Immediate postmastectomy reconstruction is associated with improved breast cancer‐specific survival

BACKGROUND:

Although immediate breast reconstruction is increasingly offered as part of postmastectomy psychosocial rehabilitation, concerns remain that it may delay adjuvant therapy or impair detection of local recurrence. No single population‐based study has examined the relationship between immediate breast reconstruction and breast cancer‐specific survival.

METHODS:

By using data from the US National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries, breast cancer‐specific survival was compared for female unilateral mastectomy patients who did or did not undergo immediate breast reconstruction. Cox proportional hazards models were fitted, adjusting for known demographic and disease severity variables and stratifying on reconstruction type (implant or autologous) and age.

RESULTS:

Improved breast cancer‐specific survival was observed among all immediate breast reconstruction patients compared with patients who underwent mastectomy alone (hazard ratio [HR] = 0.74; 95% confidence interval [CI], 0.68 to 0.80). Implant reconstruction patients below 50 years of age demonstrated the greatest apparent survival benefit (HR = 0.47; 95% CI 0.28 to 0.80). Similarly, autologous reconstruction was associated with improved cancer‐specific survival among patients below the age of 50 (HR = 0.58; 95% CI, 0.42 to 0.80) and between ages 50 to 69 (HR = 0.61; 95% CI, 0.43 to 0.85).

CONCLUSIONS:

Immediate breast reconstruction is associated with decreased breast cancer‐specific mortality, particularly among younger women. We believe this association is more likely attributable to imbalances in socioeconomic factors and access to care than to inadequate adjustment for tumor characteristics and disease severity. Further research is needed to identify additional prognostic factors responsible for the improved cancer survival among women undergoing immediate postmastectomy reconstruction. Cancer 2009. © 2009 American Cancer Society.     

Risk factors for brain relapse in patients with metastatic breast cancer.

BACKGROUND: The occurrence of brain metastases is an emerging problem in patients with metastatic breast cancer. In the present study, we looked at risk factors for brain metastasis among patients with metastatic breast cancer. PATIENTS AND METHODS: The risk factors for brain metastasis were first determined in a series of 215 patients with metastatic breast cancer. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic breast cancer. All the patients had been included in prospective randomized trials that evaluated chemotherapy or endocrine therapy in an adjuvant setting. RESULTS: In the first series, the presence of lung metastases (hazard ratio = 4.3, 95% CI: 1.9-9.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.7-11, P=0.002) were the only predictive factors associated with the occurrence of brain metastases in the multivariate analysis. The second series confirmed that the presence of lung metastases and negative hormone receptor status were associated with the occurrence of brain metastases. CONCLUSION: The presence of lung metastases as the first site of relapse and a negative hormone receptor status are predictive for the occurrence of brain metastases in patients with metastatic breast cancer. A prophylactic treatment should be evaluated in these subsets of patients.     

Radiological response of leptomeningeal metastases according to revised RANO criteria is associated with overall survival in breast cancer patients

Assessment of treatment response in patients (pts) with leptomeningeal metastases (LM) represents a significant challenge and standardized criteria are needed. In 2017, the RANO LM Working Group proposed a standardized scorecard to evaluate MRI findings (further simplified in 2019). Here, we aim to validate the prognostic impact of response to treatment assessed using this tool in a multicentric cohort of breast cancer (BC) pts. Pts with BC-related LM diagnosed at two institutions between 2005 and 2018 were identified. Baseline and follow-up MRI scans were centrally reviewed and response assessment was evaluated using 2019 revised RANO LM criteria. A total of 142 pts with BC-related LM and available baseline brain MRI imaging were identified; 60 of them had at least one follow-up MRI. In this subgroup, median overall survival (OS) was 15.2 months (95%CI 9.5-21.0). At first re-evaluation, radiological response by RANO criteria was: complete response (CR) in 2 pts (3%), partial response (PR) in 12 (20%), stable disease (SD) in 33 (55%) and progression of disease (PD) in 13 (22%). Median OS was 31.1 months (HR 0.10, 95%CI 0.01-0.78) in pts with CR, 16.1 months (HR 0.41, 95%CI 0.17-0.97) in pts with PR, 17.9 months (HR 0.45, 95%CI 0.22-0.91) in pts with SD and 9.5 months in pts with PD (P = .029). A second blinded evaluation showed a moderate interobserver agreement (K = 0.562). Radiological response according to 2019 RANO criteria is significantly associated with OS in pts with BC-related LM, thus supporting the use of this evaluation tool both in trials and clinical practice.     

