Survival outcome of weak estrogen/progesterone receptor expression in HER2 negative breast cancer is similar to triple negative breast cancer

Background

Recent publications have suggested that human epidermal growth factor receptor 2 (HER2)-negative breast cancers with “weak” estrogen receptor (ER)/progesterone receptor (PR) expression levels by immunohistochemical (IHC) analysis were considered as the triple-negative (TN) subtype. This study aimed to evaluate the overall survival (OS), disease-free survival rates (DFS), and disease-specific survival (DSS) based on ER and PR expression levels into one of three groups, ER and PR <1%, ER and PR 1%–20%, and ER or PR >20% by hormone therapy.

The clinical value of progesterone receptor expression in luminal breast cancer: A study of a large cohort with long-term follow-up

Background

The routine assessment of progesterone receptor (PR) expression in breast cancer (BC) remains controversial. This study aimed to evaluate the role of PR expression in luminal BC, with emphasis on the definition of positivity and its prognostic significance as compared to Ki67 expression.

Methods

A large cohort (n = 1924) of estrogen receptor (ER)-positive/HER2-negative BC was included. PR was immunohistochemically (IHC) stained on full face sections and core needle biopsies (CNB) where the optimal scoring cutoff was evaluated. In addition, the association of PR with other clinicopathological factors, cellular proliferation, disease outcome, and response to adjuvant therapy were analyzed.

Results

Although several cutoffs showed prognostic significance, the optimal cutoff to categorize PR expression into two clinically distinct prognostic groups on CNB was 10%. PR negativity showed a significant association with features of aggressive tumor behavior and poor outcome. Multivariate analyses indicated that the association between PR negativity and poor outcome was independent of tumor grade, size, node stage, and Ki67. PR negativity showed independent association with shorter survival in patients who received endocrine therapy whereas Ki67did not.

Conclusion

PR IHC expression provides independent prognostic value superior to Ki67. Routine assessment of PR expression in BC using 10% cutoff in the clinical setting is recommended.

Plain Language Summary

• In this study, we have established an optimal approach to determine the prognostic value of progesterone receptor expression in estrogen receptor-positive breast cancer patients.
• To do this, the levels of progesterone receptor were measured in a large cohort of estrogen receptor-positive breast cancer patients.
• We have refined the definition of progesterone receptor positivity in estrogen receptor-positive breast cancer.
• We show that progesterone receptor expression adds prognostic and predictive value of endocrine therapy in estrogen receptor-positive breast cancer patients, and our results show that the absence of progesterone receptor is associated with poorer outcomes independent of tumor grade, size, node stage, and Ki67 expression.

     

Use of immunohistochemical markers can refine prognosis in triple negative breast cancer

Background  

Basal-like breast cancer has been extensively characterized on the basis of gene expression profiles, but it is becoming increasingly common for these tumors to be defined on the basis of immunohistochemical (IHC) staining patterns, particularly in retrospective studies where material for expression profiling may not be available. The IHC pattern that best defines basal-like tumors is under investigation and various combinations of ER, PR, HER2-, CK5/6+ and EGFR+ have been tested.     

Selecting for BRCA1 testing using a combination of homogeneous selection criteria and immunohistochemical characteristics of breast cancers

Background  

BRCA1 gene-related tumours are more frequently estrogen receptor (ER) and progesterone receptor (PR) negative with a lower prevalence of human epidermal growth factor receptor 2 (HER2) overexpression or amplification. We evaluated the effectiveness of a combination of homogeneously selected criteria and immunohistochemical (IHC) characteristics of Familial Breast Cancers (FBCs) in detecting BRCA1 mutation carriers.     

Receptor conversion in distant breast cancer metastases

Introduction

When breast cancer patients develop distant metastases, the choice of systemic treatment is usually based on tissue characteristics of the primary tumor as determined by immunohistochemistry (IHC) and/or molecular analysis. Several previous studies have shown that the immunophenotype of distant breast cancer metastases may be different from that of the primary tumor (receptor conversion), leading to inappropriate choice of systemic treatment. The studies published so far are however small and/or methodologically suboptimal. Therefore, definite conclusions that may change clinical practice could not yet be drawn. We therefore aimed to study receptor conversion for estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in a large group of distant (non-bone) breast cancer metastases by re-staining all primary tumors and metastases with current optimal immunohistochemical and in situ hybridization methods on full sections.

