Overall Survival in Metastatic Breast Cancer Patients: Real-World Data from 1,000 Patients Treated at the NCT Heidelberg between 2014 and 2022

BACKGROUND: Breast cancer (BC) that is metastatic at initial diagnosis (i.e. de novo metastatic or stage IV) has not been well described, especially in the general population. OBJECTIVE: To describe demographics, tumor characteristics and survival in a population-based cohort of patients with de novo metastatic BC (MBC). METHODS: We studied all 6268 de novo MBC cases diagnosed in California women between 1/1/2005 and 12/31/2011, as reported to the California Cancer Registry. Molecular subtypes were classified according to HER2 and hormone receptor (HR, based on estrogen and progesterone receptor) status. Median overall survival (OS) was calculated by Kaplan-Meier methods. Cox proportional hazards regression was used to assess independent predictors of OS. RESULTS: 5% of all newly diagnosed BC were metastatic, representing 6% of all newly diagnosed HR+/HER2+, 8% of all HR-/HER2+, 4% of all HR+/HER2- and 6% of all triple negative BC (TNBC). Compared to patients with early BC, MBC patients were of similar age (mean age at diagnosis, (interquartile range): 61,(51-71) vs. 60, (50-70) years)). They were slightly more likely to be black (10% vs. 6%) or Hispanic (19% vs. 17%) but substantially more likely to be unmarried (56% vs. 40%), to live in neighborhoods of the lowest socioeconomic quintiles (39% vs. 29%), and to have public (e.g., Medicaid) or no insurance (39% vs. 21%). Most MBC patients presented with large tumors; however, 13% of patients had tumor sizes 2 cm or less, compared with 60% of patients with early BC (of TNBC: 15% MBC vs. 44% early BC were ≤2 cm). A minority of patients with de novo MBC received breast surgery (39%), with 24% receiving full or partial mastectomy, 9% lumpectomy, 3% bilateral mastectomy and 3% other/unknown surgery . 64% of de novo MBC patients received chemotherapy and 33% received radiation. Median survival after MBC diagnosis was 27 months (mos), but varied substantially by patient characteristics including age (<40: 40 mos, 85+: 8 mos), race/ethnicity (Asian: 34 mos, black: 16 mos), and neighborhood socioeconomic quintile (lowest: 20 mos, highest 34 mos) and molecular subtype (HR+/HER2+: 45 mos, TNBC: 12 mos). In a multivariate Cox model including all available variables, TNBC was the most important predictor of death (Hazard Ratio 2.8, 95% CI: 2.4-3.3 vs. HR+/HER2+). Other significant and important predictors included HR-/HER2+ subtype (Hazard Ratio 1.6, 95% CI: 1.3-18 vs. HR+/HER2+), being unmarried, living in low socioeconomic status neighborhoods, and high tumor grade status. CONCLUSIONS: In this large diverse population, de novo MBC was more likely to be diagnosed for certain breast cancer subtypes, and among minority and underserved women (black or Hispanic race, low socioeconomic neighborhood, no or public health insurance) that may have contributed to the detection of their tumor only after it had metastasized. A high proportion of patients with MBC are not treated surgically, but most receive chemotherapy. Median survival remains poor, with worse survival strongly associated with tumor biology (triple negative and HR-/HER2+ molecular subtypes) and patient characteristics indicative of low socioeconomic status. Citation Format: Christina A Clarke, Laura Chu, Li Tao, Lisa Wang, Lisa Moy, Melissa Brammer, Chunyan Song, Marjorie Green, Scarlett Lin Gomez. Characteristics of de novo metastatic breast cancer in California, 2005-2011 [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 P3-07-26.

