HER2 overexpression and correlation with other significant clinicopathologic parameters in Ivorian breast cancer women

Receptor status (ER, PgR and HER2) discordance between primary tumor and locoregional recurrence in breast cancer

Backgrounds Reproductive factors, such as age at menarche, parity, age at first birth, and breast feeding, are known to be associated with risk of breast cancer. Recent studies show the association between the reproductive factors and the molecular subtypes of breast cancer, especially in luminal-like subtypes. Nulliparity is known a risk factor of breast cancer, multiparity is considered a protective factor. However, pregnancy associated breast cancers show the high expression of HER2, Therefore, we hypothesized the number of birth (multiparity) is correlated with the over-expression of HER2. Methods We reviewed the database of 2,594 breast cancer patients were over 20 years of age, diagnosed between January 2000 and April 2017 at Korea University of Anam Hospital, Seoul, Korea. According the number of birth, nulliparous (the number of birth = 0; 271 patients), primiparous (the number of birth = 1; 420 patients) and multiparous (the number of birth≥2; 1,903 patients) groups were classified. Results The median age (range) of nulliparous, primiparous and multiparous groups was 43 (22-77), 48 (27-87) and 51 (26-86) years (P<0.001). In univariate analysis, the number of birth was associated with the expression of ER and HER2, nulliparous patients showed higher ER positivity (P=0.013) and multiparous patients showed higher HER2 overexpression (P=0.048). There was no association with PR and Ki-67 level. In logistic regression with age, the parity was negative correlation with ER positivity (OR 0.83, 95% CI 0.72-0.95, P=0.010) and positive correlation with HER2 overexpression (OR1.18, 95% CI 1.02-1.36, P=0.021) P=0.009) and multiparity was higher HER2 overexpression (OR 1.41, 95% CI 1.02-1.94, P=0.033). By subgroup analysis with menopausal status, there was statistically significance in only premenopausal women, not in postmenopausal women. In premenopausal women, the parity was negatively associated with ER positivity (OR 0.78, 95%CI 0.64-0.94, P=0.010) and multiparity was associated with HER2 overexpression (OR 1.72, 95%CI 1.12-2.63, P=0.013), there was no difference in HER2 overexpression between nulliparous and primiparous patients. Conclusion Parity was associated with ER and HER2 expression, multiparous patients were associated with ER negativity and HER2 overexpression, especially in premenopausal women. This suggests that pregnancy could affect risk of breast cancer, especially in HER2 positive breast cancer subtype (ER- HER2+ tumors), before menopause. We need further investigation and evaluation. Citation Format: Bae SY, Kim J, You JY, Jung SP, Bae JW. The association age-related parity and HER2 over-expression in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-09.

e21081 Background: Activation of the EGFR signaling can lead to the activation of MAPK, PI3K/AKT, the STAT pathway resulting in tumor growth, inhibition of apoptosis, cell migration and invasion. Tumor cells that over-express both EGFR and HER2, exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. HER2 overexpression has been found to correlate with a worse prognosis in breast cancer. However, the clinical significance of EGFR status in the HER2 positive early breast cancer remains to be evaluated. Methods: This study aims to evaluate EGFR status and its clinical impact in HER2 positive in early breast cancer. To address this issue, biomarker evaluation was performed using immunohistochemistry to semiquantitate estrogen (ER), progesterone (PR), HER2, and EGFR expression in the large cohort of cases with early breast cancers. Amplification of HER2 was confirmed by fluorescent in situ hybridization. Results: HER2 overexpression was found in 24.8% of early breast cancers with available tissue specimens from the primary tumor (236 of 952 cases) EGFR coexpression was identified in 10.6% of HER2 overexpressing early breast cancers. (25 of 236 patients) EGFR expression was significantly associated with age greater than 50 years (p = 0.032), absence of ER (p < 0.001) and PR (p = 0.028). The EGFR coexpression in patients with HER2 amplified early breast cancers demonstrated trends toward poorer overall survival (EGFR positive vs. EGFR negative, 86.1 months [95% confidence interval {CI}, 69.7-102.4 months] vs. 122.3 [C.I. 115.5-129.0], p = 0.109). Conclusions: EGFR co-expression was found in 10.6% of early breast cancer with HER2 overexpression. Our data demonstrated that simultaneous EGFR and HER2 expression is negatively correlate with hormone receptor expression in early breast cancer. The molecular significance of EGFR and HER2 co-expression in early breast cancer needs to be further investigated. No significant financial relationships to disclose.