The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients

We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p_(adjusted)=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p_(adjusted)=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p_{(interaction)}=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1-mediated regulatory pathway.     

Good clinical response of breast cancers to neoadjuvant chemoendocrine therapy is associated with improved overall survival.

BACKGROUND: We present extended follow-up from a prospective randomised trial evaluating the role of neoadjuvant chemoendocrine therapy in the treatment of operable breast cancer. PATIENTS AND METHODS: 309 women were randomised to primary surgery followed by eight cycles of adjuvant mitoxantrone, methotrexate with tamoxifen (2MT) or 2MT with mitomycin-C (3MT) versus the same regimen for four cycles before followed by four cycles after surgery. For this analysis the median follow-up of patients was 112 months. RESULTS: After 10 years follow-up there is still no statistically significant difference in disease-free survival (DFS) (71% versus 71%) or overall survival (OS) (63% versus 70%) when comparing adjuvant versus neoadjuvant treatment, respectively. Of 144 evaluable patients in the neoadjuvant arm, 74 achieved a good clinical response and 70 patients achieved a poor clinical response. Good responders had a superior DFS (80% versus 64%, P=0.01) and OS (77% versus 63%, P=0.03) compared to poor responders. CONCLUSIONS: At 10 years, neoadjuvant and adjuvant treatment continue to have equivalent OS and DFS. Good clinical response to neoadjuvant chemotherapy is associated with superior DFS and OS. This supports the use of clinical response of primary breast cancer to neoadjuvant therapy as a surrogate marker of survival benefit.     

The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer

Background:

The importance of lymphocyte subtypes in determining outcome in primary operable ductal invasive breast cancer remains unclear. The aim of present study was to examine the relationship between tumour lymphocyte subsets infiltrate and standard clinico-pathological factors and survival in patients with primary operable invasive ductal breast cancer.

Methods:

The analysis of the inflammatory cell infiltrate, including lymphocyte subtypes, was undertaken using immunohistochemical techniques and visual quantitative and semi-quantitative techniques in 338 patients with ductal breast cancer.

Results:

The majority (91%) of patients had high grade inflammatory cell infiltrate. The median follow-up of the survivors was 164 months. During this period, 65 died of their cancer. On univariate analysis, tumour inflammatory cell infiltrate, macrophages infiltrate (P<0.05), lymphocytic infiltrate (P<0.001) and CD8+ T-lymphocytic infiltrate (P<0.01) were associated with improved cancer-specific survival, whereas neutrophil (P<0.05) and CD138+ B-lymphocytic infiltrate (P<0.001) were associated with poorer cancer-specific survival. On multivariate analysis, tumour lymphocytic infiltrate (P<0.001), macrophage infiltrate (P<0.05), CD8+ T-lymphocytic infiltrate (P<0.01) and CD138+ B-lymphocytic infiltrate (P<0.001) were independently associated with cancer survival. When the significant inflammatory cell types were included with tumour-based factors in multivariate analysis only tumour size (Hazard ratios (HR): 2.55, 95% confidence interval (CI): 1.53–4.27, P<0.001), Ki-67 index (HR: 2.08, 95% CI: 1.08–4.00, P<0.05), lymphovascular invasion (HR: 4.40, 95% CI: 2.07–9.35, P<0.001), macrophage infiltrate (HR: 0.49, 95% CI: 0.33–0.73, P<0.001), lymphocytic infiltrate (HR: 0.11, 95% CI: 0.05–0.23, P<0.001), CD8+ T-lymphocytic infiltrate (HR: 0.57, 95% CI: 0.38–0.87, P<0.001) and CD138+ B-lymphocytic infiltrate (HR: 2.86, 95% CI: 1.79–4.56, P<0.001) were independently associated with cancer survival.

