Receptor Discordance Research Articles

Receptor discordance after neoadjuvant chemotherapy and its impact on disease-free survival.

e12518Background: The purposes of this study were to determine estrogen, progesterone and HER2 receptors discordances after neoadjuvant chemotherapy in patients with locally advanced breast cancer and their impacts on disease-free survival (DFS). Methods: Patients hormone and HER2 receptors status were assessed before and after neoadjuvant chemotherapy. Univariate, multivariate analyses, Kaplan Meier and Log-rank test and Cox regression analysis were used Results: Thirty-eight patients had stage II cancer, 148 patients had stage III cancer. One-hundred thirty-eight patients (74%) had hormone receptor positivity and 79 patients (42%) had HER2 positivity. Hormone receptor discordance was detected in 63 patients (34%), HER2 receptor discordance was detected in 33 patients (18%). After neoadjuvant chemotherapy, fifty-three patients with positive hormone receptor had negative hormone receptor status and 24 patients (13%) with positive HER2 receptor had negative HER2 receptor status. Median 5-year DFS in patien...

Abstract B21: Intratumoral hormone receptor heterogeneity is a characteristic of high-grade breast cancer and is associated with inter-laboratory hormone receptor status discordance

Abstract Introduction: Intratumoral hormone receptor (HR) heterogeneity may have implications for molecular classification of breast tumors which, in turn, may impact clinical decision making and epidemiologic research. Prior studies show that 10-20% of patients have discordant estrogen receptor (ER) or progesterone receptor (PR) status upon repeat assay. While technical factors contribute to this discordance, intratumoral HR heterogeneity may also play a role. We examined the association between intratumoral HR heterogeneity, measured at a single research laboratory, and clinical HR status, tumor characteristics and demographic variables. Methods: We used paraffin-embedded blocks from 932 invasive breast cancer cases, of which 497 were African-American, from the population-based Carolina Breast Cancer Study Phase 3, part of the African-American Breast Cancer Epidemiology and Risk (AMBER) Consortium. Two to four 1mm tumor cores per case were assembled into tissue microarrays and stained for ER and PR at a single research laboratory. ER and PR status (positive: ≥1% positive tumor cells; negative: <1%) were assigned to each core by automated digital image analysis and ER and PR status were assigned to each case by core-to-case collapsing, using the weighted average of positive cells across all cores. Intratumoral heterogeneity status (i.e. ‘homogeneous’ vs. ‘heterogeneous’) was assigned based on ‘identical’ or ‘different’ HR status between cores from a single case. Multivariable logistic regression was used to evaluate the association between heterogeneity status and patient and tumor characteristics, overall and stratified by menopausal status. Clinical HR status (positive vs. negative) was abstracted from medical records and concordance between clinical and research ER and PR status were examined, overall and stratified by heterogeneity status. Results: Of 932 cases, 95 (10%) had ER heterogeneity while 149 (16%) had PR heterogeneity. Overall, there was high agreement between clinical and research ER status (93% concordance; 95% confidence interval (CI) 92-95%) and PR status (89%; 95%CI 87-91%), consistent with previously reported inter-laboratory concordance rates. However, agreement was lower in cases with intratumoral heterogeneity (ER: 74%; 95%CI 65-83% and PR: 61%; 95%CI 53-69%), relative to homogeneous cases (ER: 96%; 95%CI 95-97% and PR: 94%; 95%CI 92-96%). Obesity, defined as BMI≥30kg/m2, was associated with increased odds of ER heterogeneity (adjusted odds ratio (OR)obese vs. normal weight 1.76; 95%CI 0.95-3.29), with a stronger association among postmenopausal women (OR 2.52; 95%CI 1.14-5.56). High tumor grade was associated with increased odds of both ER and PR heterogeneity (ORgrade III vs. I 3.14; 95%CI 1.47-6.70 and ORgrade III vs. I 2.28; 95%CI 1.26-4.14, respectively). There were no associations between intratumoral heterogeneity and age, race or menopausal status. Conclusions: Intratumoral heterogeneity may account for a portion of the well-documented inter-laboratory discordance in ER and PR status, with implications for tumor subtype classification. Intratumoral heterogeneity was more prevalent in high grade tumors, indicating that it may be a feature of aggressive breast cancer. Furthermore, obese postmenopausal women were more likely to have intratumoral ER heterogeneity, suggesting a potential mechanism underlying the association between obesity and worse breast cancer prognosis. Although these data do not support an association between intratumoral heterogeneity and race, given that both high grade disease and obesity are more common in African Americans, future studies should explore a possible role for intratumoral heterogeneity in breast cancer racial disparities. Citation Format: Emma H. Allott, Joseph Geradts, Xuezheng Sun, Stephanie M. Cohen, Thaer Khoury, Wiam Bshara, Gary Zirpoli, Julie R. Palmer, Christine B. Ambrosone, Andrew F. Olshan, Melissa A. Troester. Intratumoral hormone receptor heterogeneity is a characteristic of high-grade breast cancer and is associated with inter-laboratory hormone receptor status discordance. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B21.