BMI is an independent prognostic factor for late outcome in patients diagnosed with early breast cancer: A landmark survival analysis

Background: HER2 is the target of the therapeutic agents which are used to treat HER2-positive breast cancer. Reports have shown that the HER2 oncogene expression and its association with clinicopathological factors remain unclear in breast cancer (BC) patients. This study aimed to determine the correlation between HER2 expression and clinicalpathological characteristics of breast cancer in Vietnamese women. Methods:Between June 2016 and August 2018, paraffin-embedded specimens from 237 patients with primary invasive breast carcinoma in Hue University Hospital and Hue Center Hospital, Hue city, Vietnam were examined for pathological features. The gene expression of HER2, ER, PR and Ki-67 were determined by immunohistochemistry (IHC). The gene amplification of Her2 was assessed by using Dual color in situ hybridization (DISH). Results:The most frequent histological type was invasive carcinoma of no special type (NST) with 77.35%, the highest percentage of patients with Grade II was detected (59.36%), tumor size > 2 cm accounted for 71.31% of cases, Lymph node metastases were available in 57.86% cases. Most patients were diagnosed at stage II (59.18%). The majority of patients were classified as moderate Nottingham prognostic index (54.9%). Estrogen receptor and Progesterone receptor were positive in 53.16% and 50.63%, respectively. 76.37% of cases were in high expression group of Ki-67 (≥14%). HER2 IHC 2+, 3+ were accounted for 28.69% and HER2 gene amplification was detected in 31% cases. HER2 gene amplification and/or overexpression was significantly associated with cell proliferation index Ki67. Furthermore, HER2 gene expression tended to be more frequently found in tumors with large tumor size, high grade, high stage and high Nottingham prognostic index and confirmed their prognostic independent role. Conclusions: Our data indicated that HER2 gene expression was significantly correlated with cell proliferation index Ki67, but not significantly associated with another clinicopathological factors in breast cancer of Vietnamese women.

