HER2 expression and efficacy of preoperative paclitaxel/FAC chemotherapy in breast cancer

Purpose We examined the correlation between HER2 expression and pathologic complete response (pCR) to paclitaxel/FAC (T/FAC) preoperative chemotherapy in breast cancer. Patients and Methods Retrospective analysis of data including 534 patients treated with preoperative T/FAC was performed. Gene expression results were available from two datasets of 132 and 286 patients, and were used to examine the co-expression of HER2 and topoisomerase II α (TOP2A) and microtubule associated protein tau (MAP-Tau). Results Of the 534 patients, 105 (20%) had HER2-overexpressing breast cancer. The pCR rates were 33% and 15% for patients with HER2+ and HER2- tumors (P < 0.001). The 5-year relapse-free survival rates were 94% and 70% in HER2+ tumors with and without pCR (P = 0.009). HER2 overexpression (odds ratio 2.3, 95%CI: 1.3–3.9, P = 0.004), estrogen receptor (ER) status, grade and weekly schedule of paclitaxel were each significantly and independently associated with pCR in multivariate analysis. When patients were stratified by ER status, the pCR rates were 50% for HER2+/ER−, 30% for HER2−/ER−, 19% for HER2+/ER+, and 6% for HER2−/ER+ tumors. HER2 overexpression was associated with lower expression of MAP-tau (P = 0.001 and P < 0.001) and higher expression of TOP2A mRNAs (P = 0.048 and P = 0.001) in patients with ER+ disease. ER− cancers had low MAP-tau expression regardless of HER-status. Conclusion HER2 overexpression is associated with higher rate of pCR to preoperative T/FAC chemotherapy regardless of ER status. HER2 overexpression also correlates with increased TOP2A and decreased MAP-tau expression in ER-positive cancers.     

Vandetanib as a potential new treatment for estrogen receptor‐negative breast cancers

The receptor tyrosine kinase RET is implicated in the progression of luminal breast cancers (BC) but its role in estrogen receptor (ER) negative tumors is unknown. Here we investigated the expression of RET in breast cancer patients tumors and patient‐derived xenografts (PDX) and evaluated the therapeutic potential of Vandetanib, a tyrosin kinase inhibitor with strong activity against RET, EGFR and VEGFR2, in ER negative breast cancer PDX. The RT‐PCR analysis of RET expression in breast tumors of 446 patients and 57 PDX, showed elevated levels of RET in ER+ and HER2+ subtypes and in a small subgroup of triple‐negative breast cancers (TNBC). The activity of Vandetanib was tested in vivo in three PDX models of TNBC and one model of HER2+ BC with different expression levels of RET and EGFR. Vandetanib induced tumor regression in PDX models with high expression of RET or EGFR. The effect was associated with inhibition of RET/EGFR phosphorylation and MAP kinase pathway and increased necrosis. In a PDX model with no expression of RET nor EGFR, Vandetanib slowed tumor growth without inducing tumor regression. In addition, treatment by Vandetanib decreased expression of murine Vegf receptors and the endothelial marker Cd31 in the four PDX models tested, suggesting inhibition of tumor vascularization. In summary, these preclinical results suggest that Vandetanib treatment could be useful for patients with ER negative breast cancers overexpressing Vandetanib's main targets.     

Predicting invasive phenotype with CDH1, CDH13, CD44, and TIMP3 gene expression in primary breast cancer