Hormone receptors as a marker of poor survival in epithelial ovarian cancer

ObjectiveAndrogen receptor (AR), estrogen receptor α and β (ERα, ERβ), and progesterone receptor (PR) are potential therapeutic targets in epithelial ovarian cancer. In this study we evaluate the prognostic value of these hormone receptors in ovarian cancer patients. MethodsIn a prospective multicenter randomized controlled phase II trial 196 ovarian cancer patients were randomized to carboplatin/docetaxel±celecoxib. Of 121 patients sufficient tumor tissue was available for hormone receptor analysis. Tissue micro-arrays were stained for AR, ERα, ERβ, and PR. Cluster analysis was performed to identify subgroups based on hormone receptor expression profile. Receptor expression was correlated to progression-free survival (PFS) and overall survival (OS) in uni- and multivariate analysis. ResultsAR, ERα, ERβ, and PR were expressed in respectively 10%, 31%, 73%, and 19%. In patients with synchronous metastasis tissue available (n=69 patients), discordant receptor expression was observed in 9–32%. ERβ-expression was associated with poor PFS and OS (hazard ratios 1.88 and 1.92). Clustering analysis revealed a subgroup with hormone receptor negative disease that had a favorable PFS and OS. ConclusionHormone receptors are expressed in the majority of ovarian cancer tumors and may serve as therapeutic targets. Clustering analysis can reveal subgroups with different outcome, which may prove valuable in selecting patients for endocrine therapy.

Hormone receptor discordance between local and central pathology with RT-PCR analysis: Results from multicenter Phase III WSG-PlanB trial.

e11555 Background: Discordances between local and central pathology regarding ER, PR, and HER2 status may occur at varying frequencies, which may be attributable to technical factors (tissue handli...

Abstract P3-13-11: Response to treatment and prognosis of recurrent breast cancer patients with receptor discordance

Abstract BACKGROUND Estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor -2 (HER2) statuses are clinically used to select treatments. Several studies reported that discordance between primary and metastatic lesions lead to detrimental outcome. Although biopsy of recurrent breast cancer has been recently recommended by international clinical guidelines, prognostic relevance remains to be elucidated. The aim of the present study is to evaluate response to treatment and prognosis of patients with receptor discordance, compared with patients with receptor concordance. Patients and METHODS We retrospectively identified recurrent breast cancer patients who had biopsies or resections of recurrent lesions between January 2007 and April 2012 at Keio University Hospital. HR status was assessed by immunohistochemistry (IHC) and determined using the Allred score. HR status was defined as positive when score was 3 and more. HER2 status was assessed by IHC and fluorescence in situ hybridization (FISH) analysis. We defined HER2 positivity as 3+ staining intensity by IHC or the presence of HER2 gene amplification by FISH. Tumors were classified as luminal (HR+ and HER2-), luminal/HER2 (HR+ and HER2+), HER2 (HR- and HER2+), or triple negative (HR- and HER2-). Treatment was decided according to the receptor status of recurrent tumors. RESULTS Among 38 patients undergoing biopsy or resection, 13.2% (5) were loco-regional recurrences and 86.8% (33) were distant metastases (lung 21; liver 6; brain 3; pleura 1). Overall, 10 patients (26.3%) changed subtypes at recurrent lesions (table1) and all of them had a change in treatment plan. Discordance in subtype between primary tumor and recurrent lesion Recurrent lesion (%) LuminalLuminal/HER2HER2Triple negativeDiscordance rate (%)Primary tumor (%)Luminal18 (66.7)2 (8.3)1(4.2)3(12.5)6/24 (25.0)Luminal/HER21 (14.3)6 (85.7)001/7 (14.3)HER201 (100.0)001/1 (100.0)Triple negative1 (16.7)1 (16.7)04(66.7)2/6 (33.3)Total20101710/38 (26.3) Changes in management included the addition of trastuzumab in patients with gain of HER2 (n=3), the use of chemotherapy in those with loss of HR (n=6) and provision of endocrine therapy for those with gaining HR (n=3). Response rate of discordant group and concordant group were 10.0% and 21.4%, respectively (p=1.000). Clinical benefit rate of discordant group and concordant group were 40.0% and 67.9%, respectively (p=0.150). There is no significant difference of time to progression (TTP) between the discordant and concordant groups (169.5days vs.319.5days, p= 0.081). CONCLUSION Patients with receptor discordance tended towards worse response rate and shorter TTP, leading to the poor prognosis of the recurrent breast cancer patients with receptor discordance. Citation Format: Hanako Ueno, Hiromitsu Jinno, Takamichi Yokoe, Toshiaki Kurihara, Masaru Takemae, Aiko Nagayama, Maiko Takahashi, Tetsu Hayashida, Kaori Kameyama, Yuko Kitagawa. Response to treatment and prognosis of recurrent breast cancer patients with receptor discordance [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-11.

