Patterns of metastasis in women with metachronous contralateral breast cancer

Background:

The understanding of metastatic patterns after metachronous contralateral breast cancer (CBC) may help determine the biological nature of CBC.

Methods:

A cohort of 8478 women with breast cancer treated at Guy''s and St Thomas'' NHS Foundation Trust between 1975 and 2006 were studied. Organ-specific 5-year cumulative incidence and incidence rate ratios were assessed for women diagnosed with unilateral breast cancer (UBC), CBC within 5 years and CBC more than 5 years of the initial diagnosis.

Results:

Women diagnosed with CBC within 5 years had a higher incidence of metastases in all organs compared with UBC. Women with a short interval time to CBC developed metastasis more rapidly and were more likely to develop visceral and distant cutaneous metastases compared with bone metastasis.

Conclusion:

These findings explain poor prognosis of women with early occurring CBC and suggest that some of these CBCs are indicators of aggressive and/or systemic disease.     

Effectiveness of routine follow-up in the detection of contralateral breast cancer in young women with early breast cancer

Background

The purpose of the study was to determine the effectiveness of routine follow-up to detect contralateral breast cancer (CBC) in young women.

Methods

We used the data of the population-based Eindhoven Cancer Registry, which covers the southern part of the Netherlands. Between 1988 and 2005, 1451 women aged ≤40 years were treated for early-stage breast cancer with breast-conserving treatment or mastectomy.

Results

Of the 94 patients who developed CBC 17 had an in situ carcinoma. Fifty-seven CBCs (61%) were diagnosed more than 5 years after the primary tumour. Forty-two CBCs (45%) were detected during routine follow-up visits, while 52 (55%) presented between two visits. Of the CBC diagnosed between two visits, only 27 (60%) were visible on mammography. Of the invasive CBCs more than 25% was larger than 2 cm in diameter and in 34% positive axillary lymph nodes were found.

Conclusions

These figures indicate that routine follow-up does not guarantee early detection of CBC in young women with breast cancer.     

Estimating Contralateral Breast Cancer Risk

Purpose of review

Accurate estimates of contralateral breast cancer (CBC) risk are necessary around the time a first breast cancer is diagnosed to aid surgical decision-making. This review will discuss the known risk factors for contralateral breast cancer (CBC) and present methods for calculating CBC risk that can be utilized when breast surgeons counsel patients.

Recent findings

In addition to the well-known factors that impact contralateral breast cancer risk, such as BRCA1/BRCA2 mutation carrier status and history of chest wall radiation, other factors that affect CBC risk are being better defined. Recent studies that take into account important covariates in contralateral breast cancer risk, such as BRCA1 and BRCA2 mutation carrier status, family history, and systemic treatment, are further improving estimates of contralateral risk. Recent studies show family history, especially of breast cancer in a young relative or of bilateral breast cancer, hormone receptor status, lobular histology, and breast density are important in accurately estimating contralateral breast cancer risk. The Manchester formula, a pen and paper calculation for contralateral breast cancer risk estimation, and CBCRisk, a recently developed online CBC risk calculator, are two tools now available to clinicians.

Summary

Despite a decreasing incidence of contralateral breast cancer over the last few decades, there has been a steady increase in the number of women undergoing contralateral prophylactic mastectomy (CPM). The reasons for this are multifactorial, but fear of a contralateral breast cancer and a tendency to overestimate the risk of a contralateral breast cancer are two factors. Therefore, a critical element in decision-making for women considering CPM is having an accurate estimate of contralateral breast cancer risk. Models for estimating contralateral breast cancer risk are not widely used, but are available.

     

Relation of risk of contralateral breast cancer to the interval since the first primary tumour

Background:

There is no consensus on how to separate contralateral breast cancer (CBC) occurring as distant spread of the primary breast cancer (BC) from an independent CBC.

Methods:

We used standardised incidence ratios (SIRs) to analyse the variations in the risk of CBC over time among 6629 women with BC diagnosed between 1954 and 1983. To explore the most appropriate cutoff to separate the two types of CBC, we analysed the deviance between models including different cutoff points as compared with the basal model with no cutoff date. We also performed a prognostic study through a Cox model.

Results:

The SIR was much higher during the first 2 years of follow-up than afterwards. The best cutoff appeared to be 2 years. The risk of early CBC was linked to tumour spread and the risk of late CBC was linked to age and to the size of the tumour. Radiotherapy was not selected by the model either for early or late CBC risk.