Background The human epidermal growth factor receptor 2 (ERBB2) can be altered by somatic mutations (with/without ERRB2 amplification) that likely drive tumorigenesis. Here, we present the first study that thoroughly investigates the behavior of patients with ERBB2 mutated tumors in a large unselected cohort of metastatic breast cancer (MBC) patients. Patients and Methods We included retrospectively all MBC patients with sufficient tumor material available, independent of hormone receptor or ERBB2 amplification status, diagnosed between 2000 and 2015 at the Multidisciplinary Breast Center of University Hospitals Leuven. Genomic DNA extracted from primary breast tumors was subjected to deep targeted re-sequencing using an assay covering 5 exons (exons 8, 17, 19, 20 and 21) known to accumulate ERBB2 hotspot mutations. Clinical characteristics, treatment response and outcomes (excluding bilateral BC) were compared between patients with and without ERBB2 mutations. Results We established and validated a research use only next-generation sequencing assay across five exons of ERBB2. Somatic ERBB2 mutations with an allelic frequency of ≥5% in at least one independent analysis, were observed in 1.8% (13/721) of MBC patients. MBC patients with ERBB2 mutant primary tumors appear to have similar patient and tumor characteristics (TNM stage, grade, and receptor and HER2 status) compared to non-mutant patients and ERBB2 mutations occur in all molecular subtypes (7 ER+/HER2-, 4 HER2+, 2 triple negative). However, we see a small trend towards enrichment in the invasive lobular carcinomas (ILC) in the ERBB2 mutant patients vs. the non-mutant patients (4/13 (31%) vs. 97/695 (14%), p=0.086). ER+ patients with an ERBB2 mutant tumor who received first line aromatase inhibitor (AI) (n=3) had a worse median time to progression (TTP) compared to non-mutant patients (n=156) (TTP 103 vs. 311 days, p=0.04), AI use in any line had also a worse TTP (n=8 vs. 376; TTP 74 vs. 213 days, p=0.006). TTP was not significantly different for other standard therapies, but numbers were small. Median distant disease free survival (DDFS) defined as time from primary diagnosis to first metastasis, was slightly shorter for ERBB2 mutant tumors (n=9 vs 514; DDFS 1.4 vs. 2.9 years, p=0.066). However, in ER+/HER2- ERBB2 mutant tumors, median DDFS was significantly shorter in non-mutant patients (n=5 vs. 328; DDFS 0.8 vs. 4.0 years, p=0.02). Median overall survival (OS) after diagnosis of MBC was numerically lower for mutant patients in all subtypes vs. non-mutant patients (n=11 vs. 669; OS 1.1 vs. 2.3 years, p=0.457), and in ER+/HER2- disease (n=6 vs. 431; OS 1.0 vs. 2.9 years, p=0.07). Conclusion In our large MBC cohort, patients with ERBB2 mutant tumors appear to have similar tumor and patient characteristics as ERBB2 non-mutant tumors. ERBB2 mutations do not seem to occur more or less often in specific breast cancer subtypes except for a slight increase for ILC. In ER+/HER2- MBC, patients with ERBB2 mutant tumors appear to be adversely prognostic; having a shorter DDFS after early breast cancer treatment, and in metastatic disease, they respond worse on AI and have a trend for worse OS compared to non-mutant cases. Citation Format: Jongen L, Floris G, Lambrechts D, Laenen A, Neven P, Mann G, Cutler Jr. RE, Lalani AS, Wildiers H. Identification, clinical characteristics and treatment outcomes of somatic human epidermal growth factor receptor 2 (ERBB2) mutations in metastatic breast cancer patients [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 P3-04-03.

286P - The Effect of Molecular Subtypes on Disease-Free Survival in 3358 Turkish Women with Primary Breast Cancer

Clinicopathological features and prognoses of very young patients (≤35 years) with breast cancer: a retrospective population-based study in China.

Background: This study aimed to identify the association of local surgery of the primary tumor in metastatic breast cancer (MBC) patients with overall survival (OS) and prognostic factors. Patients and Methods: Patients with primary MBC (1990-2006) were included in our retrospective analysis (n = 236). 83.1% had surgery for the primary tumor. OS was evaluated using Kaplan-Meier estimates. Predictive factors for OS were determined. Results: Median follow-up was 123 months for all patients still alive at the time of analysis. In univariate analysis, patients with surgery of the primary tumor had significantly prolonged OS (28.9 vs. 23.9 months). Within the surgery group, patients with MBC limited to 1 organ system had a better outcome (39.3 vs. 24.9 months), as did asymptomatic patients. Independent risk factors for shorter OS were hormone receptor negativity, symptoms, and involvement of ≥ 1 organ system. Conclusion: Patient selection for local therapy was confounded by a more favorable profile and a lesser tumor burden before surgery, which might implicate a bias. Nevertheless, our univariate results indicate that local surgery of the primary tumor in MBC patients could be considered as part of the therapeutic regimen in selected patients. However, larger patient numbers are needed to prove these findings in the multivariate model.