Prognostic implications of receptor discordance between primary and recurrent breast cancer.

Discordance rates of hormone receptor (HR) and human epidermal growth factor-2 (HER2) status between primary and recurrent breast cancer were reported to be in the wide range of 10-40 %, although its prognostic relevance remains to be elucidated. Fifty-five breast cancer patients had biopsies or resections of recurrent lesions. Pathological assessments of the HR and HER2 status of primary and recurrent lesions were performed in a single laboratory at Keio University Hospital. Tumors were classified as luminal (HR+ and HER2-), luminal/HER2 (HR+ and HER2+), HER2 (HR- and HER2+), or triple negative (HR- and HER2-). Discordance rates in estrogen receptor (ER), progesterone receptor (PgR) and HER2 status between primary tumors and recurrent lesions were 16.4, 30.9 and 10.2 %, respectively. Overall, 14 patients (25.5 %) changed subtypes at recurrent lesions. Patients with a gain in ER and PgR status had a significantly longer disease-free interval compared with the corresponding concordant-negative patients (ER: 99.0 vs. 18.5 months, p = 0.037, PgR: 141.0 vs. 24.4 months, p = 0.011). Patients with a loss of HER2 status experienced a trend toward shorter time to progression, compared with patients who maintained HER2 positivity (4.0 vs. 18.4 months, p = 0.051). Discordance in receptor status between primary and recurrent breast cancers were seen in 10-30 %. A gain in HR status was significantly associated with better prognosis.

Receptor Expression Discrepancy between Primary and Metastatic Breast Cancer Lesions

SummaryBackground: Recent studies have shown that the expression status of hormone receptors and human epidermal growth factor receptor 2 (HER2) in breast cancer may change during disease progression. The aim of this study was to determine and compare the estrogen receptor (ER), progesterone receptor (PR), and HER2 expression status in primary breast cancer and metastatic lesions. Methods: 58 patients with registered biopsy reports or available samples of the primary tumor and distant metastases were included in the final analysis. Biopsy samples were re-stained using immunohistochemical methods to determine receptor status (if not already recorded in previous reports) and re-examined by 2 independent pathologists. Results: Discordance rates for receptor expression status of the primary tumor and distant metastases for ER, PR, and HER2 were 17.4, 45.4, and 13.3%, respectively. No statistically significant difference in overall survival due to receptor expression discordance between the primary tumor and metastatic sites (p > 0.05) was found, although a tendency toward worse survival time was observed in patients with HER2 expression discrepancies. Conclusion: This study showed receptor discordance rates between primary and metastatic breast cancer sites for ER, PR, and HER2 of 17.8, 45.4, and 13.3%, respectively. Re-biopsy and IHC evaluation of metastatic sites for receptor status may change treatment decisions in patients with relapsed/progressed BC.

Deciding site of biopsy at metastatic relapse.

To the editor, The problem of tumour heterogeneity has been noted since the earliest use of targeted therapy, hormonal therapy for endocrine responsive breast cancer, and biopsy of the metastatic site is now an accepted procedure to assess receptor discordance. It is recommended that the biopsy site ‘should be selected considering easy access, low risk of complications’ [Foukakis et al. 2012]. Similarly, Janku suggests that ‘liquid biopsies’ using cell free DNA in plasma/serum can be used to monitor tumour heterogeneity at multiple time points, being a noninvasive approach with less risk to patients and at a lower cost [Janku, 2014]. Both recommendations ignore that fact that all metastases are not created equal. For example, brain metastases in breast cancer have graver prognostic significance (survival measured in months) than lymph node or bone metastases (survival measured in years). Thus, it is not surprising that there are no reports that altering treatment based on biopsy of most accessible metastasis, lead to improvement in survival. If the plan is to use targeted therapy, and with the knowledge that tumour heterogeneity exists [Hoefnagel et al. 2013], it is imperative that the clinically important metastasis be biopsied, irrespective of its accessibility. Thus, the decision on biopsy site should be based on clinical significance rather than accessibility. Visceral metastases with graver prognostic significance (brain, liver, lungs) should be biopsied rather than those easily accessible, especially if targeted therapy is planned. In future, molecular imaging of targets should soon replace invasive biopsies [Sorensen et al. 2014; Fleuren et al. 2014].