Methods

A total of 233 distant breast cancer metastases from different sites (76 skin, 63 liver, 43 lung, 44 brain and 7 gastro-intestinal) were IHC stained for ERα, PR and HER2, and expression was compared to that of the primary tumor. HER2 in situ hybridization (ISH) was done in cases of IHC conversion or when primary tumors or metastases showed an IHC 2+ result.

Results

Using a 10% threshold, receptor conversion by IHC for ERα, PR occurred in 10.3%, 30.0% of patients, respectively. In 10.7% of patients, conversion from ER+ or PR+ to ER-/PR- and in 3.4% from ER-/PR- to ER+ or PR+ was found. Using a 1% threshold, ERα and PR conversion rates were 15.1% and 32.6%. In 12.4% of patients conversion from ER+ or PR+ to ER-/PR-, and 8.2% from ER-/PR- to ER+ or PR+ occurred. HER2 conversion occurred in 5.2%. Of the 12 cases that showed HER2 conversion by IHC, 5 showed also conversion by ISH. One further case showed conversion by ISH, but not by IHC. Conversion was mainly from positive in the primary tumor to negative in the metastases for ERα and PR, while HER2 conversion occurred equally both ways. PR conversion occurred significantly more often in liver, brain and gastro-intestinal metastases.

Conclusions

Receptor conversion by immunohistochemistry in (non-bone) distant breast cancer metastases does occur, is relatively uncommon for ERα and HER2, and is more frequent for PR, especially in brain, liver and gastro-intestinal metastases.     

Novel image analysis approach for quantifying expression of nuclear proteins assessed by immunohistochemistry: application to measurement of oestrogen and progesterone receptor levels in breast cancer

Introduction

Manual interpretation of immunohistochemistry (IHC) is a subjective, time-consuming and variable process, with an inherent intra-observer and inter-observer variability. Automated image analysis approaches offer the possibility of developing rapid, uniform indicators of IHC staining. In the present article we describe the development of a novel approach for automatically quantifying oestrogen receptor (ER) and progesterone receptor (PR) protein expression assessed by IHC in primary breast cancer.

Methods

Two cohorts of breast cancer patients (n = 743) were used in the study. Digital images of breast cancer tissue microarrays were captured using the Aperio ScanScope XT slide scanner (Aperio Technologies, Vista, CA, USA). Image analysis algorithms were developed using MatLab 7 (MathWorks, Apple Hill Drive, MA, USA). A fully automated nuclear algorithm was developed to discriminate tumour from normal tissue and to quantify ER and PR expression in both cohorts. Random forest clustering was employed to identify optimum thresholds for survival analysis.

Results

The accuracy of the nuclear algorithm was initially confirmed by a histopathologist, who validated the output in 18 representative images. In these 18 samples, an excellent correlation was evident between the results obtained by manual and automated analysis (Spearman's ρ = 0.9, P < 0.001). Optimum thresholds for survival analysis were identified using random forest clustering. This revealed 7% positive tumour cells as the optimum threshold for the ER and 5% positive tumour cells for the PR. Moreover, a 7% cutoff level for the ER predicted a better response to tamoxifen than the currently used 10% threshold. Finally, linear regression was employed to demonstrate a more homogeneous pattern of expression for the ER (R = 0.860) than for the PR (R = 0.681).

Conclusions

In summary, we present data on the automated quantification of the ER and the PR in 743 primary breast tumours using a novel unsupervised image analysis algorithm. This novel approach provides a useful tool for the quantification of biomarkers on tissue specimens, as well as for objective identification of appropriate cutoff thresholds for biomarker positivity. It also offers the potential to identify proteins with a homogeneous pattern of expression.     

Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome

Background

Promoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT), is associated with improved treatment outcome for newly diagnosed glioblastoma (GBM) treated with standard chemoradiation. To determine the prognostic significance of MGMT protein expression as assessed by immunohistochemistry (IHC) and its relationship with methylation, we analyzed MGMT expression and promoter methylation with survival in a retrospective patient cohort.

Methods

We identified 418 patients with newly diagnosed GBM at University of California Los Angeles Kaiser Permanente Los Angeles, nearly all of whom received chemoradiation, and determined MGMT expression by IHC, and MGMT promoter methylation by methylation-specific PCR (MSP) and bisulfite sequencing (BiSEQ) of 24 neighboring CpG sites.