Conclusion:

The majority of patients with invasive ductal breast cancer had high-grade inflammatory cell infiltrate. In these patients, inflammatory cells including macrophage and lymphocytic infiltrate, and subsets CD8+ T-lymphocytic infiltrate and CD138+ B-lymphocytic infiltrate had superior prognostic value, compared with hormone status and lymph node involvement in patients with primary operable invasive ductal breast cancer.     

Current or recent pregnancy is associated with adverse pathologic features but not impaired survival in early breast cancer

BACKGROUND:

Pregnancy‐associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer.

METHODS:

A single‐institution retrospective chart review was performed of 99 patients identified with PABC between 1992 and 2007. Non‐PABC controls were matched 2:1 to PABC cases by year of diagnosis and age. The differences in clinical features were compared between cases and controls using chi‐square tests. Univariate and multivariate analyses were performed to assess the effect of PABC on survival.

RESULTS:

Of the 99 PABC cases, breast cancer was diagnosed during pregnancy in 36 patients, and after delivery in 63. PABC cases were more likely than controls to be negative for estrogen receptor (59% vs 31%, P < .0001) and negative for progesterone receptor (72% vs 40%, P < .0001). Cases were also more likely to have advanced T class (P = .0271) and N class (P = .0104) and higher grade tumors (P = .0115). With a median follow‐up of 6.3 years for cases and 4.7 years for controls, overall survival did not differ between cases and controls (P = .0787). On multivariate analysis, the independent prognostic factors for overall survival were estrogen receptor status (P = .0031) and N class (P = .0003). The diagnosis of PABC was not an independent prognostic factor (P = .1317).

CONCLUSIONS:

PABC is associated with more adverse tumor features than non‐PABC matched for age and year of diagnosis. After correcting for pathologic features, the diagnosis of PABC is not in itself an adverse prognostic factor for survival. Cancer 2011. © 2011 American Cancer Society.     

乳腺癌中cyclin E的表达及其预后意义

目的：研究细胞周期素E蛋白在乳腺癌中的表达，并探讨其临床预后意义。方法：总结67例乳腺癌病例的临床病理特点，同时运用免疫组化技术检测cyclinE蛋白的表达，分析其临床病理特点及预后的相关性。结果：cyclinE蛋白的表达与乳腺癌的预后关系密切，同时与乳腺癌的组织学分型相关；与乳腺癌的受体情况，肿瘤大小，淋巴结转移情况以及是否绝经无明显相关性。结论：cyclinE蛋白的表达是有效的预后预测因子。     

High expression of stem cell marker ALDH1 is associated with reduced BRCA1 in invasive breast carcinomas

Background: Cancer stem cells (CSC) have been described in a variety of malignancies, including breastcarcinomas. Among several markers, aldehyde dehydrogenase 1 (ALDH1) has been identified as reliable for breastcancer stem cells. Knockdown of BRCA1 in primary breast epithelial cells leads to an increase in cells expressingALDH1. Methods: We examined 127 breast carcinomas for expression of ALDH1, using immunohistochemistryand correlated with clinicopathological parameters as well as the BRAC1 status. Results: Comparing the resultsfor both ALDH1 and BRCA1 expression showed a significant inverse association between the two, indicatingthat reduced BRCA1 was more often seen in breast cancer cells expressing ALDH1 (p-value = 0.044). A totalof 24/110 (22%) of tumours displayed the ALDH1 + / BRCA1 -/low phenotype, which showed a trend for arelation with a high grade (p-value= 0.056). Cytoplasmic expression of ALDH1 was not correlated with tumourcharacteristics. Conclusion: Taken together, our findings suggest that increased ALDH1 is inversely correlatedwith decreased BRCA1 in a series of unselected breast carcinomas. Therefore, ALDH1 positive (cancer stem)cells with reduced BRCA1 phenotype may indicate a subset of patients for whom specific targeting of the CSCmarker ALDH1 and more aggressive adjuvant treatment is appropriate.     

Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients

Breast cancer brain metastases (BCBM) are detected with increasing incidence. In order to detect potential genes involved in BCBM, we first screened for genes down-regulated by methylation in cell lines with site-specific metastatic ability. The expression of five genes, CADM1, SPARC, RECK, TNFAIP3 and CXCL14, which were also found down-regulated in gene expression profiling analyses of BCBM tissue samples, was verified by qRT-PCR in a larger patient cohort. CADM1 was chosen for further down-stream analyses. A higher incidence of CADM1 methylation, correlating with lower expression levels, was found in BCBM as compared to primary BC. Loss of CADM1 protein expression was detected most commonly among BCBM samples as well as among primary tumors with subsequent brain relapse. The prognostic role of CADM1 expression was finally verified in four large independent breast cancer cohorts (n=2136). Loss of CADM1 protein expression was associated with disease stage, lymph node status, and tumor size in primary BC. Furthermore, all analyses revealed a significant association between loss of CADM1 and shorter survival. In multivariate analyses, survival was significantly shorter among patients with CADM1-negative tumors. Loss of CADM1 expression is an independent prognostic factor especially associated with the development of brain metastases in breast cancer patients.     

High preoperative plasma TIMP-1 is prognostic for early relapse in primary breast carcinoma

TIMP-1 is a natural inhibitor of extracellular matrix degrading enzymes called matrix metalloproteinases. In addition to its capacity to inhibit matrix degradation, TIMP-1 has been shown to promote cell growth and inhibit apoptosis. The expression of TIMP-1 in tumor tissue, as well as in circulating blood, has therefore been shown to associate with worsened survival in several malignancies. In our study, a prospective series of 213 patients with primary breast carcinoma was assessed. Circulating pre- and postoperative TIMP-1 levels were assayed using enzyme-linked immunosorbent assay analysis. It was shown that high preoperative plasma TIMP-1 was a powerful predictor of systemic early relapse in breast carcinoma, with HR 8.1 (95% CI 1.8-37.6) (p = 0.007) as a log-transformed continuous variable in Cox regression univariate analysis. It was shown to be independent of, and superior to, nodal status as a prognostic variable in multivariate analysis, and not associated with any known prognostic clinicopathological parameters. Kaplan-Meier analysis showed that the patients belonging to the highest quartile of circulating TIMP-1 levels had a worsened recurrence-free survival of 79% compared to 94% RFS among patients in the lower quartiles (p = 0.016). The postoperative levels of circulating plasma TIMP-1 were not found to be prognostic for relapse. In conclusion, preoperative plasma TIMP-1 was found to be a powerful prognostic factor for early systemic relapse in primary breast carcinoma.     

Cyclin A is a prognostic indicator in early stage breast cancer with and without tamoxifen treatment

Overexpression of G1-S regulators cyclin D1 or cyclin A is frequently observed in breast cancer and is also to result in ligand-independent activation of oestrogen receptor in vitro. This might therefore, provide a mechanism for failure of tamoxifen treatment. We examined by immunohistochemical staining the effect of deregulation of these, and other cell cycle regulators on tamoxifen treatment in a group of 394 patients with early stage breast cancer. In univariate analysis, expression of cyclin A, Neu, Ki-67 index, and lack of OR expression were significantly associated with worse prognosis. When adjusted by the clinical model (for lymph node status, age, performance status, T-classification, grade, prior surgery, oestrogen receptor status and tamoxifen use), only overexpression of cyclin A and Neu were significantly associated with worse prognosis with hazard ratios of, respectively, 1.709 (P=0.0195) and 1.884 (P=0.0151). Overexpression of cyclin A was found in 86 out of the 201 OR-positive cases treated with tamoxifen, and was the only independent marker associated with worse prognosis (hazard ratio 2.024, P=0.0462). In conclusion, cyclin A is an independent predictor of recurrence of early stage breast cancer and is as such a marker for response in patients treated with tamoxifen.     