Abstract P6-05-07: Discordance in estrogen receptor, progesterone receptor and HER-2/neu status between primary and metastatic breast cancer: A systematic review

Abstract BACKGROUND AND OBJECTIVE Systemic treatment choices for metastatic breast cancer are based, in part, on the estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor (HER2) status of the primary cancer. Receptor discordance between primary and associated metastases is well recognized and could have important therapeutic implications. A systematic review of all relevant studies was conducted to assess the extent of discordance in ER, PR and HER2 status between primary breast cancers and their paired metastases. METHODS A search was performed using EMBASE (1980-2013), Medline (1966-2013) and Cochrane Central Register of Controlled Trials (CENTRAL, 2013 issue 1), references of included studies, relevant review articles and conference abstracts. Only English-language cohort studies reporting ER, PR, and HER2 expression for matching primary breast cancer and metastatic sites were eligible. Title and abstract screening was performed by one reviewer; full text articles of potentially relevant citations were independently screened by two reviewers. Using pre-defined criteria, two reviewers performed data extraction of the included studies, as well as methodologic quality assessment (QUADAS-2) and risk of bias assessment. Disagreements by reviewers were adjudicated by consensus. Median discordance and interquartile range (IQR) of discordance of each of the biomarkers (ER, PR, HER2) between primary breast cancer and their paired metastases were calculated. Association between receptor discordance and site of metastasis site was also explored. RESULTS Of the 5034 citations identified, 58 studies (representing a total of 3,522 matched primary and metastatic pairs) met our inclusion criteria. Studies were generally small, as reflected by the median number of matched pairs of 42 (range 4-370). Median discordance rates between primary and paired metastases were 18% (IQR10–29%) for ER, 23% (IQR16–43%) for PR and 9% (IQR 4–14%) for HER2 respectively. Discordance rates were higher if the metastatic site was a lymph node [ER: 42% (42–60%); PR: 48% (46–50%); HER2: 25% (11–38%)] as compared to all other sites of disease (e.g. bone marrow, lung, liver and brain) [ER: 25% (14-42%); PR: 36%(19-45)%; HER2: 13% (5-21%)]. Overall, receptor loss was more common than receptor gain across all metastatic sites. CONCLUSION This is the first systematic review we are aware of, that evaluates the extent, direction, and relationship of ER, PR and HER2 discordance between primary breast cancer and their paired metastases. Discordance varied from 10-60% depending on the receptor type and site of metastasis. When discordance occurs, loss of a biomarker is most common and most frequent with PR. These results could have important therapeutic implications in the treatment of recurrent and metastatic breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-07.

Abstract P1-13-14: Discordance of ER and PR status between primary and recurrent breast cancer in association with endocrine therapy

Abstract Background: Discordance in tumor receptor status between primary and recurrent tumors has been previously reported. Discordant ER/PR status has been used to differentiate recurrences from new primaries. We evaluated discordance rates of ER and PR expression between the primary and locoregional/contralateral recurrences and examined the relationship with adjuvant endocrine therapy (ET). Methods: We conducted a retrospective chart review of breast cancer patients (pts) treated with lumpectomy and adjuvant locoregional radiation (RT) from 1999-2005 at the Princess Margaret Cancer Centre. Tumor recurrence was classified as locoregional recurrence (LRR) for ipsilateral breast or lymph node recurrence, contralateral disease (CD) or distant recurrence. ER and PR were assessed by immunohistochemistry; positive if >10% tumor cells staining, borderline if 10% staining, and negative if <10% staining. Univariate analyses were applied to determine the association of receptor discordance with age, menopausal status, tumor grade, endocrine therapy or adjuvant chemotherapy. Results: All 441 pts had a lumpectomy with negative margins and RT, and had a median follow-up of 8.3 years. The median age at primary surgery was 57, and 67% of pts were postmenopausal. ET (tamoxifen and/or aromatase inhibitors) was initiated in 294 (84%) eligible patients. There were 24 (5.4%) pts with LRR, 20 (4.5%) pts with CD, and 28 (6.3%) with distant metastases. Nine pts with LRR also had distant disease, and 3 pts with CD also had distant disease. Among pts with LRR, 17 had ER/PR status available for comparison. Discordance rates for ER and PR were (1/17) 5.9% and (3/17) 17.6%, respectively, and the most common change was ER becoming positive, and PR becoming negative (75%). For pts with CD, 18 had ER/PR status available for comparison. Discordance rates for ER and PR were (7/18) 38.9% and (9/18) 50%, respectively. The most common change was ER becoming positive (86%), and PR becoming positive (75%). Distant disease receptor status was only available for two patients, therefore not included. The patient with LRR and discordant ER did not receive ET, while pts with LRR and discordant PR all received ET. Among patients with CD, 15% of patients with discordant ER status received ET, and 33% with discordant PR received ET. There was no statistically significant association between discordance rates in either LRR or CD groups and use of ET. Similarly, discordance rates were not associated with the other patient or tumor variables studied, or the development of distant metastases or death. Conclusions: Discordance of ER and PR expression was low in LRR and higher in CD, where the majority of changes were from negative to positive receptor status. Receptor discordance was not associated with endocrine therapy. This study suggests that the biology of LRR and CD may be different, and re-evaluation of receptor status could lead to additional treatment options becoming available from an endocrine standpoint. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-14.