Results

With use of the median percentage of cells staining by IHC as the threshold, patients with <30% staining had progression-free survival (PFS) of 10.9 months and overall survival (OS) of 20.5 months, compared with PFS of 7.8 months (P < .0001) and OS of 16.7 months (P < .0001) among patients with ≥30% staining. Inter- and intrareader correlation of IHC staining was high. Promoter methylation status by MSP was correlated with IHC staining. However, low IHC staining was frequently observed in the absence of promoter methylation. Increased methylation density determined by BiSEQ correlated with both decreased IHC staining and increased survival, providing a practical semiquantitative alternative to MSP. On the basis of multivariate analysis validated by bootstrap analysis, patients with tandem promoter methylation and low expression demonstrated improved OS and PFS, compared with the other combinations.

Conclusions

Optimal assessment of MGMT status as a prognostic biomarker for patients with newly diagnosed GBM treated with chemoradiation requires determination of both promoter methylation and IHC protein expression.     

Treatment of hormone positive uterine leiomyosarcoma with aromatase inhibitors

Background

Aromatase inhibitors (AIs) have not been used consistently as part of the management of hormone receptor positive uterine leiomyosarcomas (ULMS). As a result, the published data regarding the efficacy of AIs in this subtype of ULMS are sparse.

Methods

We performed a retrospective electronic medical record review of patients with ULMS treated with an AI, in the 1st or the 2nd line setting, at the Sarcoma Unit of the Royal Marsden Hospital between 2001 and 2012. We assessed progression-free survival (PFS), objective response and toxicities and explored the correlation of the intensity of the hormone receptor status, as well as of the grade with PFS.

Results

Sixteen patients with measurable advanced ULMS were treated with an AI in our unit. All of them were oestrogen receptor (ER) and progesterone receptor (PgR) positive. Letrozole was used in all patients as 1st line endocrine therapy, while exemestane was mainly prescribed as 2nd line (83%). Median PFS in 1st line was 14 months (95% CI: 0 – 30 months), and prolonged PFS was more likely to be observed in patients with low grade compared to high grade ULMS (20 months vs. 11 months), and in moderately/strongly ER positive compared to weakly ER positive ULMS (20 months vs. 12 months). Best response was partial response (PR) in 2/16 patients (12.5%) and clinical benefit (CB), defined as complete response (CR)?+?PR?+?stable disease ≥6 months, was observed in 10/16 patients (CB rate (CBR) 62.5%). Median duration of 2nd line was 3 months and median PFS was not reached. The 1-year progression-free rate for the 2nd line AI was 80%. Best response was PR in one patient and CBR was 50%. AIs were well tolerated in both lines of treatment.

Conclusions

In this population of patients with hormone positive ULMS, AIs achieved a significant CBR (62.5%) in 1st line, which was retained in 2nd line (CBR: 50%). The relatively prolonged median PFS (14 months), along with the favourable toxicity profile could place AIs among the first choices of systemic treatment in hormone positive ULMS, preferably in strongly positive (>90%), and/ or low grade and low volume disease.

     

Immunohistochemical detection of estrogen receptor,progesterone receptor,and human epidermal growth factor receptor 2 expression in breast carcinomas

BACKGROUND:

Fine‐needle aspiration (FNA) is a rapid and accurate procedure for the detection of breast carcinomas. The evaluation of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression by immunohistochemistry (IHC) is performed routinely on formalin‐fixed, paraffin‐embedded needle‐core (NC) or excision tissue block (TB) preparations, according to the American Society of Clinical Oncology/College of American Pathologist guidelines. In this retrospective study, the authors compared expression levels of ER, PR, and HER2 in ethanol‐fixed BC FNA cell block (CB) samples with expression levels in formalin‐fixed NC and TB samples.

METHODS:

Forty‐one breast carcinoma CB samples with concurrent or subsequent NC and TB samples were identified. Patients who had received neoadjuvant or adjuvant chemotherapy were excluded. CB samples initially were fixed in 50% ethanol (4‐12 hours), and this was followed by formalin fixation (minimum, 6 hours). NC samples were placed promptly in formalin for a minimum of 6 hours. Within 4 to 8 hours, TB samples were fixed in formalin for 6 to 48 hours. Fluorescence in situ hybridization (FISH) results were also compared.