We aimed to determine changes in the expression of the genes CDH1, CDH13, CD44, and TIMP3 to look for any relationship between them, HER2 and ESR1 expression at the RNA level, and the histopathological properties of tumors. We also analyzed the expression properties of double‐negative (estrogen receptor [ER] and human epidermal growth factor receptor [HER2] both negative) breast tumors. Expression status was studied in fresh tissue at the mRNA level with quantitative PCR using hydrolysis probes. Sixty‐two cancer patients and four normal controls were included in the study. When the tumor group was analyzed as a whole, the correlations of ESR1 with CDH1, CDH13, and TIMP3 were P < 0.05, P < 0.005, and P < 0.005, respectively. In ER‐positive tumors, CDH1 and CDH13 were correlated directly (P < 0.005) when HER2 was correlated with CDH1, CDH13, and TIMP3 indirectly (P < 0.005, P < 0.005, and P < 0.05, respectively). CDH1 and CD44 had a strong indirect correlation (P < 0.005) in ER‐negative tumors. There were significant differences in the expression levels of the CDH13, TIMP3, and CD44 genes (P < 0.005, P < 0.005, and P < 0.05, respectively) between the ER‐positive and ‐negative groups. All four genes were found to be correlated with invasive properties in both ER‐positive and ‐negative tumors. In double‐negative tumor samples, only CD44 had a significant and strong correlation with stage, lymph node involvement, and metastasis (P < 0.05, P < 0.005, and P < 0.05, respectively). As a conclusion, a decrease in CDH1, CDH13, and TIMP3 expression levels with an increase in CD44 can be used as an indicator for invasion in both ER‐positive and ‐negative breast tumors. In double‐negative tumor tissues, CD44 can be considered a marker for aggressive properties. (Cancer Sci 2009; 100: 2341–2345)     

Clinicopathologic features,patterns of recurrence,and survival among women with triple‐negative breast cancer in the National Comprehensive Cancer Network

BACKGROUND:

The objective of this study was to describe clinicopathologic features, patterns of recurrence, and survival according to breast cancer subtype with a focus on triple‐negative tumors.

METHODS:

In total, 15,204 women were evaluated who presented to National Comprehensive Cancer Network centers with stage I through III breast cancer between January 2000 and December 2006. Tumors were classified as positive for estrogen receptor (ER) and/or progesterone receptor (PR) (hormone receptor [HR]‐positive) and negative for human epidermal growth factor receptor 2 (HER2); positive for HER2 and any ER or PR status (HER2‐positive); or negative for ER, PR, and HER2 (triple‐negative).

RESULTS:

Subtype distribution was triple‐negative in 17% of women (n = 2569), HER2‐positive in 17% of women (n = 2602), and HR‐positive/HER2‐negative in 66% of women (n = 10,033). The triple‐negative subtype was more frequent in African Americans compared with Caucasians (adjusted odds ratio, 1.98; P < .0001). Premenopausal women, but not postmenopausal women, with high body mass index had an increased likelihood of having the triple‐negative subtype (P = .02). Women with triple‐negative cancers were less likely to present on the basis of an abnormal screening mammogram (29% vs 48%; P < .0001) and were more likely to present with higher tumor classification, but they were less likely to have lymph node involvement. Relative to HR‐positive/HER2‐negative tumors, triple‐negative tumors were associated with a greater risk of brain or lung metastases; and women with triple‐negative tumors had worse breast cancer‐specific and overall survival, even after adjusting for age, disease stage, race, tumor grade, and receipt of adjuvant chemotherapy (overall survival: adjusted hazard ratio, 2.72; 95% confidence interval, 2.39‐3.10; P < .0001). The difference in the risk of death by subtype was most dramatic within the first 2 years after diagnosis (overall survival for 0‐2 years: OR, 6.10; 95% confidence interval, 4.81‐7.74).

CONCLUSIONS:

Triple‐negative tumors were associated with unique risk factors and worse outcomes compared with HR‐positive/HER2‐negative tumors. Cancer 2012. © 2012 American Cancer Society.     

HER2 and tau expression as potential markers for response and survival to first line taxane plus cisplatin therapy in non‐small cell lung cancer

Aim: The aim of this study was to assess the role of various HER2, tau and bcl2 as prognostic markers of responsiveness to taxane and cisplatin therapy in patients with advanced NSCLC. Methods: Amplification of HER2 gene determined by chromogenic in situ hybridization (CISH) and HER2, tau and bcl2 protein expression determined by immunohistochemistry were assessed in 49 patients with NSCLC enrolled in our four clinical trials of taxane plus cisplatin chemotherapy. Results: The patients were classified as responders or non‐responders, a negative tau expression was associated with a significantly higher rate of response compared to a positive tau expression (OR 3.33, 95% CI 1.01–10.97, P = 0.043). Patients with more than stable disease compared to those with progressive disease showed that negative amplification of the HER2 gene was associated with a significantly higher rate of disease control compared to positive amplification (OR 7.35, 95% CI 0.83–65.21, P = 0.048). Furthermore, HER2 gene amplification was strongly associated with the overall survival: 20 months (95% CI 9.007–30.993) in patients with negative amplification of the HER2 gene versus 12 months (95% CI 6.584–17.416) in patients with positive amplification of the HER2 gene (P = 0.040). A multivariate analysis with the Cox proportional hazards model confirmed that HER2 gene amplification was a significant independent prognostic factor with a hazard ratio of 2.334 (95% CI 1.060–5.142, P = 0.035). Conclusion: Tau protein expression and HER2 gene amplification are the prognostic factors in NSCLC patients treated with a taxane and cisplatin combination.     