Discordant ER, PR, and HER2 status between primary and metastatic breast cancer as prognostic factor.

1039 Background: The receptor status including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) of metastases may be different from that of the primary breast cancer. This discordance of receptor status may influence patient prognosis. We investigated discordance of receptor status between primary breast cancer and distant metastases in the same patients and its effect on prognosis. Methods: ER, PR, and HER2 status in metastases were available in 173 patients. The receptor status was compared between primary tumors and metastases. Tumors were classified as triple-negative breast cancer (TNBC) or non-triple-negative breast cancer (non-TNBC) according to receptor status and as concordant and discordant depending on the difference of receptor status between primary and metastatic breast cancer. Survival analysis was performed depending on concordant or discordant receptor status. Results: Discordance for ER, PR, and HER2 was 18.5%, 23.7%, and 10.4%, respectively. Concordant non-TNBC and TNBC between primary tumors and metastases was 69.9% and 17.9%, respectively. Discordant TNBC was 12.1%. On multivariate analysis, patients with discordant TNBC had unfavorable survival compared with patients with concordant non-TNBC (relative risk 2.544, 95% confidence interval, 1.220-5.303, p = 0.013). The median survival after recurrence was 41.8 months for patients with concordant non-TNBC, 20.7 months for patients with concordant TNBC, and 19.9 months for patients with discordant TNBC (p < 0.0001). Conclusions: The change of ER, PR, and HER2 status between primary and metastatic tumors occur and discordant TNBC is associated with poor survival.

Differences in the Receptor Status between Primary and Recurrent Breast Cancer - The Frequency of and the Reasons for Discordance

Objective: Receptor discordances between primary and recurrent breast cancer have been described for years, but only a few analyses have elucidated the factors that influence receptor changes. Methods: Explorative analyses of prospective data from a breast cancer database of a tertiary breast cancer unit. Results: Recurrent tumours that had expressed oestrogen (ER) and progesterone receptors (PR) and human epidermal growth factor receptor 2 (HER2) as primary tumours were negative for the respective receptor in 22.8, 41.4 and 40.8% of cases. ER, PR and HER2 expression was found in 19.8, 16.7 and 11.5% of recurrent tumours, although no expression had been observed in primary tumours. Receptor discordances in recurrent disease leading to different therapeutic approaches were noted in 126 of 411 patients (30.7%). In patients with tumours expressing primary ER and HER2, independent factors associated with discordance were endocrine therapy and treatment with trastuzumab. Conclusion: High rates of receptor discordance were found. The impact of factors that influence receptor changes is small so that no subgroup of patients with recurrent breast cancer should be excluded from biopsy. Whenever possible, a biopsy should be taken to confirm the diagnosis of a possible relapse as well as the receptor status of patients with breast cancer.

Abstract 108: Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status.

Abstract Whether coffee modulates response to endocrine therapy in breast cancer patients is currently unknown. The CYP1A2 and CYP2C8 enzymes contribute to tamoxifen and caffeine metabolism. The aim was to investigate the impact of coffee consumption on tumor characteristics and disease-free survival in relation to breast cancer treatment and CYP1A2 and CYP2C8 genotypes. Questionnaires regarding lifestyle were completed preoperatively by 592 patients in Southern Sweden. CYP1A2*1F and CYP2C8*3 were genotyped. Clinical data and tumor characteristics were obtained from patients’ charts, population registries, and pathology reports. Coffee consumption was categorized as low (0-1 cups/day), moderate (2-4 cups/day), or high (5+cups/day). The proportion of estrogen receptor negative (ER-) tumors increased with increasing coffee consumption (Ptrend=0.042). Low consumption was associated with higher frequency of discordant receptor status (ER+PgR-) OR 2.61 (1.59-4.29) compared to higher consumption. Median follow-up time was 4.92 years. Tamoxifen-treated patients with low consumption had significantly increased risk for early events compared to patients who consumed two or more cups/day, adjusted HR 2.50 (1.20-5.26). Low coffee consumption was also associated with higher risk for distant metastases in tamoxifen-treated patients with ER+ tumors, adjusted HR 2.43 (1.00-5.88). Low consumption combined with at least one CYP1A2*1F C-allele or CYP2C8*3 was associated with a high risk for early events in tamoxifen-treated patients, adjusted HRs 3.49 (1.54-7.90) and 6.14 (2.46-15.34), respectively. In conclusion, a moderate to high coffee consumption of caffeinated coffee was associated with significantly lower risk for early breast cancer events in tamoxifen-treated patients. This may be due to modification of the hormone receptor status or altered CYP enzyme activity. If confirmed, new recommendations regarding coffee consumption during tamoxifen-treatment may be warranted. Citation Format: Maria Simonsson, Viktoria Söderlind, Maria Henningson, Maria Hietala, Carsten Rose, Christian Ingvar, Helena C. Jernström. Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 108. doi:10.1158/1538-7445.AM2013-108

Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status

Whether coffee modulates response to endocrine therapy in breast cancer patients is currently unknown. The CYP1A2 and CYP2C8 enzymes contribute to tamoxifen and caffeine metabolism. The purpose was to investigate the impact of coffee consumption on tumor characteristics and risk for early events in relation to breast cancer treatment and CYP1A2 and CYP2C8 genotypes. Questionnaires regarding lifestyle were completed preoperatively by 634 patients in southern Sweden. CYP1A2*1F and CYP2C8*3 were genotyped. Clinical data and tumor characteristics were obtained from patients' charts, population registries, and pathology reports. Coffee consumption was categorized as low (0-1 cups/day), moderate (2-4 cups/day), or high (5+ cups/day). The proportion of estrogen receptor negative (ER-) tumors increased with increasing coffee consumption (p trend = 0.042). Moderate to high consumption was associated with lower frequency of discordant receptor status (ER + PgR-) OR 0.38 (0.23-0.63) compared to low consumption. Median follow-up time was 4.92 (IQR 3.01-6.42) years. Tamoxifen-treated patients with ER+ tumors (n = 310) who consumed two or more cups/day had significantly decreased risk for early events compared to patients with low consumption, adjusted HR 0.40 (0.19-0.83). Low consumption combined with at least one CYP1A2*1F C-allele (n = 35) or CYP2C8*3 (n = 13) was associated with a high risk for early events in tamoxifen-treated patients compared to other tamoxifen-treated patients, adjusted HRs 3.49 (1.54-7.91) and 6.15 (2.46-15.36), respectively. Moderate to high coffee consumption was associated with significantly decreased risk for early events in tamoxifen-treated patients and modified hormone receptor status. If confirmed, new recommendations regarding coffee consumption during tamoxifen treatment may be warranted.

Discordant hormone receptor and human epidermal growth factor receptor 2 status in bone metastases compared to primary breast cancer

Background. In patients with metastatic breast cancer, the evaluation of the biological characteristics of metastatic bone deposits may be a valuable adjunct in clinical practice. We assessed the discordance in expression levels for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) between primary tumor and bone metastases and its clinical impact on patient management. Material and methods. We retrospectively reviewed 363 CT-guided bone biopsies performed from January 1997 to December 2009. The proportions of ER, PgR and HER2 positive tumors at primary diagnosis and bone metastases, determined by IHC and/or FISH, were compared using McNemar's test. The impact of the biopsy reassessment on treatment choice was evaluated with Fisher's exact test. Results. We selected 109 metastatic breast cancer patients with histologically confirmed bone metastases. Among 107 assessable patients the overall discordance rate was detected in 22 (20.5%) and in 47 (43.9%) patients for ER and PgR, respectively, and in six of 86 assessable patients (6.9%) for HER2 status. The indication to change endocrine therapy occurred in 62% and 30% of patients with ER discordance and ER concordance, respectively (p = 0.01). The indication to change targeted therapy occurred in 67% and 8% of patients with HER2 discordance and HER2 concordance, respectively (p = 0.002). Conclusions. We confirm that biopsy of metastases, including bone metastases, for reassessment of biology should be considered, since it is likely to impact on treatment choice.

Discordance in receptor status between primary and recurrent breast cancer has a prognostic impact: a single-Institution analysis

Tumor phenotype may change during breast cancer progression. This study evaluates the prognostic impact of receptor discordance between paired primaries and recurrences. One hundred and thirty-nine patients underwent histological sampling of suspected breast cancer recurrence. All the pathology assessments [ER, PgR and human epidermal growth factor receptor 2 (HER2)] on both primaries and confirmed recurrences were performed at the same laboratory. A breast cancer recurrence was confirmed in 119 cases. Rates of discordance were 13.4%, 39% and 11.8% for ER, PgR and HER2, respectively. Ninety-two patients maintained the same tumor phenotype [i.e. the same hormone receptors (HR) and HER2 status], whereas 27 (22.7%) changed during progression. The loss of HR positivity and the loss of HER2 positivity resulted in a worse post-recurrence survival (P=0.01 and P=0.008, respectively) and overall survival (OS; P=0.06 and P=0.0002, respectively), compared with the corresponding concordant-positive cases. Tumor phenotype discordance was associated with worse post-recurrence and OS (P=0.006 and P=0.002, respectively); those cases who turned into triple-negative experienced the poorest outcome, respect to the concordant group (P=0.001, OS). We demonstrated for the first time an impact on OS of phenotype discordance between primary breast cancer and relapse. Among discordant cases, receptor loss resulted in the main determinant of poorer outcome.