RESULTS:

IHC for ER on alcohol‐fixed CB samples had good correlation with NC and TB samples. PR results on TB samples had excellent agreement with NC samples. A higher discordance rate wais observed when PR results were compared between CB samples and NC samples. HER2 detection on ethanol‐fixed CB samples resulted in a higher rate of positive and equivocal staining than NC or TB samples. HER2 IHC on TB samples demonstrated better correlation with FISH results than CB or NC samples.

CONCLUSIONS:

Alcohol fixation did not affect ER results in breast carcinoma, but it may alter tumor cell PR antigenicity. The authors concluded that CB samples could be used to triage patients for tamoxifen therapy, but they are not reliable for the assessment of HER2 status; therefore, CB results should be correlated with results from NC or TB samples. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Targeted Therapy of Advanced Gallbladder Cancer and Cholangiocarcinoma with Aggressive Biology: Eliciting Early Response Signals from Phase 1 trials

Purpose

Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few therapeutic options for relapsed disease.

Methods

Given the overall poor prognosis in this population and the availability of novel targeted therapies, we systematically analyzed the characteristics and outcomes for GC and CC patients treated on phase I trials with an emphasis on targeted agents and locoregional therapies.

Results

Of 40 treated patients (GC=6; CC=34; median age, 60 years), 8 (20%) had stable disease (SD) &gt; 6 months, 3 (8%) partial response (PR), on protocols with hepatic arterial drug infusion and anti-angiogenic, anti-HER-2/neu or novel MAPK/ERK kinase (MEK) inhibitors. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0), 3.0 months (95% CI 2.3, 4.6), and 3.0 months (95% CI 2.4, 3.9) for their first-, second-, and last-line FDA-approved therapy. In univariate analysis, &gt;3 metastatic sites, elevated alanine aminotransferase (ALT) (&gt;56IU/L), serum creatinine (&gt;1.6mg/dL), and CA19-9 (&gt;35U/mL) were associated with a shorter PFS. Mutational analysis revealed mutation in the KRAS oncogene in 2 of 11 patients (18%). The SD &gt;6 months/PR rate of 28% was seen with hepatic arterial infusion of oxaliplatin, and inhibitors of angiogenesis, HER-2/neu or MEK.

Conclusions

The PFS in phase I trials was similar to that of the first, second, and last-line therapy (P=0.95, 0.98, 0.76, respectively) with FDA-approved agents given in the advanced setting, emphasizing a role for targeted agents in a clinical trials setting as potentially valuable therapeutic options for these patients.     

Leisure-time physical activity and breast cancer risk by hormone receptor status: effective life periods and exercise intensity

Objective  

Physical activity may decrease breast cancer risk. However, it is unclear what intensity of exercise and during which life periods this effect on decreasing risk is efficiently expressed, and whether the associations differ by the estrogen-/progesterone- receptor (ER/PR) status of tumors. We investigated associations between age- and intensity-specific leisure-time physical activity and ER/PR-defined breast cancer risk.     

Hepatic resection for breast cancer liver metastases: Impact of intrinsic subtypes

IntroductionThe role of surgery for breast cancer liver metastases (BCLM) remains controversial. This study aimed to analyze survival in patients treated with hepatectomy plus systemic therapy or systemic therapy alone for BCLM and to determine selection factors to guide surgical therapy.Materials and methodsPatients who underwent hepatectomy plus systemic therapy (n = 136) and systemic therapy alone for isolated BCLM (n = 763) were compared. Overall survival (OS) was analyzed after propensity score matching. Intrinsic subtypes were defined as: luminal A (estrogen receptor [ER]+ and/or progesterone receptor positive [PR]+, human epidermal growth factor receptor 2 [HER2]–), luminal B (ER and/or PR+, HER2+), HER2-enriched (ER and PR–, HER2+), and basal-like (ER, PR, HER2–).ResultsAfter hepatectomy, independent predictors of poor OS were number and size of liver metastases, and intrinsic subtype (hazard ratios, 1.11, 1.16, and 4.28, respectively). Median OS was 75 and 81 months among patients with luminal B and HER2-enriched subtypes, compared with 17 and 53 months among patients with basal-like and luminal A subtypes (P < .001). Median progression-free survival (PFS) was 60 months with the HER2-enriched subtype, compared with 17, 16, and 5 months with luminal A, luminal B, and basal-like subtypes, respectively (P < .001). After propensity score matching, 5-year OS rates were 56% vs. 40% in the surgery vs. systemic therapy alone groups (P = .018).ConclusionSurgical resection of BCLM yielded higher OS compared with systemic therapy alone and prolonged PFS among patients with the HER2-enriched subtype. These findings support the use of surgical therapy in appropriately selected patients, based on intrinsic subtypes.     