Postdiagnosis weight change is associated with poorer survival in breast cancer survivors: A prospective population‐based patient cohort study

More women are surviving after breast cancer due to early detection and modern treatment strategies. Body weight also influences survival. We aimed to characterize associations between postdiagnosis weight change and prognosis in postmenopausal long‐term breast cancer survivors. We used data from a prospective population‐based patient cohort study (MARIE) conducted in two geographical regions of Germany. Breast cancer patients diagnosed 50 to 74 years of age with an incident invasive breast cancer or in situ tumor were recruited from 2002 to 2005 and followed up until June 2015. Baseline weight was ascertained at an in‐person interview at recruitment and follow‐up weight was ascertained by telephone interview in 2009. Delayed entry Cox proportional hazards regression was used to assess associations between relative weight change and all‐cause mortality, breast cancer mortality, and recurrence‐free survival. In total, 2216 patients were included. Compared to weight maintenance (within 5%), weight loss >10% increased risk of all‐cause mortality (HR 2.50, 95% CI 1.61, 3.88), breast cancer mortality (HR 3.07, 95% CI 1.69, 5.60) and less so of recurrence‐free survival (HR 1.43, 95% CI 0.87, 2.36). Large weight gain of >10% also increased all‐cause mortality (HR 1.64, 95% CI 1.02, 2.62) and breast cancer mortality (HR 2.25, 95% CI 1.25, 4.04). Weight maintenance for up to 5 years in long‐term breast cancer survivors may help improve survival and prognosis. Postdiagnosis fluctuations in body weight of greater than 10% may lead to increased mortality. Survivors should be recommended to avoid large deviations in body weight from diagnosis onwards to maintain health and prolong life.     

Chemotherapy and pattern of metastases in breast cancer patients

A retrospective analysis of all breast cancer patients who died of their disease at Harper Grace Hospital during 1962 to 1976, was conducted to determine the pattern of metastases and its relation to chemotherapy. The autopsy incidence of distant metastases, to all organ sites, was noted to be higher among patients who previously received cytotoxic therapy, compared with those who did not. Such incidence was unrelated to differences in patients' age, menopausal status, and disease-free interval. It is postulated that chemotherapy contributes to the wider metastases, especially to the central nervous system and meninges, in a breast cancer patient. This is possibly due to a longer survival of patients treated.     

Predictors for patterns of brain relapse and overall survival in patients with non-small cell lung cancer

Our goal was to investigate prognostic factors for different patterns of brain relapse and overall survival so that treatments could be tailored and treatment outcomes improved. We studied 292 patients with non-small cell lung cancer (NSCLC) who had symptomatic, solitary, or multiple brain metastases (isolated or not isolated from extracranial metastases) that had developed early (≦6 months) or late (>6 months) from initial diagnosis. Factors affecting patterns of relapse and survival were analyzed by univariate and multivariate analyses. Good ECOG performance status (PS) at the time of NSCLC diagnosis was the most important factor that predicted late (rather than early) relapse and improved survival, and was the only factor that predicted isolated brain metastases. Patients whose lungs showed a complete response (CR) to treatment had a higher rate of late brain relapses than non-responders (NR) did (67.3% vs. 7.8%, P < 0.001). CR patients also experienced a longer median overall survival than NR patients. Patients with late brain relapses showed better median survival times (18 months vs. 4 months, P < 0.0001) than patients with early relapses, and this was an independent factor by Cox regression analysis. Our findings provide a justification for enrolling patients with good PS and controlled lung lesions into clinical trials for the prevention of early, non-isolated brain relapse. More aggressive therapeutic approaches should be applied to patients with late, isolated and solitary relapses to improve both quality and quantity of life.     