Conclusion:

A clearer pattern of CBC risk might appear if studies used a similar cutoff time after the initial BC.     

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.     

Prognosis of metachronous contralateral breast cancer: importance of stage, age and interval time between the two diagnoses

Studies comparing the prognosis after contralateral breast cancer (CBC) with that after unilateral breast cancer (UBC) shows conflicting results. We assessed the risk of breast cancer-specific death for women with metachronous CBC compared to those with a UBC in 8,478 women with invasive primary breast cancer registered in the Guy’s and St. Thomas’ Breast Cancer Tissue and Data Bank. Risk factors associated with breast cancer-specific death for women with CBC were estimated using Cox proportional hazards modelling. Prognoses after UBC and CBC were compared, with survival time for women with CBC calculated: (i) from CBC, (ii) from the initial cancer with CBC as a time-dependent covariate. Women diagnosed with CBC within 5 years after the initial primary breast cancer had a worse prognosis than those with CBC after 5 years and those with UBC. Women with CBC who had positive lymph nodes at the initial breast cancer diagnosis were at an increased risk of dying from breast cancer compared to those without [HR 2.5 (95% CI 1.5–4.0)]. For all stages of the initial breast cancer, a worse prognosis was observed after CBC. CBC increased the hazard originating from the initial cancer at any follow-up time, but the highest hazards were associated with a short interval to CBC. Metachronous CBC adds to the risk of dying from breast cancer. The risk increases substantially when it occurs shortly after the initial cancer, indicating a CBC in some instances may be an indicator of active distant disease. The occurrence of CBC implies a new surveillance and therapeutic situation.     

Risk of contralateral second primary breast cancer according to hormone receptor status in Germany

Introduction

Hormone receptor (HR) status has become an established target in treatment strategies of breast cancer. Population-based estimates of contralateral breast cancer (CBC) incidence by HR subtype in particular are limited. The aim of this study was to provide detailed data on CBC incidence for Germany.

Methods

Invasive breast cancer data were extracted on 49,804 women yielding 594 second primaries from the cancer registries of the Federal States of Brandenburg and Saarland and the area of Munich for the period from 1998 to 2007. Multiple imputation was used on missing values for HR status. We estimated standardized incidence ratios (SIRs) with 95% confidence intervals (95%CIs).

Results

SIR estimates of CBC among women diagnosed with an invasive first primary breast cancer (FBC) of any HR subtype ranged from 1.0 to 1.5 in the three registries. Pooling three registries’ data, the SIR of HR-positive CBC was 0.7 (95%CI: 0.6 to 0.8) among women with HR-positive FBC. For those women with HR-negative FBC, the SIR of HR-negative CBC was 8.9 (95%CI: 7.1 to 11.1). Among women with FBC diagnosed before the age of 50 years, incidence of CBC was increased, especially for HR-negative FBC (SIR: 9.2; 95%CI: 7.1 to 11.9).

Conclusions

HR status of the first primary and age at first diagnosis is relevant for predicting risk of CBC. Particularly, patients with HR-negative FBC had elevated risks.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-014-0452-4) contains supplementary material, which is available to authorized users.     

Hormone receptor status of contralateral breast cancers: analysis of data from the US SEER population-based registries

Background

Women diagnosed with breast cancer display higher propensity to develop second primary cancer in the contralateral breast (CBC). Identification of patients with increased risk of CBC and understanding relationships between hormone receptor (HR) statuses of the first and second breast cancers is desirable for endocrine-based prevention strategies.

Methods

Using 1992–2012 data from 13 SEER registries, the risk of developing CBC was determined as ratio of observed and expected second breast cancers (SIR). Association between HR statuses was examined by exploratory data analysis and multivariable logistic regression. Results: Women with ER-positive and ER-negative breast cancers have increased risk of developing CBC with SIR values 2.09 (CI 95 = 1.97–2.21) and 2.40 (CI 95 = 2.18–2.63), respectively. ER statuses of the CBC are moderately positively associated. In metachronous CBC, most cases with ER-positive first cancers had ER-positive second breast cancers (81.6 %; CI 95 = 80.2–82.9 %); however, considerable proportion of cases with ER-negative first cancers had ER-positive second cancers (48.8 %; CI 95 = 46.2–51.4 %).

Conclusions

Some women with ER-negative breast cancers may benefit from endocrine-based prevention of ER-positive CBC.

     

Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study

Objective

Reproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers.