Introduction: HER2 overexpression is observed on CTCs in advanced BC (ABC), but their significance is not known. We aimed to describe clinical, pathologic, and molecular associations with HER2 overexpression on CTCs in ABC patients (pts). Methods: We conducted a retrospective analysis of data from ABC pts treated at Thomas Jefferson University and Northwestern University who had evaluation of CTCs and circulating tumor DNA (ctDNA). CTCs were enumerated with the CellSearch immunomagnetic kit (Menarini Silicon Biosystems), HER2 expression on CTCs was evaluated using the CellSearch CXC Kit, and ctDNA was analyzed using the Guardant360 NGS assay (Guardant Health). Associations with the presence of HER2+ CTCs were explored through univariate and multivariate logistic regression. Kruskal-Wallis testing evaluating HER2+ CTCs as a continuous variable was also conducted to confirm consistency of findings. Time to development of HER2+ CTCs was evaluated using Cox proportional hazards regression analysis. Results: Baseline CTCs were evaluated in 209 pts (10% stage III, 90% stage IV) of whom 41% had no detectable CTCs, 23% had 1-4 CTCs, and 36% had &amp;gt;5 CTCs (stage IV aggressive). Twelve percent had CTC clusters. At least 1 HER2+ CTC was seen in 33% of pts at baseline draw. Of 39 patients with HER2+ BC, only 18% had HER2+ CTCs. Of patients with HER2+ CTCs, 55% had hormone receptor positive BC, 28% had triple negative BC, and 18% had HER2+ BC. On univariate logistic analysis, BC subtype or HER2 status was not associated with the presence of HER2+ CTCs. IBC pts represented 52% of pts and were less likely to have HER2+ CTCs (OR 0.40 95% CI 0.19-0.84). Bone metastases were associated with an increased likelihood of HER2+ CTCs (OR 2.46, 95% CI 1.12-5.38); however, other sites of metastases and number of metastatic sites were not correlated with HER2+ CTCs. Aggressive disease features including &amp;gt;5 CTCs and presence of CTC clusters were strongly associated with HER2+ CTCs (OR 15.72, 95% CI 6.89-35.8 and 8.97, 95% CI 3.23-24.89, respectively). Of 168 pts with ctDNA analysis, ERRB2 aberrations were seen in 22% of pts and were significantly associated with HER2+ CTCs (OR of 3.74, 95% CI 1.45-9.63). On multivariate analysis, the associations with &amp;gt;5 CTCs and ERBB2 alterations in ctDNA remained statistically significant. The associations of HER2+ CTCs with bone disease, &amp;gt;5 CTCs, CTC clusters, and ERBB2 alterations in ctDNA, and the inverse relationship with IBC were consistent when HER2+ CTCs were evaluated as a continuous variable with Kruskal-Wallis testing. Among pts without HER2+ CTCs at baseline, the time to detection of HER2+ CTCs correlated with the presence of bone metastases (HR 3.40, 95% CI 1.14-10.19), &amp;gt;5 CTCs (3.77, 95% CI 1.33-10.70), and visceral disease (HR 3.00, 95% CI 1.07-8.44). Conclusions: HER2+ CTCs are common in ABC, independent of HER2 status of the tumor, and, in fact, common in the luminal BC. HER2+ CTCs were also strongly associated with CTC characteristics of aggressive disease with poor survival (CTCs clusters and &amp;gt;5 CTCs) and ERBB2 aberrations in ctDNA. Further studies will be investigating the role of HER2+ CTCs in endocrine resistance and the potential of anti-HER2 therapy in this unique CTC-defined setting. Citation Format: Shah AN, Gerratana L, Davis AA, Zhang Q, Zhang Y, Rossi G, Wang C, Strickland K, Yang H, Flaum L, Abu-Khalaf M, Behdad A, Ye Z, Platanias L, Gradishar WJ, Cristofanilli M. HER2-positive circulating tumor cells (CTCs) in advanced breast cancer (BC): A feature independent of BC subtype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-01-19.

Introduction The clinical importance of androgen receptor (AR) status in breast cancer is uncertain. The existing knowledge regarding the association of androgen receptor expression with clinicopathological factors of breast cancer is also limited. The main aim of this study is to evaluate the AR expression in breast cancer and to correlate it with the Ki67 proliferative index and other clinicopathological prognostic factors. Methods Theexpression of AR was evaluated in 192 invasive mammary carcinoma cases and the expression patterns were correlated with various clinicopathological prognostic factors such as age, tumor size, pathological primary tumor (pT) stage, nodal status,histological grade, estrogen receptor (ER) expression, progesterone receptor (PgR) expression, human epidermal growth factor receptor 2 (Her2) status, molecular subtype, and Ki67 labeling index. Immunohistochemistry was performed to assess AR, ER, PgR, Her2, and Ki67 expression. The clinicopathological data required for the analysis were obtained from the laboratory information system. Results Out of the 192 breast carcinoma cases, 139 (72.4%) showed AR-positive expression. The average age of the AR-positive cases was slightly higher than the AR-negative cases. AR-positive tumors tended to have a lower histological grade and positive ER and PgR expression. The expression of ARdid not correlate with tumor size, pT stage, nodal status, Her2 status, and Ki67 labeling index. Conclusion The expression of AR is noted in a significant proportion of breast carcinoma cases. AR expression may be related to good prognostic factors such as ER expression, PgR expression, and lower histologic grade. We also observed that AR expression did not have any association with the Ki67 proliferative index.