A cut-off of 5 circulating tumor cells (CTCs) per 7.5 ml of blood in metastatic breast cancer (MBC) patients is highly predictive of outcome. We analyzed the relationship between CTCs as a continuous variable and overall survival in immunohistochemically defined primary tumor molecular subtypes using an artificial neural network (ANN) prognostic tool to determine the shape of the relationship between risk of death and CTC count and to predict individual survival. We analyzed a training dataset of 311 of 517 (60%) consecutive MBC patients who had been treated at MD Anderson Cancer Center from September 2004 to 2009 and who had undergone pre-therapy CTC counts (CellSearch(®)). Age; estrogen, progesterone receptor, and HER2 status; visceral metastasis; metastatic disease sites; therapy type and line; and CTCs as a continuous value were evaluated using ANN. A model with parameter estimates obtained from the training data was tested in a validation set of the remaining 206 (40%) patients. The model estimates were accurate, with good discrimination and calibration. Risk of death, as estimated by ANN, linearly increased with increasing CTC count in all molecular tumor subtypes but was higher in ER+ and triple-negative MBC than in HER2+. The probabilities of survival for the four subtypes with 0 CTC were as follows: ER+/HER2- 0.947, ER+/HER2+ 0.959, ER-/HER2+ 0.902, and ER-/HER2- 0.875. For patients with 200 CTCs, they were ER+/HER2- 0.439, ER+/HER2+ 0.621, ER-/HER2+ 0.307, ER-/HER2- 0.130. In this large study, ANN revealed a linear increase of risk of death in MBC patients with increasing CTC counts in all tumor subtypes. CTCs' prognostic effect was less evident in HER2+ MBC patients treated with targeted therapy. This study may support the concept that the number of CTCs, along with the biologic characteristics, needs to be carefully taken into account in future analysis.

277 Background: The real-world effectiveness of third- or later-line (3L+) therapies in patients (pts) with HER2-positive gastric cancer remains unknown. We report a multicenter, retrospective, observational study at 20 centers in Japan to investigate the outcomes of 3L+ therapy in pts with HER2-positive advanced gastric/gastroesophageal junction (G/GEJ) cancer previously receiving trastuzumab (UMIN000040853). Methods: Pts aged ≥20 years with HER2-positive advanced G/GEJ cancer who were previously treated with trastuzumab and newly initiated on nivolumab, irinotecan, or trifluridine/tipiracil monotherapy as 3L+ therapy (Sep 2017 to Mar 2020) were evaluated for overall survival (OS), progression-free survival (PFS), duration of response (DOR), time to treatment failure (TTF), objective response rate (ORR), and disease control rate (DCR). An exploratory analysis for factors affecting OS was conducted using a multivariate Cox regression model, with HER2 status as a covariate. Results: The overall analysis population was 117 pts (median: age, 71 years; number of prior treatment lines, 2; days since the initiation of first-line treatment, 431 days). Median (95% confidence interval) OS, PFS, and TTF were 6.2 months (4.5–8.0), 1.9 months (1.5–2.3), and 1.8 months (1.5–2.2), respectively, at a median follow-up of 150 days. Outcomes by treatment groups are shown in the Table. ORR and DCR in 100 pts with evaluable target lesions were 9.0% and 32.0%, respectively, and median DOR was 8.4 months. A higher neutrophil-lymphocyte ratio (≥2.540), Glasgow prognostic score (≥1), ECOG PS (≥2), and hepatic metastasis significantly impacted OS. Conclusions: The real-world effectiveness of 3L+ therapies was limited in this study. New HER2 treatment agent is expected to improve outcomes in pts with HER2-positive G/GEJ cancer.[Table: see text]

The prognostic value of harmonized pretreatment volume-based quantitative fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters in metastatic breast cancer patients was investigated. Records of 65 stage IV breast cancer patients, including 29 estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 23 HER2-positive, and 13 triple-negative cases, from four different institutions were retrospectively reviewed. Harmonized standardized uptake value (SUVmax) of the primary tumor (pSUVmax), highest SUVmax of all malignant lesions (wSUVmax), whole-body metabolic tumor volume (WB MTV), and whole-body total lesion glycolysis (WB TLG) shown by pretreatment 18F-FDG PET/CT imaging were calculated. Cox proportional hazards model and log-rank test results were used to evaluate relationships among clinicopathological factors, volume-based quantitative 18F-FDG PET/CT parameters, progression-free survival, and overall survival (OS). Disease progression occurred in 54 patients and 28 died during a median follow-up period of 52.5 months (range 2.6-133.6 months). Univariate analysis of all cases showed associations of negative ER and progesterone receptor (PR) status (P=0.0025), and high T/N stage (P=0.037/P=0.019), pSUVmax (P=0.049), WB MTV (P=0.021), and WB TLG (P=0.0010) with significantly shorter OS. Multivariate analysis confirmed negative ER and PR status (hazard ratio [HR]: 6.42, 95% confidence interval [CI]: 2.27-19.38; P=0.0054), high T stage (HR: 5.10, 95% CI:1.96-18.61, P=0.0064) and WB TLG (HR: 4.69, 95% CI:1.67-12.79, P=0.049) as independent negative OS predictors. In two groups of ER-positive/HER2-negative and triple-negative, WB TLG had a significant association with death (P=0.021 and P=0.037, respectively) on univariate analysis. In a HER2-positive group, no independent negative OS predictors were observed. In metastatic breast cancer patients, harmonized pretreatment quantitative volume-based 18F-FDG PET/CT parameters, especially whole-body TLG, are potential surrogate markers for prognosis.