Assessment of the contribution of the IHC4+C score to decision making in clinical practice in early breast cancer

Background:

The immunohistochemical (IHC) 4+C score is a cost-effective prognostic tool that uses clinicopathologic factors and four standard IHC assays: oestrogen receptor (ER), PR, HER2 and Ki67. We assessed its utility in personalising breast cancer treatment in a clinical practice setting, through comparison with Adjuvant! Online (AoL) and the Nottingham Prognostic Index (NPI).

Methods:

We prospectively gathered clinicopathologic data for postmenopausal patients with hormone receptor-positive, HER2-negative, N0-3 resected early breast cancer treated consecutively at our institution. We retrospectively calculated and compared prognostic scores. The primary endpoint was the proportion of patients reclassified from AoL-defined intermediate-risk by application of the IHC4+C score.

Results:

The median age of the 101 patients included in the analysis was 63. In all, 15 of the 26 patients classified as intermediate-risk by AoL were reallocated to a low-risk group by application of the IHC4+C score and no patient was reclassified as high-risk group. Of the 59 patients classified as intermediate-risk group by the NPI, 24 were reallocated to a low-risk group and 13 to a high-risk group.

Conclusion:

IHC4+C reclassifies more than half of the patients stratified as being in intermediate-risk group by the AoL and NPI. The use of IHC4+C may substantially improve decision-making on adjuvant chemotherapy.     

Prospective comparison of switches in biomarker status between primary and recurrent breast cancer: the Breast Recurrence In Tissues Study (BRITS)

Introduction  

Immunohistochemistry of primary breast cancer is routinely used to guide changes in therapy at the time of relapse. Retrospective reviews suggest that the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) receptor may differ between the primary and loco-regional recurrence or distant metastases. The Breast Recurrence In Tissues Study (BRITS) was a large, multicentre, prospective study to examine changes in ER, PR and HER2.     

Estrogen receptor negative/progesterone receptor positive breast cancer is not a reproducible subtype

Introduction

Estrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. While the clinical utility of ER as a predictive biomarker to identify patients likely to benefit from hormonal therapy is well-established, the added value of PR is less well-defined. The primary goals of our study were to assess the distribution, inter-assay reproducibility, and prognostic significance of breast cancer subtypes defined by patterns of ER and PR expression.

Methods

We integrated gene expression microarray (GEM) and clinico-pathologic data from 20 published studies to determine the frequency (n = 4,111) and inter-assay reproducibility (n = 1,752) of ER/PR subtypes (ER+/PR+, ER+/PR-, ER-/PR-, ER-/PR+). To extend our findings, we utilized a cohort of patients from the Nurses’ Health Study (NHS) with ER/PR data recorded in the medical record and assessed on tissue microarrays (n = 2,011). In both datasets, we assessed the association of ER and PR expression with survival.

Results

In a genome-wide analysis, progesterone receptor was among the least variable genes in ER- breast cancer. The ER-/PR+ subtype was rare (approximately 1 to 4%) and showed no significant reproducibility (Kappa = 0.02 and 0.06, in the GEM and NHS datasets, respectively). The vast majority of patients classified as ER-/PR+ in the medical record (97% and 94%, in the GEM and NHS datasets) were re-classified by a second method. In the GEM dataset (n = 2,731), progesterone receptor mRNA expression was associated with prognosis in ER+ breast cancer (adjusted P <0.001), but not in ER- breast cancer (adjusted P = 0.21). PR protein expression did not contribute significant prognostic information to multivariate models considering ER and other standard clinico-pathologic features in the GEM or NHS datasets.

Conclusion

ER-/PR+ breast cancer is not a reproducible subtype. PR expression is not associated with prognosis in ER- breast cancer, and PR does not contribute significant independent prognostic information to multivariate models considering ER and other standard clinico-pathologic factors. Given that PR provides no clinically actionable information in ER+ breast cancer, these findings question the utility of routine PR testing in breast cancer.     