Breast cancer subtype approximations and loco-regional recurrence after immediate breast reconstruction

Background

A small but significant proportion of patients with breast cancer (BC) will develop loco-regional recurrence (LRR) after immediate breast reconstruction (IBR). The LRR also varies according to breast cancer subtypes and clinicopathological features.

Methods

We studied 1742 consecutive BC patients with IBR between 1997 and 2006. According to St Gallen conference consensus 2011, its BC approximations were applied to classify BC into five subtypes: estrogen receptor (ER) and/or progesterone receptor (PgR) positive, HER2 negative, and low Ki67 (<14%) [luminal A]; ER and/or PgR positive, HER2 negative and high Ki67(≥14%) [luminal B/HER2 negative]; ER and/or PgR positive, any Ki67 and HER2 positive [luminal B/HER2 positive]; ER negative, PgR negative and HER2 positive [HER2 positive/nonluminal]; and ER negative, PgR negative and HER2 negative [triple negative]. Cumulative incidences of LRR were compared across different subgroups by means of the Gray test. Multivariable Cox regression models were applied.

Results

Median follow up time was 74 months (range 3–165). The cumulative incidence of LRR was 5.5% (121 events). The 5-year cumulative incidence of LRR was 2.5% for luminal A; 5.0% for luminal B/HER2 negative; 9.8% for luminal B/HER2 positive; 3.8% for HER2 non luminal; and 10.9% for triple negative. On multivariable analysis, tumor size (pT) >2 cm, body mass index (BMI) ≥25, triple negative and luminal B/HER2 positive subtypes were associated with increased risk of LRR.

Conclusion

Luminal B/HER2 positive, triple negative subtypes and BMI ≥25 are independent prognostic factors for risk of LRR after IBR.     

ER,HER2, and <Emphasis Type="Italic">TOP2A</Emphasis> expression in primary tumor,synchronous axillary nodes,and asynchronous metastases in breast cancer

At recurrence of breast cancer, the therapeutic target is the metastases. However, it is current practice to base the choice of systemic treatment on the biomarker profile of the primary tumor. In the present study, confirmatory biopsies were obtained from suspected metastatic lesions and compared with the primary tumors with respect to ER, HER2, and TOP2A. In the prospective tissue-collection study, 81 patients had biopsy from a suspected relapse. Additional archived paired material was included, leaving a total of 119 patients with paired primary tumor, synchronous axillary nodes (available in 52 patients) and asyncronous metastases available for analysis. ER, HER2, and TOP2A expression of primary tumors, axillary nodes and metastases were re-analysed and determined centrally by immunohistochemistry, chromogenic in situ hybridization, and fluorescence in situ hybridization. Of the 81 patients with a biopsy from a suspected relapse, 65 (80%) were diagnosed with recurrent breast carcinoma, 3 (4%) were diagnosed with other malignancies, 6 (7%) had benign conditions, and in 7 (9%) patients the biopsy was non-representative. Discordance in ER, HER2, and TOP2A (aberration vs. normal) status between primary tumor and corresponding asynchronous metastasis was 12% (14/118), 9% (10/114), and 23% (17/75), respectively. There were no significant associations with biomarker discordance and prior adjuvant therapy, or location of biopsy. Expression of ER, HER2, and TOP2A displayed discordance with a sufficient frequency to emphasize the role of confirmatory biopsies from metastatic lesions in future management of recurrent breast cancer.     