High serum YKL-40 levels in patients with primary breast cancer is related to short recurrence free survival

YKL-40 is a growth factor for connective tissue cells and stimulates migration of endothelial cells. YKL-40 is secreted by cancer cells, and elevated serum YKL-40 in patients with metastatic breast cancer and colorectal cancer is associated with a poorer prognosis as compared to patients with normal serum YKL-40. In the present study we evaluated the associations of preoperative serum YKL-40 in 271 patients with primary breast cancer in relation to relapse-free survival and overall survival. The median follow-up time was 5.9 years. There were 77 relapses and 69 patients died. The median serum YKL-40 concentration in the patients was 57 µg/l (range 22–688 µg/l) and significantly elevated (p < 0.0001) compared to serum YKL-40 in healthy females. Nineteen percent of the patients had high serum YKL-40 (i.e., > 95 percentile of healthy females). Patients with high serum YKL-40 had shorter relapse-free interval (hazard ratio (HR) = 1.77, 95% confidence interval (CI): 1.06–2.95, p = 0.028) and overall survival (HR = 1.78, 95% CI: 1.04–3.05, p = 0.036) than patients with normal serum YKL-40. Serum YKL-40 was higher (p = 0.005) in lymph node positive patients as compared to lymph node negative patients. Multivariate analysis including lymph node status, estrogen receptor status, tumor size, age, menstrual status and serum YKL-40 showed that serum YKL-40 was an independent prognostic variable of relapse-free survival (HR = 1.73, 95% CI: 1.03–2.91, p = 0.039). Our results show that serum YKL-40 in patients with primary breast cancer at time of operation is only elevated in a small group of patients, but these patients have a shorter recurrence free interval. Further studies are required to determine the biological function of YKL-40 in breast cancer.     

Cyclin I is expressed in human breast cancer and closely associated with VEGF and KDR expression

Summary In the present study, cyclin I protein expression in 114 invasive human breast cancers was correlated with cell cycle and angiogenesis-related proteins and clinico-pathological data. A strong association was found between cytoplasmic cyclin I staining and VEGF (p = 0.001) as well as the VEGF receptor KDR (p = 0.001), suggesting a link between cyclin I and angiogenesis.     

High level of messenger RNA for BRMS1 in primary breast carcinomas is associated with poor prognosis

BRMS1 is regarded as a metastasis suppressor gene for its ability to reduce metastatic potential of human and murine breast cancer cells as well as human melanoma cells. However, BRMS1 association to human tumor progression is not clearly understood. In the present study we analyzed BRMS1 mRNA expression in tumor progression and its potential prognostic value for breast carcinoma. BRMS1 mRNA expression level was quantified by real-time PCR in 47 tumoral, in 14 peritumoral and in 15 metastatic microdissected cellular populations from 47 breast cancer patients with 10-year follow up. We found BRMS1 expression to be higher in carcinoma cells than in matching normal epithelial cell populations in 10 out of 14 cases (p = 0.0005), while lymph-nodal carcinoma cells showed lower BRMS1 expression in 9 out of 15 cases (p = 0.001). Using both in vivo (human mammary breast carcinomas) and in vitro systems (breast cancer cell lines) we were able to demonstrate that BRMS1 overexpression was not a bias effect induced by cell proliferation rate. BRMS1 expression levels did not correlate with standard breast cancer prognostic factors but BRMS1 higher expression was associated with patient shorter disease-free and overall survival. Our findings are apparently inconsistent with the concept of BRMS1 as a metastasis suppressor gene. One possible explanation is that epithelial cells increase their BRMS1 expression as a compensatory response to tumor formation or metastasis progression, which is elevated in proportion to tumor aggressiveness, whereas those cells of the primary tumor that cannot upregulate BRMS1 escape to form metastasis.