Background: ER expression in normal breast epithelium (NBR) is higher in women with a history of breast cancer (BC) compared to controls. In adjuvant setting, metanalysis showed effective Tamoxifen treatment was restricted to ER positive cancers. However, it is also known prophylactic oophorectomy (a form of estrogen suppression) significantly reduces the incidence of BC in BRCA1 carriers. This is in contrast with the 80% rate of ER negative tumors in BRCA1 patients. The aim of this study is to quantify ER expression in NBR away from tumor in women with BC and to correlate it with BC subtypes. Methods: 204 consecutive patients were identified for whom NBR away from tumor was available. 27 reduction mammoplasty (RM) tissues from women with no history of BC were used as controls. Tissue microarrays were constructed and slides were stained with ER and scanned using Aperio XT Scan Scope. Normal terminal duct lobular epithelium was manually circled on scanned images and annotations were recorded in separate digital layers. ER staining was quantitated in marked areas of the electronic image using an optimized scoring nuclear IHC algorithm (Aperio technologies, Inc., Vista, CA). Clinical information and tumor characteristics (menopausal status, ER, HER2 expression, grade, size, number of positive nodes, stage) were recorded based on pathology reports and tumor registry data. Results: The mean ER positivity in NBR was 16 ± 12.4 % (range: 0-5-5.7%) for all patients with BC, 20.8±13.9% for postmenopausal (n=74) and 13.7 ±10.9% for peri+ premenopausal (n=170) subgroups. ER positivity was higher in patients with BC compared to those undergoing RM with no history of BC. ER positivity in NBR did not vary by tumor size, positive lymph nodes status, tumor grade, or stage in post-menopausal, and pre + perimenopausal women. Older age at diagnosis was significantly associated (p&amp;lt;0.0001) with ER in NBR. In post- menopausal women ER expression in NBR was significantly higher in patients with ER negative or triple negative tumors. Estrogen receptor expression in normal terminal duct lobular units of post-menopausal women with breast cancer in relation to tumor subtypes. Postmenopausal (N=74) NMean % (SD)P ValueTumor ER Status 0.05 Negative1427.4 (13.9) Positive6019.3 (13.6) Tumor HER2 Status 0.34 Negative5721.8 (14.9) Positive817.7 (5.7) Tumor Triple Negative 0.05 No5319.7 (13.6) Yes1228.5 (14.7) HER2 status was not known in some cases and was excluded from statistical calculations. Conclusion: This computer assisted image analysis study confirms ER expression in NBR increases with age and menopausal status in women with BC. We report, for the first time, a significant association between ER expression in normal breast epithelium with ER negative and triple negative cancers in post-menopausal women. Our study suggests that ER expression in normal epithelium may play a role in development of hormone receptor negative breast cancers. Citation Format: H Evin Gulbahce, Cindy Blair, Carol Sweeney, Rachel Factor, Mohamed Salama. Digital quantification of estrogen receptor expression in normal breast in post-menopausal women with breast cancer and association with tumor subtypes [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 P5-02-06.

The objective of this study is to investigate how the change of hormone receptor (HR) and human epidermal growth factor receptor-2 (Her-2) status is related to patients' clinical features. One hundred ninety-three cases of patients treated at general hospital of PLA from 2000 to 2015 with advanced breast cancer were included. All patients developed recurrence that were re-biopsied and had complete pathological profile both at initial diagnosis and at relapse. HR status before and after relapse were available for all patients, while only 143 cases had Her-2 status at the two stages. The changes of ER, PR, and Her-2 status and their association with clincopathological factors and DFS were analyzed. The discordant rates of ER, PR, and Her-2 status between primary breast cancer and recurrent tumor were 34.2, 38.3, and 16.8%, respectively. At relapse, the rates of gain of ER and PR positivity were 10.9 and 13.5%, respectively; the rates of loss of ER and PR positivity were 23.3 and 24.9%. Loss of positivity was more frequent than gain of positivity (p ER < 0.000, p PR = 0.001). Among patients with Her-2 negative primary tumors, 15.4% acquired Her-2 positivity at relapse; and among Her-2 positive patients at initial diagnosis, 1.4% turned to Her-2 negative at relapse; gain of positivity was more frequent than loss of positivity (p < 0.000). Patients with tumor larger than 2cm in diameter were more likely to experience change of Her-2 status (25.0 vs 5.8%, p = 0.005). Yet, the change of ER/PR was not significantly associated with the size of primary tumor. Patients with ER positive recurrent disease and PR positive primary tumor had a DFS of more than 40months. Compared to patients who maintained PR negative, patients who gained PR positivity at relapse had significantly longer DFS by 8.5% (35.2 vs 26.7months, p = 0.024). Patients losing ER positivity at relapse had shorter DFS by 7.8months compared to those with stable ER positive tumors; patients gaining ER positivity experienced longer DFS by 8.3months; but both differences were not statistically significant. Loss of Her-2 positivity was associated with longer DFS by 13.8months as opposed to stable Her-2 status, without statistical significance. For patients with Her-2 negative primary tumor, the changes of Her-2 status were not associated with DFS. 34.2, 38.3, and 16.8% of breast cancer patients had their ER, PR, and Her-2 status changed after recurrence, and these changes of receptor status were associated with DFS to some degree. Gain of PR positivity at relapse was significantly correlated with longer DFS.