Oxidant stress as a major determinant of platelet activation in invasive breast cancer

The hypothesis that increased oxidative stress in breast cancer (BC) patients could induce enhanced lipid peroxidation, which, in turn, would contribute to platelet activation and poor clinical outcome is attractive. To address this issue, we investigated pre‐surgical urinary 8‐iso‐prostaglandin (PG)F_2α (marker of in vivo oxidative stress) and 11‐dehydro‐thromboxane (TX)B₂ (marker of in vivo platelet activation) levels in patients with primary BC (n = 115) compared with control women paired for comorbidities and their association with patients' metabolic profile and clinical prognostic factors. The results obtained showed that presurgical urinary excretion of both biomarkers was enhanced in BC patients compared to controls and was associated with patients' estrogen receptor (ER) expression, but not HER2 status or Ki67 proliferation index. Accordingly, both urinary biomarkers were increased in patients with luminal‐like BC molecular subtypes compared with triple negative or HER2‐enriched tumors. ER status was an independent predictor of 8‐iso‐PGF_2α urinary levels, which, in turn, significantly predicted 11‐dehydro‐TXB₂ urinary levels together with disease stage and ER status. The prognostic value of 11‐dehydro‐TXB₂ was then evaluated showing a significant correlation with BC pathological response to neoadjuvant treatment. Furthermore, among relapsing patients, those with elevated urinary biomarker levels were more likely to develop distant metastasis rather than local recurrence. In conclusion, we may speculate that enhanced oxidative stress due to estrogen‐related mechanisms might cause a condition of persistent platelet activation capable of sustaining BC growth and progression through the release of bioactive stored molecules, ultimately contributing to tumor invasiveness. Further studies specifically addressing this hypothesis are presently needed.     

p53 accumulation is a strong predictor of recurrence in estrogen receptor‐positive breast cancer patients treated with aromatase inhibitors

Aromatase inhibitors have played a central role in endocrine therapy for estrogen receptor (ER)‐positive breast cancer in postmenopausal women. However, factors predictive of the efficacy of aromatase inhibitors, and prognostic factors, both for early and late recurrence in women treated with adjuvant aromatase inhibitors have not been identified. Whole genome analysis identified that a TP53 gene mutation exists in ER‐positive breast cancers, although the frequency of TP53 gene mutation in luminal tumors is lower compared with basal‐like or human epidermal growth factor receptor type 2 (HER2)‐positive breast cancers. We examined expression of p53, as well as ER, progesterone receptor, HER2 and Ki‐67 using immunohistochemistry in postmenopausal ER‐positive breast cancer patients who were treated with aromatase inhibitors as adjuvant endocrine therapy. There were 53 (21%) tumors that contained 10% or more p53‐positive cells. High p53 expression was positively correlated with tumor grade, HER2 score and Ki‐67 expression. Significant association was observed between disease‐free survival and high p53 expression in multivariate analysis (P < 0.0001). Compared with women without recurrence, women with early recurrence had significantly higher p53 expression (P < 0.0001), as did women with late recurrence (P = 0.037). The present study demonstrates that p53 accumulation is a strong predictor of both early and late recurrence in ER‐positive breast cancer patients treated with aromatase inhibitors as adjuvant endocrine therapy. TP53 gene alteration might be a key biological characteristic of ER‐positive breast cancer.     

Predictive factors for anthracycline-based chemotherapy for human breast cancer

Predictive factors for anthracycline-based chemotherapy have yet to be incorporated into daily practice. Meta-analyses of studies using anthracycline-based treatment regimens have shown an improved prognosis for human epidermal growth factor receptor type 2 (HER2)-positive tumors, but not for HER2-negative tumors compared with results of non-anthracycline regimens. Currently it is believed that the positive association between HER2 status and anthracycline sensitivity is indirect, that is, their association may be mediated through topoisomerase II alpha (TOP2A), a target molecule of anthracyclines, since TOP2A is near HER-2 and co-amplification of the TOP2A gene frequently occurs in HER2-amplified tumors. This strongly suggests that TOP2A gene amplification is a predictive factor for anthracyline-based regimens. The Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society has demonstrated that TOP2A-positive and BRCA1-negative subsets evaluated by immunohistochemical staining show a significantly higher pathological complete response when treated with preoperative epirubicin-containing regimens. Combining these findings with the observation that triple-negative tumors and basal-like tumors respond to anthracycline treatment suggests that not only HER2-positive tumors but also a distinct subset of HER2-negative tumors may be sensitive to anthracycline-based regimens.     

