Invasive ductal carcinoma of the breast with the “triple-negative” phenotype: prognostic implications of EGFR immunoreactivity

Invasive ductal carcinomas (IDC) of the breast with the triple negative phenotype (steroid hormone receptor absent, negative HER2 status) are characterized by poor clinical outcome. Additional tumor markers might allow identification of patients at higher risk. We evaluated clinical and biological features of 284 consecutive patients with pT1-3, pN1-3 M0 triple-negative IDC. Median follow-up was 70 months (interquartile range 59–94 months). Statistically significant worse disease-free and overall survival were observed in multivariate analysis, for patients with EGFR immunoreactivity in ≥50% invasive tumor cells (HR 2.39, 95% CI, 1.32–4.34, P = 0.004 for DFS; HR 2.34, 95% CI, 1.20–4.59 P = 0.01 for OS). Age ≥ 70 years and PVI were additional independent predictors of reduced overall survival. EGFR immunoreactivity significantly correlates with worse prognosis in patients with triple-negative IDC, supporting further studies on the correlation between the degree of EGFR expression and outcome of triple negative breast cancer.     

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.     

Bone mineral density and risk of postmenopausal breast cancer

To determine if higher bone mineral density (BMD) is a risk factor for breast cancer in women age 50 years and older. 37,860 women ≥50-year old with no previous breast cancer diagnosis had baseline BMD assessment between January 1999 and December 2007. Cox proportional hazards models were created for time to a new breast cancer as a function of lumbar spine or femoral neck BMD quartile (1st = lowest as reference) with adjustment for relevant covariates. A secondary analysis was performed to look for an association with estrogen receptor-positive (ER-positive) breast cancers. 794 invasive and in situ breast cancers (484 ER-positive) occurred with a median follow up of 5.4 years. Increased breast cancer risk was seen for the 3rd and 4th quartiles of lumbar spine BMD with hazard ratios (HRs) of 1.26 (95% CI, 1.01–1.58) and 1.45 (95% CI, 1.16–1.81), respectively and for the 3rd quartile of femoral neck BMD with a HR of 1.33 (95% CI, 1.07–1.64). A test for linear trend showed that lumbar spine BMD (P < 0.001) and femoral neck BMD (P = 0.04) were associated with increased risk. Higher lumbar spine BMD was also associated with increased risk of ER-positive breast cancer with HR of 1.45 (95% CI, 1.08–1.94), and 1.68 (95% CI, 1.24–2.27) for women in the 2nd and 4th quartiles, respectively. A test for linear trend showed lumbar spine BMD was associated with increasing risk of ER-positive breast cancer (P = 0.003). Increased ER-positive breast cancer risk was seen for the 3rd quartile of femoral neck BMD with a HR of 1.43 (95% CI, 1.08–1.89). Higher lumbar spine and femoral neck BMD are associated with higher risk of breast cancer in women ≥50-year old. Lumbar spine and femoral neck BMD are associated with increased risk of ER-positive breast cancer.     

Optimal delivery of anthracycline-based chemotherapy in the adjuvant setting improves outcome of breast cancer patients

To evaluate the dose–response effect of an adjuvant anthracycline-based non-taxane chemotherapy in early breast cancer patients. This was a retrospective database analysis. Selection criteria included patients treated for early breast cancer from years 1980 to 2000 with an adjuvant anthracycline-based non-taxane chemotherapy. The delivery of chemotherapy was assessed through the number of delayed cycles, the number of delayed days and the relative dose intensity (RDI) administered (≥85%, <85%). Seven hundred and ninety-three breast cancer patients were included. The Kaplan–Meier disease-free survival (DFS) was affected by the number of delayed cycles (P < 0.0001), the number of delayed days (P < 0.0001) and the RDI (P = 0.0029). The Kaplan–Meier overall survival (OS) was also affected by the number of delayed cycles (P = 0.0008) and days (P = 0.0115), as well as the RDI (P = 0.0055). The Cox regression models showed that, when the number of nodes affected and the hormonal receptor status were controlled, all the study variables maintained their significance on DFS, but not on OS. The dose–response effect is a crucial factor in the administration of anthracycline-based non-taxane schedules for the adjuvant treatment of early breast cancer. Delays and/or reductions of chemotherapy should be avoided if possible to achieve the maximal benefit.     

Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes

Insulin-like growth factor-1 receptor (IGF-1R) is expressed in normal and malignant breast tissue and has been implicated in cell survival and resistance to cytotoxic therapies. We sought to assess the prognostic impact of IGF-1R expression among patients with early breast cancer and among breast cancer subtypes. Patients with stages I–III breast cancer with archival tumor tissue were included. Paraffin tissue blocks were used to construct a tissue microarray that was stained for ER, PR, Ki-67, HER2, EGFR, and cytokeratins 5/6 to classify the breast subgroups and for expression of IGF-1R, p27, and Bcl2 by immunohistochemistry. Kaplan–Meier plots were created by subtypes. Associations between IGF-1R and prognostic variables were examined in multivariate analysis. Among 2,871 eligible women the prognostic cut point for IGF-1R expression for breast-cancer-specific survival (BCSS) was Allred score <7 versus ≥7. IGF-1R was ≥7 in 52% (LuminalA), 57.5% (LuminalB), 44.8% (LuminalHER2), 9.7% HER2-enriched, and 22.5% (Basal-like), P = 1.3 × 10⁻⁵². IGF-1R+ was associated with age ≥50, lower histopathology grade, ER+, HER2 negativity (−), high p27 and high Bcl2 score. IGF-1R ≥7 was associated with better BCSS among LuminalB patients, hazard ratio = 0.64 (0.49–0.84); P = 1.2 × 10^−3, and worse outcome in the HER2-enriched subtype, hazard ratio = 2.37 (1.21–4.64); P = 0.012. IGF-1R correlates with good prognostic markers among patients with early breast cancer and is differentially expressed with variable prognostic impact among breast cancer subtypes. Results may have relevance to the development of therapeutics targeting IGF-1R.     

Mitotic activity and bone marrow micrometastases have independent prognostic value in node positive breast cancer patients

The purpose of this article is to investigate the prognostic value of the mitotic activity index (MAI) and the presence of disseminated tumor cells (DTCs) in bone marrow (BM), in clinically operable breast cancer patients. We compared routinely assessed MAI, classic prognosticators and BM DTCs, detected by a real-time RT-PCR multimarker assay including cytokeratin 19, mammaglobin A and TWIST1 mRNA, in 179 consecutive patients with operable breast cancer. Over a median follow-up of 96 months (range: 1–126 months), 31 (17.3%) patients experienced a systemic relapse and 26 (14.5%) died of breast cancer-related causes. MAI (≥ 10) was strongly associated with breast cancer-related death in lymph node (LN)-negative patients (hazard ratio (HR): 7.0, confidence interval (CI) 1.74–27.9), whereas both BM DTC-status (HR: 3.3, CI 1.25–8.52) and MAI (HR: 3.1, CI 1.08–8.8) were significant in LN-positive patients. With multivariate Cox regression, MAI was the only significant predictor of breast cancer-specific survival (HR 7.0, CI 1.7–27.9) in LN-negative patients. In LN-positive patients, both BM DTC-status and MAI were strong independent predictors of breast cancer-specific survival (HR 3.3, CI 1.25-8.49 and HR 3.1, CI 1.1–8.9), respectively. Where, however, MAI and BM DTC-status as single parameters were replaced by a combination of these, this showed to be the most significant prognostic marker in both LN-negative (HR 7.7, CI 1.2-50) and LN-positive (HR 6.0, CI 1.4 to 26.4) patients with regard to breast cancer-specific survival. A combination of MAI and BM DTC detection identified both LN-negative and LN-positive breast cancer patients with poor prognosis.     

Prognostic factor analysis in patients with brain metastases from breast cancer: how can we improve the treatment outcomes?