The state of HER-2 status

Background: HoR+ breast cancer (BC) is an heterogeneous disease, comprising 4 molecular subtypes (i.e.Luminal A [LumA], Luminal B [LumB]), HER2-Enriched [HER2E] and Basal-like [BL]). In HoR+ MBC, non-LumA subtypes appear to be associated with poorer survival outcome compared to LumA. Here, we present a meta-analysis to validate the prognostic value of IS inHoR+ MBC. Methods: We performed a systematic review and trial-level meta-analysis of all available prospective phase II/III trials in HoR+ MBC where the prognostic role of the IS was assessed in terms of progression-free survival (PFS) or time-to-progression (TTP), if the former was not available. Hazard ratios (HR) and 95% confidence intervals (CI) had to be available or computable. Subgroup analyses according to treatment, menopausal and HER2 status were also performed. The random-effect model of Der Simonian and Laird was applied. Heterogeneity was assessed through Cochran’s Q and I2. Funnel plot with Egger’s and Begg’s test for publication bias, multiple sensitivity analyses and risk of bias analysis were also conducted. Revman 5.4 and R 3.6.1 for MacOS X were used for statistical analyses. Tests were two-sided and the threshold for significance was set at p&amp;lt;0.05. Results: Overall, 360 records were screened from Pubmed and the Cochrane CENTRAL. Six randomized phase III trials of either endocrine therapy (ET)±target therapy (TT) or chemotherapy (only 1 study) and 1 single arm phase II trial of ET+TT were included, for a total of 2,536 patients (pts). 1,401 (55.2%) pts presented with non-LumA BC and 1,135(44.8%) presented with LumA BC. Within non-LumA BC, 574 (50.0%) were LumB, 280 (20.0%) HER2E and 62 (4.4%) BL. Compared to LumA, non-LumA tumors were associated with worse PFS/TTP (HR: 1.77, 95% CI: 1.54 - 2.05, p&amp;lt;0.001), independently of HER2 (HER2+ vs. HER2-negative, psubgroup difference[psub]=0.16), systemic treatment (ET vs. ET+TT vs. CT, psub=0.96) and menopausal status (pre vs. post, psub=0.12). Compared to LumA, each IS showed a statistically significant poorer outcome (psub=0.01), with LumB (HR: 1.46, 1.21 -. 1.77) showing a better prognostic effect than HER2E (HR: 2.39, 1.78 - 3.21) and BL (HR:2.67, 1.61 - 4.43). Heterogeneity was moderate (I2=61%, pheterogeneity[pH]&amp;lt;0.001). Sensitivity analyses confirmed the robustness of the main result, which did not significantly vary by removing the most influential cases sequentially or concomitantly. No publication bias was observed (Egger’s p=0.492; Begg’s p=0.719) and risk of bias analysis did not raise concerns regarding studies’ internal validity. Conclusions: Compared to LumA, the other subtypes are consistently associated with poorer survival outcome in HoR+ MBC, independently of HER2, treatment and menopausal status. Future trial designs in HoR+ MBC should consider this biological heterogeneity. Table 1.Included studies characteristicsStudy ReferenceTrial NameBreast CancerSubgroupMenopausal StatusTrial TypeTreatmentNon-Luminal ALuminal APrat A. et al. The Oncologist 2019BOLERO2HR+/HER2-negPostmenopausalRandomizedEverolimus+exemestane vs exemestane139122Jørgensen C.L.T. et al. Acta Oncologica 2014DBCGMainly HR+/HER2-negMixedRandomizedDocetaxel+gemcitabine vs docetaxel18684Prat A. et al. JAMA Oncol 2016EGF30008HR+/HER2+ and negPostmenopausalRandomizedLetrozole+lapatinib vs letrozole424377Prat A. et al. J Clin Oncol 2021MONALEESA 2HR+/HER2-negPostmenopausalRandomizedRibociclib+letrozole vs letrozole--Prat A. et al. J Clin Oncol 2021MONALEESA 3HR+/HER2-negPostmenopausalRandomizedRibociclib+fulvestrant vs fulvestrant618542Prat A. et al. J Clin Oncol 2021MONALEESA 7HR+/HER2-negPremenopausalRandomizedRibociclib+AI/TAM vs AI/TAM--Ciruelos E. et al. Clin Can Res 2020PATRICIAHR+/HER2+PostmenopausalNon-RandomizedPalbociclib+/-letrozole+trastuzumab3410 Citation Format: Francesco Schettini, Olga Martínez-Sáez, Nuria Chic, Fara Brasó-Maristany, Patricia Galván, Debora Martínez, Laia Paré, Maria Vidal, Barbara Adamo, Montserrat Muñoz, Tomás Pascual, Eva Ciruelos, Charles M Perou, Lisa A Carey, Aleix Prat. Prognostic value of intrinsic subtypes (IS) in hormone receptor-positive (HoR+) metastatic breast cancer (MBC): A systematic review and meta-analysis of prospective trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-08.