Male breast cancer according to tumor subtype and race

BACKGROUND:

Breast cancer occurs rarely in men. To the authors' knowledge, no population‐based estimates of the incidence of human epidermal growth factor receptor 2 (HER2)‐positive breast cancer or of the distribution of breast cancer subtypes among male breast cancer patients have been published to date. Therefore, the objective of the current study was to explore breast tumor subtype distribution by race/ethnicity among men in the large, ethnically diverse population of California.

METHODS:

This study included men who were diagnosed with invasive breast cancer between 2005 and 2009 with known estrogen receptor (ER) and progesterone receptor (PR) (together, hormone receptor [HR]) status and HER2 status reported to the California Cancer Registry. Among the men with HR‐positive tumors, survival probabilities between groups were compared using log‐rank tests.

RESULTS:

Six hundred six patients were included. The median age at diagnosis was 68 years. Four hundred ninety‐four men (81.5%) had HR‐positive tumors (defined as ER‐positive and/or PR‐positive and HER2‐negative). Ninety men (14.9%) had HER2‐positive tumors, and 22 (3.6%) had triple receptor‐negative (TN) tumors. Among the patients with HR‐positive tumors, non‐Hispanic black men and Hispanic men were more likely to have PR‐negative tumors than non‐Hispanic white men. No statistically significant differences in survival were observed according to tumor subtype (P = .08). Differences in survival according to race/ethnicity were observed among all patients (P = .087) and among those with HR‐positive tumors (P = .0170), and non‐Hispanic black men had poorer outcomes.

CONCLUSIONS:

In this large, representative cohort of men with breast cancer, the distribution of tumor subtypes was different from that reported for women and varied by patient race/ethnicity. Non‐Hispanic black men were more likely to have TN tumors and ER‐positive/PR‐negative tumors than white men. Cancer 2013. © 2013 American Cancer Society.     

Immunohistochemical surrogate markers of breast cancer molecular classes predicts response to neoadjuvant chemotherapy

BACKGROUND:

Complete pathologic response to neoadjuvant chemotherapy (NACT) is predominantly seen in “ERBB2” and “basal‐like” tumors using expression profiling. We hypothesize that a similar response could be predicted using semiquantitative immunohistochemistry for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2).

METHODS:

ER, PR, and HER2 were used to classify 359 tumors treated with NACT into 6 groups: luminal A (strong ER+, HER2 negative), luminal B (weak to moderate ER+, HER2 negative), triple negative (negative for ER, PR, and HER2), ERBB2 (negative for ER and PR, but HER2+), luminal A‐HER2 hybrid (strong ER+ and HER2+), and luminal B‐HER2 hybrid (weak to moderate ER+ and HER2+). Complete pathologic response was defined as absence of invasive carcinoma in the breast and regional lymph nodes.

RESULTS:

Thirteen percent (48 of 359) demonstrated complete pathologic response. The highest rate of complete pathologic response was seen in ERBB2 (33%; 19 of 57) and triple negative (30%; 24 of 79) tumor classes. Among the ER+ “molecular” group, the highest rate of complete pathologic response was seen among luminal B‐HER2 hybrid tumors, 8% (2 of 24). Remainder of ER+ tumors demonstrated a very low rate of complete pathologic response, 1.5% (3 of 198). The 5‐year survival for patients achieving complete pathologic response was 96% compared with 75% in patients that failed to achieve complete pathologic response. The overall survival was worse in the ER‐negative group (ERBB2 and triple negative) compared with the ER‐positive group.

CONCLUSIONS:

We confirm the recently defined “triple negative paradox,” or rather “hormone receptor negative paradox,” that despite the best response to NACT, ERBB2 and triple negative tumors show the worst overall survival because of higher relapse among those with residual disease. Cancer 2010. © 2010 American Cancer Society.     