Purpose  We conducted this study to analyze clinicopathologic features and treatment outcomes for various treatment modalities in breast cancer patients with brain metastases. Patients and methods  Retrospective analysis was performed using medical records of patients who were diagnosed with metastatic brain tumors from breast cancer. The treatment modalities applied included whole-brain radiotherapy (WBRT), surgical resection, stereotactic radiosurgery (SRS) and systemic treatments such as chemotherapy and endocrine therapy. Results  Among 125 female breast cancer patients with brain metastases, 87.2% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2. The median overall survival (OS) was 6.6 months (95% CI 3.9–9.2). A multivariate analysis using the Cox-regression test identified three risk factors; poor PS (P = 0.023), HER2 positivity (P = 0.013), and no additional systemic treatment (P = 0.006). Those patients who had no risk factors showed outstanding outcome (median OS 49 months). On the contrary, the patients who had all risk factors (poor PS with HER2 positive and did not receive additional systemic chemotherapy) showed dismal prognosis (median OS 2 months). Conclusions  Our new classification according to the suggested risk factors for patients with metastatic brain tumor from breast cancer reflects particular characteristics of each subset of the patients with good prognostic capacity. B.-B. Park and J. E. Uhm contributed equally to the work.     

Association of age and overall survival in capecitabine-treated patients with metastatic breast cancer in clinical trials

We sought to determine if an association exists between age and capecitabine efficacy among patients with metastatic breast cancer (MBC). Pooled analysis of five phase II or III registration trials of capecitabine 2,500–2,510 mg/m²/day for 2 weeks and 1 week off, or combination therapy was performed. Four trials enrolled patients previously exposed to other chemotherapy, generally a taxane. Of 570 patients, 193 (34%) were 18–49 years old, 246 (43%) were 50–64, and 131 (23%) were ≥65. Median average daily dose was 2,067 mg/m² in the 18- to 49-year-old group and 2,105 mg/m² in the 50–64 and ≥65 year groups. Overall survival (OS) in all groups was similar by log-rank test for the individual trials (P = 0.71–0.95) and Cox regression of the pooled trials. Univariate analysis demonstrated no difference in clinical benefit or objective response between groups. Treatment failure analysis showed 283 (50%) patients experienced progressive disease, while 114 (20%) withdrew for safety. Serious adverse events (AEs) occurred in 71 (36.8%), 85 (34.6%), and 59 (45.0%) patients in the 18–49, 50–64, and ≥65 years groups, respectively. There was no statistically significant association between age and OS, clinical benefit, or objective response in patients with MBC treated with capecitabine. Frequency of AEs and serious AEs was not related to age at treatment, although women ≥65 years were more likely to withdraw from treatment because of an AE than younger women.     

The prognostic role of circulating tumor cells (CTCs) detected by RT-PCR in breast cancer: a meta-analysis of published literature

The prognostic significance of circulating tumor cells (CTCs) in patients with breast cancer is controversial. We performed a meta-analysis of published literature to assess whether the detection of CTCs in patients diagnosed with primary breast cancer can be used as a prognostic factor. We searched Medline, Science Citation Index, and Embase databases as well as reference lists of relevant articles (including review articles) for studies that assessed the prognostic relevance of tumor cell detection in the peripheral blood (PB). A total of 24 eligible studies with 4,013 cases and 1,333 controls were included. Meta-analyses were performed using a random-effects model, using the hazard ratio (HR) and 95% confidence intervals (95% CIs) as effect measures. The positive detection of CTCs in patients was significantly associated with poor overall survival (OS) (HR = 3.00 [95% CI 2.29–3.94], n = 17, P < 0.0001) and recurrence-free survival (RFS) (HR = 2.67 [95% CI 2.09–3.42], n = 22, P < 0.0001). CTC-positive breast cancers were significantly associated with high histological grade (HR = 1.21 [95% CI 1.09–1.35], n = 34, P < 0.0001), tumor size (>2 cm) (HR = 1.12 [95% CI 1.02–1.22], n = 31, P = 0.01). and nodal status (≥1) (HR = 1.10 [95% CI 1.00–1.21], n = 32, P = 0.037), but cytokeratin-19 (CK-19) mRNA-positive CTCs were not associated with these clinicopathological parameters of breast cancer. Furthermore, the presence of CTCs was not associated with estrogen receptor (ER) negativity, progesterone receptor (PR) negativity, or human epidermal growth factor receptor type 2 (HER2) positivity. Detection of CTCs in the PB indicates poor prognosis in patients with primary breast cancer. Larger clinical studies are required to further evaluate the role of these markers in clinical practice.     