Over the last two decades we have seen a number of important advances in the biological underpinnings of breast cancer that have had a significant impact either directly or indirectly on the management and ultimately on the prognostic outcome of this disease. First, we now know that breast cancer is a heterogeneous disease made up of a number of unique subtypes each with its own natural history and associated prognostic outcome [1]. Second, some of these subtypes have specific targets (including ER and HER2) that have associated unique targeted therapeutic agents that significantly impact the natural history of this disease [2]. Third, data indicate that these targets are not static with approximately 30% of tumors showing discordance in the expression of hormone receptor or HER2 between the primary and associated metastatic tumor [3]. The therapeutic implications of such discordance have understandably resulted in most oncologists seeking to biopsy metastatic sites whenever possible. Despite these advances we have a long way to go with current research focusing on looking for biomarkers that have a dual prognostic and predictive function. An ideal biomarker being one able to accurately predict for early recurrence or progression of disease, provide information to guide therapeutic decisions, reliably predict response to specific treatment, provide an easy platform for testing of markers such as ER and HER2 at various time points along a cancer history continuum, and allow for the identification of unique targets that would help specific drug development. Circulating tumor cells (CTCs) is one such biomarker that has been actively investigated over the last decade and has shown promising results in a number of malignancies including breast cancer. The presence of epithelial cells in the circulation that are similar in appearance to primary tumor cells was first described by TR Ashworth about 150 years ago in a woman with metastatic breast cancer [4]. These detectable cancer cells are CTCs that represent a rare cell population in the circulation usually representing less than 10 cells/ml. These cells can originate from either the primary or metastatic tumor tissue and require special enrichment techniques for their detection [5]. These techniques are based either on the biological properties of the CTCs such as protein secretion or cell surface antigen expression or are based on the physical characteristics of these cells such as presence of electric charges, size of the cell, density or deformability. Currently the only FDA approved CTC enumeration Using circulating tumor cells to guide therapy in breast cancer: could this replace biopsies?