Expression of proteins involved in DNA damage response in familial and sporadic breast cancer patients

Understanding the expression of proteins involved in DNA damage response could improve knowledge of the pathways that contribute to familial and sporadic breast cancer (BC). We aimed to assess the different roles of BRCA1, poly(ADP‐ribose) polymerase‐1 (PARP1), BRCT‐repeat inhibitor of hTERT expression (BRIT1) and novel SWItch 5 (SWI5) expression in 130 sporadic and 73 familial BC samples, by immunohistochemistry. In the sporadic group, negative nuclear BRCA1 (nBRCA1) expression was associated with positive PgR (p = 0.037). Negative association was found between nBRCA1 expression and HER2 (p = 0.001). In the familial group, nBRCA1 expression was associated with ER (p = 0.002). Reduced nBRCA1 expression was associated with higher histological grade and positive Ki67 both in sporadic (p = 0.0010, p = 0.047) and familial groups (p < 0.001, p = 0.001). Nuclear PARP1 (nPARP1) expression was associated with histological grade (p = 0.035) and positive PgR (p = 0.047) in sporadic cases. High cytoplasmic and low nuclear BRIT1 (cBRIT1 and nBRIT1) expression were associated with high histological grade in the familial group (p = 0.013, p = 0.025). Various statistical associations between the protein expressions were observed in the sporadic group, while in familial group only few associations were found. Univariate analyses showed that nPARP1 expression is able to discriminate between sporadic and familial tumors (OR 2.80, p = 0.002). Multivariate analyses proved that its overexpression is an independent factor associated with a high risk of sporadic tumor (OR 2.96, p = 0.017). Our findings indicate that nPARP1 expression is an independent factor for sporadic BCs and PARP1 inhibitors could be a promising therapy for different phenotypes.     

The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases

BACKGROUND:

Brain metastases (BM) arising from triple‐negative breast cancer (TNBC) portend a poor prognosis. TNBC is more common in premenopausal and African‐American (AA) patients; both of these characteristics also confer a poor prognosis. In a single‐institution cohort study, the authors attempted to determine whether the inferior outcome noted with TNBC brain metastases is more reflective of a higher risk population or the subtype itself.

METHODS:

The University of North Carolina Breast Cancer Database identified patients with BC brain metastases who were diagnosed between 1988 and 2008. BC subtype was assigned by immunohistochemistry: hormone receptor (HR) positive (+);(HR, estrogen receptor [ER]+ and/or progesterone receptor [PR]+)/human epidermal growth factor receptor 2 (HER2) negative (‐), HR+/HER2+, HR‐/HER2+, and TN (ER‐/PR‐/HER2‐). Survival and disease recurrence patterns were evaluated by subtype, patient age (<40 years vs ≥40 years), and race (AA vs non‐AA) using the Kaplan‐Meier method and Cox regression analysis.

RESULTS:

Among 119 patients with BC brain metastases, 33% were AA and 31% were aged <40 years. BC subtype was confirmed in 98 patients (30% with HR+/HER2‐, 21% with HR+/HER2+, 18% with HR‐/HER2+, and 31% with TNBC). Survival after BM was found to be impacted by subtype (P = .002), and was shortest for patients with TNBC (0.24 years; 95% confidence interval, 0.17 years‐0.48 years). There were no age‐specific (P = .84) or race‐specific (P = .09) differences in survival noted after brain metastases; stratification of BC subtypes by age and race revealed no difference (all, P > .1). The receipt of systemic therapy after BC brain metastases was found to be an important predictor of survival after BC brain metastases (hazard ratio, 0.29; P = .002) when adjusted for race, age, number of central nervous system lesions, and BC subtype.

CONCLUSIONS:

TNBC confers a high risk of death after brain metastases regardless of patient race and age, supporting the need for novel agents capable of controlling both intracranial and extracranial TNBC across all races and ages. Cancer 2011. © 2010 American Cancer Society.     

Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is highly prognostic in estrogen receptor (ER) positive breast cancer

Introduction Overexpression of Topoisomerase II alpha (TOP2A) has been implicated with gene amplification of the 17q21 amplicon and consecutively with ErbB2 overexpression and amplification. However, gene amplification does not necessarily correlate with RNA and protein expression. There is growing evidence that TOP2A protein expression is a strong prognostic and TOP2A gene amplification might be a predictive marker (particularly for the use of anthracyclines). Methods Large scale analysis was performed using Affymetrix microarray data from n = 1,681 breast cancer patients to evaluate TOP2A expression. Results TOP2A expression showed a strong correlation with tumor size (χ²-test, P < 0.001), grading (P < 0.001), ErbB2 (P < 0.001) and Ki67 expression (P < 0.001) as well as nodal status (P = 0.042). Survival analysis revealed a significant prognostic value in ER positive (n = 994; log rank P < 0.001), but not in ER negative breast cancer patients (n = 369, P = 0.35). The prognostic impact of TOP2A expression was independent of Ki67 expression in ER positive tumors (P = 0.002 and P = 0.007 for high and low Ki67, respectively). Moreover a worse prognosis of high TOP2A expressing tumors was found in the subgroup of ErbB2 negative tumors (P < 0.001) and a trend among ErbB2 positive tumors (P = 0.11). The prognostic value of TOP2A was independent of whether the patients were untreated or had received adjuvant therapy. In multivariate Cox regression analysis including standard parameters TOP2A emerged to be the top prognostic marker (HR 2.40, 95% CI 1.68–3.43, P < 0.001). Conclusion TOP2A expression is an independent prognostic factor in ER positive breast cancer and could be helpful for risk assessment in ER positive breast cancer patients. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. A. Rody and T. Karn contributed equally to this work.     