Joint effects of body size,energy intake,and physical activity on breast cancer risk

To evaluate the joint effect of body size, energy intake, and physical activity on breast cancer risk, we analyzed information on body weight history, energy intake, anthropometric measurements, and physical activity patterns in a population based case–control study. Included in this analysis were 3,458 incidence breast cancer cases and 3,474 age-frequency matched controls from the Shanghai Breast Cancer Study. High weight, height, body mass index, waist-to-hip ratio, and weight gain showed stronger associations with breast cancer risk in postmenopausal women than premenopausal women. High total physical activity was inversely associated with postmenopausal breast cancer risk (p for trend = 0.026) and premenopausal breast cancer (p for trend = 0.059). The odds ratios for women with a high waist-to-hip ratio (≥0.84) and low total physical activity (≤10.9 MET-h/day) had the highest risk for breast cancer (OR = 2.7, 95% CI: 1.4–4.9 for postmenopausal women, OR = 2.1, 95% CI: 1.5–3.1 for premenopausal women) compared to their counterpart with low waist-to-hip ratio (<0.76) and high total physical activity (>20.5 MET-h/day). We did not find a statistically significant multiplicative interaction between body size, caloric intake and total physical activity on breast cancer risk.     

Breastfeeding reduces breast cancer risk: a case–control study in Tunisia

In this report, we examined the relationship between mother’s breastfeeding history and her risk of breast cancer, in a case–control study in Tunisia between 2006 and 2009. About 400 breast cancer cases and 400 controls were included. Cases and controls were interviewed using a standardized structured questionnaire to obtain information on breastfeeding and other risk factors. Mean duration of breastfeeding per child was significantly associated with a reduced risk of breast cancer for women who breastfed for >24 months per child. The OR was 0.46 (95% CI, 0.28–0.76) when compared those who breastfed for <6 months. The test for trend was significant (p = 0.01). A significantly reduced risk of breast cancer was found for those whose lifetime duration of breastfeeding was 73–108 months (OR = 0.65, 95% CI, 0.36–1.18) and for those who breastfed for ≥109 months (OR = 0.42, 95% CI, 0.20–0.84). Stratification by menopausal status showed a reduced risk of breast cancer associated with a longer duration of breastfeeding for both pre- and postmenopausal women. The risk reduction was more consistent for lifetime duration of breastfeeding, the test for trend being significant for both pre- (p = 0.03) and postmenopausal (p = 0.01) women. These results support an inverse association between breastfeeding and breast cancer risk.     

Effects of life event stress and social support on the odds of a ≥2 cm breast cancer

Objective  To examine the contribution of life event and social support factors to diagnosis with a ≥2 cm breast cancer. Methods  We studied 1,459 Australian women aged 40–69 diagnosed in 2002–2003 with a first primary invasive breast cancer 1.1 cm or larger. We measured stressful life events, perceived stress levels, and social support in the year before diagnosis and collected information on other potential risk factors and confounders. Results  The odds of a ≥2 cm breast cancer relative to a 1.1–1.9 cm breast cancer were reduced in women who reported tension or change in an intimate relationship in the year before diagnosis (OR = 0.71 95% CI 0.54–0.92; p = 0.009); the reduction was greatest in women living with a partner (OR = 0.64 95% CI 0.47–0.88; p = 0.006) and was largely unaffected by adjustment for other variables independently associated with a ≥2 cm breast cancer in our study. There was no evidence that the total number or severity of all studied life events influenced cancer size. Low partner support increased the odds of a ≥2 cm cancer but only in women not living with a partner. Conclusion  Intimate relationship stress may reduce risk of a ≥2 cm breast cancer. Suppression by stress of estrogen synthesis and metabolism is a possible mechanism.     