10516 Introduction: Tamoxifen (TAM) remains widely used in the treatment of all stages of breast cancer. Although the majority of hormone receptor (HR) positive tumors respond to TAM, many of these breast cancers will develop resistance resulting in disease recurrence or progression. Over-expression of HER2 appears to play a role in de novo tamoxifen-resistance. We have demonstrated previously that HR-positive breast cancers exposed to selective estrogen receptor modulators (SERMs), such as tamoxifen, in vivo continue to express HR but have an increase in the expression of HER2 (O'Regan Clin Cancer Res 2006). However the above finding has not been confirmed in patient samples. Materials and Methods: We evaluated 30 paired tissue samples from patients with HR positive tumors whose cancers recurred. The first tissue sample is from diagnosis and the paired sample comes from metachronous metastatic disease. Results: The median age of diagnosis was 56 (29–96). Seven patients presented with stage I disease, 11 with stage II and nine with stage III3, and three patients had missing staging information. The median time to recurrence was three years. The expression of ER decreased from diagnosis to recurrence from 79% to 59% (p=0.035). PR also decreased between diagnosis and recurrence from 34% to 22% (p=0.13). HER2 score was 2 or 3 in 27% of samples at diagnosis and in 53% at time of recurrence (p=0.01). These cancers did not have HER2 gene amplification. Conclusions: These results confirm our in vivo findings that over-expression of HER2 plays a significant role in acquired TAM- resistance. We have previously demonstrated that trastuzumab inhibits growth of SERM-resistant breast cancers in vivo despite the fact that these cancers did not have HER2 gene amplification. Taken together, our findings suggest that trastuzumab should be examined clinically in patients with TAM-resistant metastatic breast cancer, as they may be particularly sensitive to inhibition of HER2-driven pathways. No significant financial relationships to disclose.

IntroductionEndocrine therapy is the most important treatment option for women with hormone receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified.Materials and methodsThe expression of HER2, p53, and Ki67 was examined by immunohistochemistry in primary breast tumour specimens from 73 metastatic breast cancer patients who received first-line treatment with endocrine therapy on relapse, and analysed to determine whether expression of these molecular markers affected the response to endocrine therapy.ResultsOf the 73 invasive ductal carcinomas, 12.3%, 21.9%, and 35.6% were positive for HER2 overexpression, p53 protein accumulation, and Ki67 expression, respectively. All patients received endocrine therapy as first-line treatment for metastatic breast cancer; 34 patients (46.6%) responded. Patients with primary breast tumours that had p53 protein accumulation and Ki67 expression showed significantly more resistance to endocrine therapy (P = 0.0049 and P = 0.024, respectively). There were also tendencies for HER2 overexpression to correlate with resistance to endocrine therapy, but this did not reach significance. p53 protein accumulation and HER2 overexpression significantly reduced post-relapse survival (P < 0.0001 and P = 0.001, respectively), and these factors were also statistically significant in a multivariate analysis.ConclusionThese data suggest that p53 protein accumulation is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in hormone receptor-positive metastatic breast cancer.

Breast cancer is a heterogeneous disease that represents a major public health problem. The immunohistochemical determination of breast cancer subtypes with regard to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) status can contribute to improved selection of therapy and patientcare. The purpose of this study was to determine the prevalence of the molecular breast cancer subtypes and to assess their associations with classical clinicopathologic parameters for better therapeutic decisions in women with breast cancer in the Ivory Coast. Formalin- fixed and paraffin-embedded blocks of patients diagnosed with primary breast carcinoma were subjected to immunohistochemical assay for the assessment of ER/RP and HER2 expression. The one-way analysis of variance evaluated the difference between breast cancer subtypes and mean age of patients. The Chi-square Test was used to compare standard clinicopathologic prognostic parameters with tumor subtypes. Among 302 patients, 57% were premenopausal and 43% were postmenopausal. The invasive ductal carcinoma not otherwise specified (IDC NOS) (82.8%) was the most frequent histological type, and the tumor grade 2 (56%) was predominant followed by grade 3 (20.9%). The proportion of positivity of ER, PR, and HER2 was 56%, 49%, and 15.6%, respectively. Half of patients of this study (51.6%) had luminal A breast tumor type followed by TN (32.1%). Other subtypes were luminal B (10.1% ) and non-luminal HER2+ (6.3%). The findings of the present study are in line with the literature and should assist in management of breast cancer in our country.