Methods

The WECARE Study is a population-based multi-center case–control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers.

Results

None of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65–2.65 and 0.53, 95% CI 0.19–1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers.

Conclusion

For two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers.     

Predictors associated with MRI surveillance screening in women with a personal history of unilateral breast cancer but without a genetic predisposition for future contralateral breast cancer

Purpose

For women with a personal history of breast cancer (PHBC), no validated mechanisms exist to calculate future contralateral breast cancer (CBC) risk. The Manchester risk stratification guidelines were developed to evaluate CBC risk in women with a PHBC, primarily for surgical decision making. This tool may be informative for the use of MRI screening, as CBC risk is an assumed consideration for high-risk surveillance.

Methods

Three hundred twenty-two women with a PHBC were treated with unilateral surgery within our multidisciplinary breast clinic. We calculated lifetime CBC risk using the Manchester tool, which incorporates age at diagnosis, family history, genetic mutation status, estrogen receptor positivity, and endocrine therapy use. Univariate and multivariate logistic regression analyses (UVA/MVA) were performed, evaluating whether CBC risk predicted MRI surveillance.

Results

For women with invasive disease undergoing MRI surveillance, 66% had low, 23% above-average, and 11% moderate/high risk for CBC. On MVA, previous mammography-occult breast cancer [odds ratio (OR) 18.95, p < 0.0001], endocrine therapy use (OR 3.89, p = 0.009), dense breast tissue (OR 3.69, p = 0.0007), mastectomy versus lumpectomy (OR 3.12, p = 0.0041), and CBC risk (OR 3.17 for every 10% increase, p = 0.0002) were associated with MRI surveillance. No pathologic factors increasing ipsilateral breast cancer recurrence were significant on MVA.

Conclusions

Although CBC risk predicted MRI surveillance, 89% with invasive disease undergoing MRI had <20% calculated CBC risk. Concerns related to future breast cancer detectability (dense breasts and/or previous mammography-occult disease) predominate decision making. Pathologic factors important for determining ipsilateral recurrence risk, aside from age, were not associated with MRI surveillance.

     

Assessing the Effect of Lifetime Contralateral Breast Cancer Risk on the Selection of Contralateral Prophylactic Mastectomy for Unilateral Breast Cancer

Introduction

Contralateral prophylactic mastectomy (CPM) rates are rising, with fear implicated as a contributing factor. This study used a contralateral breast cancer (CBC) risk stratification tool to assess whether the selection of CPM is reflective of future CBC risk.

Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study

Background  

Microarray gene-profiling of invasive breast cancer has identified different subtypes including luminal A, luminal B, HER2-overexpressing and basal-like groups. Basal-like invasive breast cancer is associated with a worse prognosis. However, the prognosis of basal-like ductal carcinoma in situ (DCIS) is still unknown. Our aim was to study the prognosis of basal-like DCIS in a large population-based cohort.     

Common variants in genes coding for chemotherapy metabolizing enzymes, transporters, and targets: a case–control study of contralateral breast cancer risk in the WECARE Study

Purpose

Women who receive chemotherapy for a first primary breast cancer have been observed to have a reduced risk of contralateral breast cancer (CBC), however, whether the genetic profile of a patient modifies this protective effect is currently not understood. The purpose of this study is to investigate the impact of germline genetic variation in genes coding for drug metabolizing enzymes, transporters, and targets on the association between chemotherapy and risk of CBC.

Methods

From the population-based Women’s Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 636 Caucasian women with CBC (cases) and 1,224 women with unilateral breast cancer (controls). The association between common chemotherapeutic regimens, CMF and FAC/FEC, and risk of CBC stratified by genotype of 180 single nucleotide polymorphisms in 14 genes selected for their known involvement in metabolism, action, and transport of breast cancer chemotherapeutic agents, were determined using conditional logistic regression.

Results

CMF (RR = 0.5, 95 % CI 0.4, 0.7) and FAC/FEC (RR = 0.7, 95 % CI 0.4, 1.0) are associated with lower CBC risk relative to no chemotherapy in multivariable-adjusted models. Here we show that genotype of selected genes involved in the metabolism and uptake of these therapeutic agents does not significantly alter the protective effect of either CMF or FAC/FEC on risk of CBC.

Conclusion

The results of this study show that germline genetic variation in selected gene does not significantly alter the protective effect of CMF, FAC, and FEC on risk of CBC.     

Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes

Introduction  

Hyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has now been identified as a specific factor which can worsen breast cancer prognosis. In breast cancer, a high rate of mortality persists due to the emergence of pulmonary metastases.     

Radiographic features for triple negative ductal carcinoma in situ of the breast

Background  

Triple negative (TN) breast cancer is characterized as having a high malignancy potential and a poor prognosis. An understanding of the radiological features of TN DCIS will enable the early detection of intractable TN invasive breast cancer.     

The mid-long term outcome of breast-conserving patients with different ages

OBJECTIVE Breast-conserving surgery has been a standard treatment for relatively small size of breast cancer. Younger breast cancer patients have more desire to conserve their breasts. This study was to investigate the clinicopathological characteristics and prognosis of younger breast cancer patients who received breastconserving treatment in China. METHODS The data of 232 breast cancer patients who received breast-conserving treatment in Cancer Hospital of Chinese Academy of Medical Science from January Ist, 1999 to December 31st, 2005, were collected and retrospectively analyzed. According to the age, the patients were divided into 2 groups： younger group （age ≤ 35 at the time of diagnosis） and elder group （age 〉35）. The clinical features of the patients in the 2 groups were compared, and their clinical characteristics, recurrence, metastasis and survival status were summarized. RESULTS In the 232 cases, younger patients accounted for 15.9% （37/232）, the elder 84.1% （195/232）. By December 2008, the median time of follow-up was 54 months （ranging from 2 months to 118 months）. Two patients （5.41% , 2/37） in the younger group and 5 patients （2.56% 5/195） in the elder group died. The 5-year overall survival rate （OS） in the younger and elder groups was 96.08% and 97.19%, respectively （X2= 0.69, P = 0.4066）. Local recurrence （LR） or distant metastasis （DM） presented in 5 patients （5/37, 13.51%） in younger group. LR or DM presented in 10 patients （10/195, 5.13%） in elder group. The 5-year disease-free survival （DFS） rate in the younger and elder groups was 82.58% and 95.52%, respectively （X2 = 4.02, P = 0.0451）. Lymph node status and the age of 35 years old or younger were the prognosis factors affecting the DFS of patients who received breast-conserving treatment （OR = 3.467, 95%CI： 1.048-11.472, P 〈0.05; OR = 0.245, 95%CI： 0.069-0.863, P 〈 0.05）. Lymph node status was the only prognostic factor affecting the DFS of younger group patients （OR = 7.357, 95%CI： 1.030-52.563, P 〈0.05）. CONCLUSION Though the younger and elder patients have the same mid-long term survival rate, younger patients are more likely to have recurrence or metastasis than the elder patients. Breast-conserving surgery given to the younger patients especially to the younger patients with lymph nodes positive should be contemplated cautiously.     

Anterior gradient-2 plays a critical role in breast cancer cell growth and survival by modulating cyclin D1, estrogen receptor-α and survivin

Introduction  

Anterior-gradient 2 (AGR2) is an estrogen-responsive secreted protein. Its upregulation has been well documented in a number of cancers, particularly breast cancer, for which mixed data exist on the prognostic implications of AGR2 expression. Although emerging evidence indicates that AGR2 is associated with poor prognosis, its function and impact on cancer-relevant pathways have not been elucidated in breast cancer.     

CYP2D6 phenotype,tamoxifen, and risk of contralateral breast cancer in the WECARE Study

Background

Tamoxifen treatment greatly reduces a woman’s risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown.

Methods

Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS?=?2), EM/IM (AS?=?1.5), EM/PM (AS?=?1), IM/IM (AS?=?0.75), IM/PM (AS?=?0.5), and PM/PM (AS?=?0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS?=?0.5–0.75; PM, AS?=?0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS.

Results

Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20–55% reduced RR of CBC (AS?=?2, RR?=?–?0.81, 95% CI 0.62–1.06; AS?=?1.5, RR?=?0.45, 95% CI 0.30–0.68; and AS?=?1, RR?=?0.55, 95% CI 0.40–0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS?=?0.5, RR?=?1.08, 95% CI 0.59–1.96; and AS?=?0, RR?=?1.17, 95% CI 0.58–2.35) (p for homogeneity?=?–?0.02).

Conclusion

This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.

     

The influence of genetic variation in 30 selected genes on the clinical characteristics of early onset breast cancer

Introduction  

Common variants that alter breast cancer risk are being discovered. Here, we determine how these variants influence breast cancer prognosis, risk and tumour characteristics.