Serum neopterin levels in patients with breast cancer

The aim of this study was to determine the importance of serum neopterin level in female patients with breast cancer of various clinical stages. The study consisted of 75 female patients with breast cancer who were diagnosed and treated at the Gazi University Department of Medical Oncology. The patients were classified into three representative groups and a control group: group A (n = 26), patients with newly diagnosed primary breast cancer and without metastasis; group B (n = 33), patients with metastatic breast cancer who had undergone treatment for their diseases and on whom metastasis was detected during their follow-up; group C (n = 16), off-therapy patient whose cancer had been in remission for at least 5 years; group D (n = 20) healthy controls. The median serum neopterin levels of the 75 patients with breast cancer 11.0 (range, 0–23.6) nmol/L were significantly higher than those of controls (8.3 (range, 1.2–12.0) nmol/L). In group B patients, neopterin levels (12.6 (range, 0–23.6) nmol/L) were statistically significantly higher than those of controls, primary breast cancer patients, and off-therapy patients (P < .05). In group B, patients with visceral metastases had higher neopterin levels than did those with bone or local metastases; however, that difference was not statistically significant. The median serum neopterin levels of the primary breast cancer patients in group A (8.8 (range, 0–20) nmol/l) were not statistically significantly different from those in controls and off-therapy patients. Serum neopterin levels were significantly elevated in patients with metastatic breast cancer. Neopterin seems to be an indicator of metastatic cancer rather than a marker for local cancer. In patients with metastatic breast cancer, determining the serum neopterin levels may be useful in estimating survival; however, additional long-term follow-up will be needed.     

Alcohol consumption and breast cancer risk in Japanese women: the Miyagi Cohort study

Alcohol consumption is known to be a risk factor for breast cancer in Western countries, but few epidemiologic data have been available in Japan. This population-based prospective cohort study evaluated the associations of alcohol consumption with breast cancer risk in a Japanese population. A total of 19,227 women aged 40–64 years were followed from 1990 to 2003. During 246,703 person-years of follow-up, 241 breast cancer cases were identified. Hazard ratios (HRs) were estimated by the Cox proportional-hazard regression model. After adjustment for potential risk factors of breast cancer and nutritional factors, the HR and 95% confidence interval (CI) for current drinkers was 1.00 (0.74–1.34) compared with never drinkers. According to the amount of alcohol intake per day, a higher amount (≥15.0 g/day) had no significant relation to breast cancer risk (HR = 0.87, 95% CI: 0.40–1.91; P for trend = 0.85). Age upon starting to drink, and the frequency of drinking, were not associated with breast cancer risk. In analysis stratified according to exogenous female hormone use, a higher alcohol intake (≥15.0 g/day) was associated with an increased risk of breast cancer among hormone users (HR = 1.67, 95% CI: 0.17–16.73); however, this was not statistically significant. Stratification according to folate intake with energy adjustment (<219, ≥219 μg/day) found that breast cancer risk tended to increase with increasing alcohol consumption among women with a low intake of folate (P for trend = 0.09). Our findings suggest that alcohol consumption has no overall effect on breast cancer risk among Japanese women, whereas nutritional factors such as folate intake may modify the alcohol-breast cancer risk relationship.     

Phosphorylated S6K1 is a possible marker for endocrine therapy resistance in hormone receptor-positive breast cancer

Cross-talk between the estrogen receptor and the mammalian target of rapamycin (mTOR) pathway is one of the mechanisms of endocrine therapy resistance, and the phosphorylated S6 kinase 1(p-S6K1) is known to be a marker of the mTOR pathway activation. The authors assessed the prognostic significance of p-S6K1 according to the hormone receptor (HR) status. The expression of p-S6K1 was evaluated in 304 breast cancer tissues, and the association between its expression and patient outcomes was investigated. Among 197 cases with the HR (+) tumor, 70 (35.5%) were positive for p-S6K1. Most of the patients (97.5%) with the HR (+) tumor received adjuvant endocrine therapy. The expression of p-S6K1 was found to be an independent worse prognosticator affecting overall survival (OS) and breast cancer-specific survival (BCSS) in the HR (+) group (hazard ratio, 2.62; 95% confidence interval [CI], 1.19–5.76; P = 0.017 and hazard ratio, 3.25; 95% CI, 1.20–8.82; P = 0.020, respectively). In the HR (−) group, however, the p-S6K1 expression was not associated with patients’ survival. The expression of p-S6K1 is a worse prognostic factor in patients with HR (+) tumors. These results suggest that the p-S6K1 expression might be a marker for endocrine therapy resistance in patients with HR (+) tumors.     