Prognostic value of positive human epidermal growth factor receptor 2 status and negative hormone status in patients with T1a/T1b, lymph node-negative breast cancer

BACKGROUND:

The objective of this study was to evaluate prognostic factors of local and distant recurrence in patients diagnosed with T1a and T1b, lymph node‐negative breast carcinoma (BC) with emphasis on human epidermal growth factor receptor 2 (HER2) status.

METHODS:

The authors reviewed 704 women with T1aT1bN0M0 BC who received treatment at the Radiation‐Oncology Center of Florence University between November 2002 and December 2008. Patients with ductal carcinoma in situ or recurrent BC at presentation and patients who received adjuvant chemotherapy were excluded from the analysis.

RESULTS:

In total, 75 patients had HER2‐positive BC (10.7%). At a mean follow‐up of 4.9 years (standard deviation, 2.6 years; range, 0.5‐10.8 years), 19 events were identified, including 10 distant recurrences. Patients with HER2‐positive BC had worse distant recurrence‐free survival (DRFS) than patients with HER2‐negative BC (hazard ratio, 3.66; 95% confidence interval, 0.94‐14.69; P = .045). Negative hormone receptor (HR) status was associated significantly with worse DRFS (hazard ratio, 0.26; 95% confidence interval, 0.07‐0.93; P = .026). In multivariate analysis, younger age was the only significant risk factor for an event of recurrence (hazard ratio, 0.61;95% confidence interval, 0.20‐1.82; P = .029).

CONCLUSIONS:

The current results indicated that patients with T1a/T1b, lymph node‐negative BC have a low risk of distant and local recurrence, but younger age is a significant risk factor for events occurrence. Young women with HER2‐positive and HR‐negative status have a significant risk of distant recurrence and should be considered for future clinical trials with anti‐HER2 adjuvant therapy. Cancer 2011. © 2011 American Cancer Society.     

Hormone-receptor expression and activity of trastuzumab with chemotherapy in HER2-positive advanced breast cancer patients

BACKGROUND:

The relationship between quantitative immunohistochemical hormone receptor expression and response to the combination of trastuzumab with chemotherapy in HER2‐positive advanced breast cancer is currently unknown.

METHODS:

Estrogen receptor (ER) and progesterone receptor expression was studied both as a dichotomous variable (positivity set at ≥1% of positive cells) and as a continuous variable. The effect of hormone receptor expression on overall response rate and progression‐free survival in patients receiving trastuzumab‐based treatment was studied by univariate and multivariate analysis.

RESULTS:

One hundred eleven of 227 consecutive advanced breast cancer patients treated at 2 Institutions had hormone receptor‐positive tumors (49%). High expression of ER (≥30% of tumor cells) predicted reduced probability of tumor response to trastuzumab plus chemotherapy (multivariate odds ratio, 0.422; 95% confidence interval [CI], 0.222‐0.803; P = .009). In patients with hormone receptor‐positive tumors (≥1% of tumor cells), maintenance endocrine therapy added to trastuzumab upon the completion of chemotherapy was associated with a significant progression‐free survival benefit (hazard ratio, 0.521; 95% CI, 0.3325‐0.836; P = .007).

CONCLUSIONS:

Our results suggest a predictive role of hormone receptor expression in HER2‐positive tumors. Further investigation in this patient subset is warranted to optimize the use of HER2‐targeting agents, chemotherapy, and endocrine therapy. Cancer 2012;. © 2011 American Cancer Society.