure of breast tissue to low-dose radiation (e.g., from mammographic x rays or adjuvant radiotherapy) in later life.     

A model for individualized risk prediction of contralateral breast cancer

Purpose

Patients diagnosed with invasive breast cancer (BC) or ductal carcinoma in situ are increasingly choosing to undergo contralateral prophylactic mastectomy (CPM) to reduce their risk of contralateral BC (CBC). This is a particularly disturbing trend as a large proportion of these CPMs are believed to be medically unnecessary. Many BC patients tend to substantially overestimate their CBC risk. Thus, there is a pressing need to educate patients effectively on their CBC risk. We develop a CBC risk prediction model to aid physicians in this task.

Methods

We used data from two sources: Breast Cancer Surveillance Consortium and Surveillance, Epidemiology, and End Results to build the model. The model building steps are similar to those used in developing the BC risk assessment tool (popularly known as Gail model) for counseling women on their BC risk. Our model, named CBCRisk, is exclusively designed for counseling women diagnosed with unilateral BC on the risk of developing CBC.

Results

We identified eight factors to be significantly associated with CBC—age at first BC diagnosis, anti-estrogen therapy, family history of BC, high-risk pre-neoplasia status, estrogen receptor status, breast density, type of first BC, and age at first birth. Combining the relative risk estimates with the relevant hazard rates, CBCRisk projects absolute risk of developing CBC over a given period.

Conclusions

By providing individualized CBC risk estimates, CBCRisk may help in counseling of BC patients. In turn, this may potentially help alleviate the rate of medically unnecessary CPMs.

     

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.     

Variants in the ATM gene associated with a reduced risk of contralateral breast cancer

Between 5% and 10% of women who survive a first primary breast cancer will subsequently develop a second primary cancer in the contralateral breast. The Women's Environment, Cancer, and Radiation Epidemiology Study was designed to identify genetic and environmental determinants of contralateral breast cancer (CBC). In this study, 708 women with asynchronous CBC served as cases and 1,397 women with unilateral breast cancer served as controls. ATM, a serine-threonine kinase, controls the cellular response to DNA double-strand breaks, and has been implicated in breast cancer risk. Complete mutation screening of the ATM gene in all 2,105 study participants identified 240 distinct sequence variants; only 15 were observed in >1% of subjects. Among the rare variants, deleterious alleles resulting in loss of ATM function were associated with a nonsignificant increase in risk of CBC. In contrast, carriers of common variants had a statistically significant reduction in risk of CBC. Four of these 15 variants were individually associated with a significantly decreased risk of second primary breast cancer [c.1899-55T>G, rate ratio (RR), 0.5; 95% confidence interval (CI), 0.3-0.8; c.3161C>G, RR, 0.5; 95% CI, 0.3-0.9; c.5558A>T, RR, 0.2; 95% CI, 0.1-0.6; c.6348-54T>C RR, 0.2; 95% CI, 0.1-0.8]. These data suggest that some alleles of ATM may exert an antineoplastic effect, perhaps by altering the activity of ATM as an initiator of DNA damage responses or a regulator of p53.     

Survival from contralateral breast cancer

First primary, or unilateral, breast cancer (UBC) cases diagnosed in 1960–89 at the Cancer Institute (WIA), Chennai, India were followedup until December 31, 1994. Patients with UBC (n=3163) and those who developed second cancer in the contralateral breast (CBC) after the initial breast cancer (n=67 or 2.1% of UBC) were analysed.Compared to UBC patients, those who developed CBC were younger at the time of diagnosis of initial breast cancer and had higher frequency of breast cancer among the family members. The relative survival rate takes into account competing causes of death and was estimated as the ratio of observed survival rate to the expected survival rate. The cumulative relative survival from UBC at 5 and 10 years were 51% and 41%, respectively, and the corresponding rates for CBC were 47 and 30% the survival difference seen between UBC and CBC patients was not statistically significant. The survival rates among younger, middle-aged and older women were significantly different from each other in UBC but not in CBC patients. Both UBC and CBC with early stage disease had a better survival compared to late stage disease. Survival advantage was also seen among both UBC and CBC patients with family history of breast cancer compared to those without. The multivariate analysis by the life table proportional hazards model showed that the age at diagnosis is an independent prognostic factor for breast cancer. The study results should be interpreted in the light of small sample size of second cancers.     