The effect of peripheral blood values on prognosis of patients with locally advanced gastric cancer before treatment

We aimed to investigate the prognostic significance of neutrophil, lymphocyte, platelet, mean platelet value (MPV), platelet-lymphocyte ratio (PLR) and neutrophil–lymphocyte ratio (NLR) in patients with locally advanced gastric cancer (LAGC). One hundred sixty-eight patients with LAGC who had been followed-up between 2004 and 2008 were included in present study. The results of hematological (platelet, lymphocyte, neutrophil and MPV) and biochemical (uric acid and LDH) parameters were evaluated before treatment. NLR was divided into two groups as <2.56 and ≥2.57 and PLR was also divided into two groups as ≤160 and >160. Platelet counts and lymphocyte counts were also divided into two groups; ≤300.000/mm3 and >300.000/mm3, and <1,500/mm3 and ≥1,500/mm3, respectively. Results were evaluated with Kaplan–Meier and Long-rank tests. The mean age of patients at diagnosis was 60.1 ± 12.1 and 114 of patients (67.8%) were male. For 168 patients, 48 months overall survival (OS) rate was 45.2% and the median OS was 39 months (range 33–44). In patients whose PLR was less than 160 (n = 54), the median OS was 45 months (range 38–52) and also for cases whose PRL was greater than 160 (n = 114), the median OS was 27 months (range 22–32) (p = 0.006). While for fifty patients whose lymphocyte counts were less than 1,500, the median OS was 27 months (range 21–33), in cases with high lymphocyte counts (≥1,500) (n = 118), it was 41 months (range 35–48) (p = 0.03). The median OS was 41 (range 34–48) and 30 (range 23–37) months in two platelets groups, respectively (p = 0.24). However, in the patients whose NLR was less than 2.56 (n = 107), median OS was better than with cases whose NLR was greater than or equal to 2.56 (42 vs. 27 months). Routine peripheral blood counts may be useful prognostic factor for evaluating the accuracy of risk stratification in patients with radically resected gastric cancer Our results need to be confirmed by study including larger sample size in future.     

The association between biological subtype and locoregional recurrence in newly diagnosed breast cancer

We investigated the association between the risk of locoregional recurrence (LRR) and biological subtypes defined by hormonal receptors (HR) and HER-2 status in women with invasive breast cancer (BC). A total of 618 newly diagnosed BC patients were identified from a cancer registry within a single institution with standardized methods of tumor assessment for estrogen receptor (ER), progesterone receptor (PR), and HER-2. Patients were stratified based on surgical treatment, breast-conserving therapy (BCT) versus modified radical mastectomy (MRM), as well as biological subtypes: HR+/HER-2− (ER-positive or PR-positive, HER-2-negative), HR+/HER-2+ (ER-positive or PR-positive, HER-2-positive), HR−/HER-2+ (ER-negative and PR-negative, HER-2-positive) and TN (ER-negative, PR-negative and HER-2-negative). The association between clinicopathological factors, biological subtype and LRR was evaluated with univariate and multivariate Cox analysis. With a median follow-up of 4.8 years, the rate of LRR was 7.5%. On multivariate analysis, TN, tumor size ≥2 cm and lymph node (LN) positivity were associated with increased risk of LRR (P = 0.023, P = 0.048, and P = 0.0034, respectively). In BCT group, HR−/HER-2+ and LN positivity were associated with increased risk of LRR (HR 11.13; 95% CI 2.78–44.53; P = 0.0007 and HR 5.40; 95% CI 1.67–17.43; P = 0.0048, respectively). In MRM group, TN subtype and LN positivity were associated with increased risk of LRR (HR 4.72; 95% CI 1.53–14.52; P = 0.0069 and HR 3.23; 95% CI 1.44–7.29; P = 0.0047, respectively). Compared to HR+/HER-2−, HR−/HER-2+ treated by BCT and TN treated by MRM showed a significant decrease of 5-year LRR free survival (P = 0.0002 and P = 0.002, respectively). Tumor profiling using ER, PR, and HER-2 biomarkers is a promising tool to identify patients at high risk of LRR based on surgical treatment. Our findings suggest a different follow-up and locoregional treatment for patients with HR−/HER-2+ and TN subtypes.     