Abstract P1-02-02: Receptor discordance in breast cancer recurrence: Is re-biopsy a necessity?

Abstract Background: Decision making on systematic treatment of patients with metastatic breast cancer is based on features like estrogen receptor (ER), progesterone receptor (PgR), and HER2 status assessed on the primary tumor. Recent prospective studies have investigated discordance in receptor status between the primary and metastatic tumor. We evaluated the discordance of receptor status between the primary and metastatic tumor and assessed the impact of re-biopsy on patient management. Methods: In breast cancer patients who underwent surgical resection of primary tumor and re-biopsy of metastatic tumor at Aichi Cancer Center hospital, we examined the discordance of ER status, PgR status, and HER2 status between the primary and metastatic tumor. For sampling of metastases, core needle biopsy (CNB), trans-bronchial lung biopsy (TBLB), or surgical resection was performed. And fine-needle aspiration biopsy was not used. The ER and PgR status were assessed using Allreds scoring system by IHC. These statuses were categorized as positive when the total score was more than two. HER2 expression status was tested by IHC and FISH. HER2 3+ by IHC, or 2+ and FISH positive were judged as HER2 positive. Results: 48 patients underwent re-biopsy from 2003 to 2012. Twenty-eight were loco-regional (local: 25, Supraclavicular: 2, Axilla: 1) and 21 were distant (Lung: 14, Liver: 6, Bone: 1). Discordance in ER, PgR, or HER2 between the primary and metastatic tumor were 6.2% (3/48), 16.7% (8/48), and 4.2% (2/48), respectively. One patient had discordance on re-biopsy with initial triple negative primary tumor (1/5, 20%). 11/48 patients (22.9%) changed the molecular subtype (Group A), and 37/48 patients (77.1%) did not change (Group B). Time to recurrence (TTR) was significantly longer in Group A than Group B (82.3 months vs 51.2 months, p = 0.04). No significant difference in re-biopsy techniques (CNB and TBLB vs surgical resection), metastatic lesions (loco-regional vs distant), and adjuvant therapy were observed between Group A and Group B. Conclusions: Our results show the low level of discordance for ER and HER2 between the primary and metastatic tumor. But re-biopsy should be considered in the patients with long TTR, since it is likely to impact treatment choice. Further study is needed to determine the value of re-biopsy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-02-02.

Abstract P2-10-27: No Discordant Receptor Status Results among 50 Paired Breast and Axillary Metastasis Core Biopsies when Pre-analytic Variation is Controlled.

Abstract Background: Discrepancy in Her2, estrogen receptor (ER), and progesterone receptor (PR) status among primary breast tumors and their axillary lymph node metastases has been reported in the range of 6–18%, leading to uncertainty as to the optimal sample for testing. It has been hypothesized this reflects heterogeneity within a given patient's tumor, however the pre-analytic conditions (particularly time to fixation and fixation duration) for samples in these studies were either nonuniform for the sample pairs or else unspecified. Altered tissue antigenicity rather than true biologic alterations in receptor expression may account for some the discrepancy reported in the literature. This study of paired primary and metastatic tumors processed in a uniform fashion attempts to address this issue. Design: Core biopsy samples from 50 primary invasive ductal carcinomas and their corresponding ipsilateral axillary lymph node metastases obtained at the same procedure, using the same core biopsy sampling device, fixed under the same conditions, stained on the same staining runs, and analyzed using digital image analysis comprise the study cohort. Patient demographics and tumor characteristics (from subsequent excision specimens or clinical imaging) were obtained from medical records. Results: Complete agreement in Her2, ER, and PR scores was seen among all paired samples. The mean age of the 50 women was 51.72 (27–86). Mean time to fixation was 2.55 minutes and the mean duration of fixation was 12.87 hours (6.4–29.7). The Her2 scores were 0 = 2, 1+ = 13, 2+ = 12, 3+ = 23. For 3+ cases, the mean tumor size was 3.47 cm, 44% were ER negative and the mean tumor grade was 2.61 (of 3). For 0/1+ cases, the mean tumor size was 3.86 cm, the mean tumor grade was 2.46 (38% were grade 3 and triple negative). The ER (Allred) scores were 0 = 17, 3 = 1, 4 = 1, 5 = 3, 6 = 9, 7 = 7, 8 = 12. For ER negative tumors the mean tumor grade was 2.76. For ER positive tumors the mean tumor grade was 2.39 including all 3 grade 1 tumors. Only minor discrepancies in Allred scores occurred between the paired samples; 5 with a difference of 1 (6–7, 7–8, 8–7, 7–6, 8–7); and one with a difference of 2 (8–6). The PR (Allred) scores were 0 = 24, 2 = 3, 3 = 4, 4 = 8, 5 = 2, 6 = 6, 7 = 1. For PR negative tumors the mean tumor grade was 2.75. For PR positive tumors the mean tumor grade was 2.40, including all 3 grade 1 tumors. Only minor discrepancies in Allred scores occurred between the paired samples; 4 with a difference of 1 (3–4, 4–5, 4–5, 6–7); and three with a difference of two (3–5, 4–6, 4–6). The mean age did not differ significantly by any receptor status. Conclusion: Under matched processing conditions, these 50 paired primary breast tumors and their corresponding lymph node metastases show congruent Her2 and ER staining results. This number of cases should have detected discrepancies in the range of 6–18%. Minor differences in staining intensity and %positive cells were noted, but none resulted in a positive vs negative mismatch. These data suggest the possibility that these minor differences, magnified through the influence of disparate fixation conditions, could account for the higher discrepancy rates reported in the literature. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-27.