Risks for familial and contralateral breast cancer interact multiplicatively and cause a high risk

The reasons for the high risk of contralateral breast cancer are not understood, although polygenic mechanisms have been suggested to be involved. The nationwide Swedish Family-Cancer Database was used to examine the interaction of the risks for contralateral and familial cancer. Relative risks were separately determined for contralateral and familial breast cancers, and these were tested for additive and multiplicative interactions. The Database contained information on 102,176 first breast cancers. Familial risk for breast cancer was 1.76 and the risk for contralateral breast cancer was 3.40, or 5.80 when extrapolated to two breasts. When women had a family history, the risk for contralateral breast cancer was remarkably high, 5.48, or 9.96 when the risk was extrapolated to two breasts, almost identical with 10.21, which was predicted by the multiplicative model. Although the data do not rule out polygenic mechanisms, they suggest that epigenetic imprinting events may be involved for the contralateral breast cancer.     

Change of mammographic density predicts the risk of contralateral breast cancer - a case-control study

Introduction

Mammographic density is a strong risk factor for breast cancer, but it is unknown whether density at first breast cancer diagnosis and changes during follow-up influences risk of non-simultaneous contralateral breast cancer (CBC).

Methods

We collected mammograms for CBC-patients (cases, N = 211) and unilateral breast cancer patients (controls, N = 211), individually matched on age and calendar period of first breast cancer diagnosis, type of adjuvant therapy and length of follow-up (mean follow-up time: 8.25 years). The odds of CBC as a function of changes of density during follow-up were investigated using conditional logistic regression, adjusting for non-dense area at diagnosis.

Results

Patients who experienced ≥10% absolute decrease in percent density had a 55% decreased odds of CBC (OR = 0.45 95% CI: 0.24 to 0.84) relative to patients who had little or no change in density from baseline to first follow-up mammogram (mean = 1.6 (SD = 0.6) years after diagnosis), whereas among those who experienced an absolute increase in percent density we could not detect any effect on the odds of CBC (OR = 0.83 95% CI: 0.24 to 2.87).

Conclusion

Decrease of mammographic density within the first two years after first diagnosis is associated with a significantly reduced risk of CBC, this potential new risk predictor can thus contribute to decision-making in follow-up strategies and treatment.     

Epidemiologic and molecular risk factors for contralateral breast cancer among young women

Women diagnosed with a first breast cancer before the age of 45 years have a greater than 5.0-fold risk of developing a second primary contralateral breast cancer (CBC) than women in the general population have of developing a first breast cancer. Identifying epidemiologic or molecular factors that influence CBC risk could aid in the development of new strategies for the management of these patients. A total of 1285 participants in two case-control studies conducted in Seattle, Washington, who were 21-44 years of age when diagnosed with a first invasive breast carcinoma from 1983 to 1992, were followed through December 2001. Of them, 77 were diagnosed with CBC and 907 tumour tissues from first cancers were analysed. Women with body mass indices (BMIs) >/=30 kg m(-2) had a 2.6-fold greater risk (95% CI: 1.1-5.9) of CBC compared to women with BMIs 相似文献   

Increasing contralateral mastectomy use at diagnosis: Surgical prevention of contralateral breast cancer

Patients with unilateral breast cancer are at increased risk for developing contralateral breast cancer (CBC). The annual risk of clinically detected metachronous CBC is about 0.6%. Some patients choose contralateral prophylactic mastectomy (CPM) to prevent CBC. Recent studies reported that the CPM rates have markedly increased in recent years in the United States. The risk of CBC is reduced by about 95% after CPM. Because risk of systemic metastases often exceeds risk of CBC, most patients will not experience any survival benefit from CPM. Moreover, CPM is irreversible and not risk-free. Alternatives to CPM include surveillance with clinical breast examination, mammography, and possibly breast MRI. Endocrine therapy with tamoxifen or aromatase inhibitors significantly reduces risk of CBC and may be more acceptable than CPM for some patients.     

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.