Endocrine therapy in obese patients with primary breast cancer: another piece of evidence in an unfinished puzzle

Obesity, defined as a body mass index (BMI) ≥30 is an independent risk factor in breast cancer and is correlated with shorter survival and enhanced recurrence rates. The present subgroup analysis of the German BRENDA-cohort aimed to investigate the correlation between BMI, recurrence-free survival (RFS) and adjuvant endocrine therapy. In this subgroup analysis, 4,636 patients were retrospectively examined using multivariate analyses. Overall 3,759 (81.1%) patients had a BMI <30 (non-obese) and 877 (18.9%) a BMI ≥30 (obese). In the group of all 3,896 (84.0%) patients with hormone-receptor-positive (HR+) breast carcinomas a significant reduction in RFS was demonstrated for those who were obese (P = 0.002; HR = 1.45 (95% CI: 1.15–1.83)), also after adjustment for Nottingham Prognostic Index (NPI) (P = 0.028; HR = 1.30 (95% CI: 1.03–1.65)). In hormone-receptor-negative (HR−) patients BMI had no influence on RFS (P = 0.380; HR = 1.20 (95% CI: 0.80–1.81)). Considering menopausal status, a significantly shorter RFS was seen in postmenopausal obese than in non-obese patients (P < 0.001; HR = 1.61 (95% CI: 1.24–2.09)), whereas the premenopausal patient group only showed a trend towards a shorter RFS (P = 0.202; HR = 1.44 (95% CI: 0.82–2.53)). The group of HR+ postmenopausal patients with normal or intermediate weight showed a non-significant statistical trend towards a survival benefit for aromatase inhibitors (AI) compared to tamoxifen (RFS: P = 0.486; HR = 1.29 (95% CI: 0.63–2.62), while obese patients tended to benefit more from tamoxifen (RFS: P = 0.289; HR = 0.65 (95% CI: 0.29–1.45)). In accordance with recently published results we demonstrated a negative effect of a high BMI on outcome in primary breast cancer. Furthermore the efficacy of AI seems dependent on BMI in contrast to tamoxifen. Prospective studies to optimise the therapy of obese breast cancer patients are urgently needed.     

Validating the prognostic value of proliferation measured by Phosphohistone H3 (PPH3) in invasive lymph node-negative breast cancer patients less than 71 years of age

We validated and compared the prognostic value of the proliferation marker phosphohistone H3 (PPH3) with classical variables in 241 T_1–2N₀M₀ breast cancer patients less than 71 years old with long-term follow-up (median 117 months) and without adjuvant treatment. PPH3 was measured by automated digital image analysis. Thirty-seven patients (15%) developed distant metastases and 29 (12%) died. The previously established PPH3 prognostic threshold H3 <13 (n = 157; 65% of all cases) vs. ≥13 (n = 84; 35% of all cases) was the strongest prognostic threshold exceeding all other characteristics, with 10-year recurrence-free survival of distant metastases of 96 and 64%, respectively (P =  < 0.0001, hazard ratio = 7.8, 95% confidence interval = 3.4–17.9). PPH3 is robust as it showed high inter-observer reproducibility and was prognostic over wide range of thresholds around 13 and is the strongest prognostic variable in invasive node-negative breast cancer patients less than 71 years old.     

BRCA1 promoter methylation in peripheral blood cells is associated with increased risk of breast cancer with BRCA1 promoter methylation

BRCA1 promoter methylation reportedly plays an important part in the pathogenesis of human breast cancer. In the present study, we investigated whether or not BRCA1 promoter methylation in peripheral blood cells (PBCs) can serve as a risk factor for developing breast cancer. The association of BRCA1 promoter methylation in PBCs with breast cancer risk was examined in a case–control study (200 breast cancer patients and 200 controls). BRCA1 promoter methylation in PBCs and breast tumors was determined with a methylation-specific quantitative PCR assay. BRCA1 promoter methylation in PBCs was seen in 43 (21.5%) of the breast cancer patients and in 27 (13.5%) of the controls. The odds ratio for breast cancer adjusted for other epidemiological risk factors was 1.73 (1.01–2.96) and was statistically significant (P = 0.045). When breast tumors were classified into those with and without BRCA1 promoter methylation, the odds ratio was 0.84 (0.43–1.64) (P = 0.61) for BRCA1 promoter methylation-negative and 17.78 (6.71–47.13) (P < 0.001) for BRCA1 promoter methylation-positive breast tumors. BRCA1 promoter methylation in PBCs is significantly associated with risk of breast cancer with BRCA1 promoter methylation. This seems to indicate that BRCA1 promoter methylation in PBCs may constitute a novel risk factor for breast cancer with BRCA1 promoter methylation.