Synchronous bilateral breast cancer (SBBC): Concordance of receptor status between right and left breast.

572 Background: This analysis was prompted by a patient who presented with SBBC who had and ER+, HER2- cancer in one breast and an ER-, HER2+ cancer in the other. Since both breasts have the same genetic background and environmental exposures, concordance should be virtually identical unless other factors are at play. Methods: SBBC was defined as bilateral cancer diagnosed concurrently or within 6 months of each other. Cases were identified retrospectively from patients seen at Rush University Medical Center. This analysis was limited to invasive SBCC (ISBBC). Estrogen receptor (ER) and Her2/neu (HER2) status were assessed according current ASCO/CAP guidelines. Correlation between ER and HER2 status was determined using κ statistic. Results: From January 1998 to December 2012, 33 cases of ISBBC were diagnosed. In 65% of cases synchronous disease was diagnosed concurrently. The average age at diagnosis was 56. The majority were multiparous and 79% post menopausal. About half of the patients (55%) had at least one first degree relative with a history of breast or ovarian cancer and 9% of the cohort had a deleterious mutation in BRCA1 or BRCA2. Infiltrating ductal was most common (74%) followed by infiltrating lobular (21%). 53% of breasts specimens also contained ductal carcinoma in situ. 68% of tumors were ER positive and 8% were HER2 positive. Concordance in ER status was seen in 73% of cases (kappa coefficient 0.14) and in HER2 status was 64% (Kappa coefficient 0.35). Conclusions: Despite identical hereditary and environmental exposure, some patients develop ISBBC cancers with discordant receptor status. While this is the exception, it suggests that other factors influence important tumor characteristics. [Table: see text]

MammaPrint Feasibility in a Large Tertiary Urban Medical Center: An Initial Experience

Background. The MammaPrint (MP) diagnostic assay stratifies breast cancer patients into high- and low-risk groups using mRNA analysis of a 70-gene profile. The assay is validated for assessment of patients with estrogen receptor positive or negative tumors less than 5 cm with 3 or fewer malignant lymph nodes. TargetPrint (TP) is an assay for assessing estrogen, progesterone, and HER2-neu receptor status based on mRNA expression. A potential limitation of these assays is that they require an evaluation of fresh tissue samples. There is limited published experience describing MP or TP implementation. Methods. Over 10 months, 4 breast surgeons obtained samples from 54 patients for MP/TP analysis. The samples were analyzed by Agendia Labs. The tumors were independently evaluated for receptor status using immunohistochemistry (IHC). Retrospectively, we identified patients who were assessed by MP/TP during this period. Patients who underwent OncotypeDx evaluation were also identified. Results. Of the 54 patients receiving MP, 4 were found ineligible for MP risk assessment because >3 lymph nodes were found to be malignant. Out of all eligible patients, 14/50 (28%) had samples whose quantity of tumor was not sufficient for analysis (QNS). Out of eligible patients with tumors <1 cm, 7/8 (88%) had QNS samples. 7/42 with tumors ≥1 cm (17%) had QNS samples. Nine patients had discordant receptor results when evaluated by IHC versus. TP. Of patients who also underwent OncotypeDx testing, 6/14 (43%) had discordant results with MP. Conclusions. This study indicates that using MP/TP assay is feasible in a tertiary care center but there may be utility in limiting MP testing to patients with tumors between 1 and 5 cm due to high likelihood of uninformative results in subcentimeter tumors. Further study is needed to explore the discordance between oncotype and MP results.