EGFR expression and survival in patients given cetuximab and chemoradiation for stage III non-small cell lung cancer: A secondary analysis of RTOG 0324

Purpose

We investigated whether expression of epidermal growth factor receptor (EGFR) was associated with survival and disease control in this secondary analysis of a phase II trial of cetuximab + chemoradiation for stage III non-small cell lung cancer.

Methods

Patients received cetuximab weekly before and during radiation (63 Gy/35 fractions/7 weeks) with weekly carboplatin + paclitaxel. We analyzed EGFR expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in pretreatment biopsy specimens and compared findings with overall and progression-free survival (OS, PFS) and time to progression (TTP).

Results

Specimens for IHC and FISH were collected from 51 and 45 of 87 evaluable patients. Pretreatment characteristics did not differ for patients with (n = 51) or without (n = 36) EGFR IHC data, or with (n = 45) or without (n = 42) FISH data. However, patients without IHC data had worse OS (HR = 1.63, P = 0.05), worse PFS (HR = 1.88, P = 0.008), and worse TTP [HR = 1.99, P = 0.01] than those with IHC data. EGFR protein expression was not related to pretreatment characteristics or OS; FISH-positive disease was associated with better performance status but not with OS, PFS, or TTP.

Conclusions

Surprisingly, outcomes differed not by EGFR expression but by the availability of samples for analysis, underscoring the importance of obtaining biopsy samples in such trials.     

Phase II trial of saracatinib (AZD0530), an oral SRC-inhibitor for the treatment of patients with hormone receptor-negative metastatic breast cancer

Background

SRC activation is associated with cell migration, proliferation, and metastasis. Saracatinib is an oral tyrosine kinase inhibitor (TKI) selective for SRC. We performed this trial to evaluate the efficacy and safety of saracatinib monotherapy in patients with estrogen receptor (ER)^– and progesterone receptor (PR)^– metastatic breast cancer (MBC).

Patients and Methods

Patients who had undergone ≤ 1 previous chemotherapy regimen for measurable ER^– and PR^– MBC received saracatinib 175 mg orally daily. The primary endpoint was disease control defined as complete response (CR) + partial response (PR) + stable disease (SD) > 6 months. Secondary endpoints included toxicity and progression-free survival (PFS). Levels of circulating tumor cells (CTCs) in response to therapy were measured over time.

Results

Nine patients were treated on study. After a median of 2 cycles (range 1-3), no patient had achieved CR, PR, or SD >6 months. The median time to treatment failure was 82 days (12-109 days).The majority (89%) of patients discontinued saracatinib because of disease progression. One patient acquired potentially treatment-related grade 4 hypoxia with interstitial infiltrates and was removed from the study. Common adverse events included fatigue, elevated liver enzymes, nausea, hyponatremia, dyspnea, cough, and adrenal insufficiency.

Conclusions

These efficacy results were not sufficiently promising to justify continued accrual to this study. Based on this series, saracatinib does not appear to have significant single-agent activity for the treatment of patients with ER⁻/PR⁻ MBC.     

The importance of temporal effects in evaluating the prognostic impact of joint ERPR expression in premenopausal women with node-positive breast cancer

Summary Although there is abundant information about the independent effects of estrogen receptor (ER) and progesterone receptor (PR) on outcomes of breast cancer, comparatively little is known about the impact of joint (ER+PR+, ER+PR−, ER−PR+ and ER−PR−) ERPR expression. The purpose of this study was to evaluate the prognostic relevance of joint ERPR expression to progression free survival (PFS). Data from 710 patients with a median follow-up of 119 months has been analyzed retrospectively. Our results indicate that the effect of the ER+PR+ phenotype on PFS was significantly time-dependent (p < 0.0001); favorable in the first 3 years of follow-up (HR = 0.67, p = 0.0175) compared to ER−PR− phenotype, but unfavorable during the later follow-up period (HR = 2.89, p = 0.0006). Similar patterns were also observed for ER+PR− and ER−PR+ phenotypes, but the effect did not reach statistical significance. In the tree-based analysis, we found that, among patients with more than 4 positive nodes and age greater than 40, those with ER−PR+ tumors had the worst PFS ( p = 0.025), and among patients with 1–3 positive nodes and stage of T1 and T2, those with ER+PR− had the worst outcome ( p = 0.006). Our results demonstrate that failure to recognize the time-varying effect of the steroid hormonal receptors can obscure their role in the prognosis of breast cancer. We also provide more evidence to support the concept that ER−PR+ is a real group representing a distinct clinical entity.