Background: Several breast cancer studies have indicated that the expression of predictive markers including HER2, estrogen (ER) and progesterone (PR) receptor can change during the course of disease. Therefore, reassessment of these markers at the time of disease progression might help to optimize treatment decisions. In this context, characterization of circulating tumor cells (CTCs) could be of relevance in the future, since metastatic tissue may be difficult to obtain for repeated analysis. Therefore, the present study compared the HER2/ER/PR expression profile of primary tumor and metastases, primary tumor and CTCs as well as metastases and CTCs. Patients and Methods: A total of 84 patients with metastatic breast cancer from eight German University Breast Cancer Centers were enrolled in this study. Blood was obtained at the time of first diagnosis of metastatic disease or disease progression and analyzed for CTCs (EpCAM, MUC1 and HER2 transcripts) using the AdnaTest BreastCancer (AdnaGen AG, Germany). Expression of the ER and PR receptor was assessed in an additional RT-PCR. The analysis of PCR products was performed by capillary electrophoresis on the Agilent Bioanalyzer 2100. Results for HER2 status on CTCs was additionally assessed using the FDA-approved CellSearch® assay. Results: Applying the AdnaTest, the overall detection rate for CTCs was 43% (36/84 patients) with the expression rates of 50% for HER2 (18/36 patients), 14% for ER (5/36 patients) and 8% for PR (3/36 patients), respectively. Comparisons of expression profiles on CTCs with those on tissue samples were only performed in CTC-positive patients. Primary tumors and CTCs displayed a concordant HER2, ER and PR status in 59% (p = 0.262), 39% (p = 0,51) and 44% (p = 0,62) of cases, respectively. For metastases and CTCs, the concordance values were 67% for HER2 (p = 0.04), 43% for ER (p = 0.16) and 46% for PR (p = 0.6), respectively. Interestingly, in 26/36 patients with ER/PR-positive metastases, CTCs were positive in 27% of cases and in the other 10 ER/PR-negative patients, the concordance was 100% (p = 0.066). Applying the CellSearch® assay as a gold standard for CTC detection, the CTC-positivity rate was 53% (42/79 patients) with the expression rate of 29% for HER2 (12/42 patients). No significant concordance was found when HER2 status on CTCs was compared with HER2 expression on primary tumors (p = 0,28) and on metastases (p = 0,44). In addition, primary tumor and metastases displayed a concordant HER2, ER and PR status in 80% (p = 0.0013), 91% (p = 0.000002) and 89% (p = 0.000006) of cases, respectively. Conclusion: Although we could show that primary tumors and their metastases showed a highly significant concordance of the expression of predictive markers, characterization of CTCs could be of relevance in case metastatic tissue may be difficult to obtain. Here we demonstrate that the molecular detection of a HER2 overexpression in CTC using the AdnaTest is able to significantly predict the HER2 status on metastases. More detailed analysis of ER/PR expression rates in tissue samples might help in addition to decide whether CTCs might be a useful tool for treatment decisions based on each expression profile. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-3.

Introduction: The urokinase plasminogen activator (uPA), its receptor uPAR and serine protease inhibitors PAI-1 or PAI-2 play a key role in tissue membrane remodeling and invasion of basement membranes by induction of a fibrinolytic pathway. Earlier studies reported that uPA and PAI-1 protein levels assist in prediction of breast cancer response to chemotherapy. Our goal is to develop molecular signatures of candidate genes and identify novel relationships with these four protein biomarkers that demonstrate clinical utility for assessment of breast carcinoma outcomes. Methods: The retrospective study used de-identified tissue biopsies from primary breast cancers on which biomarker and clinical outcomes were stored in an IRB-approved Database. ELISA analyses of uPA, uPAR and PAI-1 performed using IMUBIND kits (American Diagnostica Inc.) used cutoff values previously reported. Estrogen (ER) and progestin receptor (PR) assays were performed either by EIA (Abbott Labs) or by radioligand binding (NEN/DuPont). Relative expression levels of 22,000 genes were determined by microarray using RNA extracted and amplified from Laser-Capture Microdissection (LCM) procured breast carcinoma cells. Univariable and multivariable Cox regression analyses, Kaplan-Meier plots, Violin and scatter grams were performed by R Studio version 3.4.1. External validation of gene subsets derived were performed with SurvExpress. Results: uPA and PAI-1 protein content of a carcinoma were predictive of overall survival (OS). Examination of biomarker gene expression by Violin plots revealed that either ER- or PR- breast cancers expressed elevated levels of UPA, UPAR and PAI2 compared to that of ER+ or PR+ carcinoma cells. Scatter grams suggested an inverse relationship between ER/PR protein levels and expression of UPA, UPAR and PAI2. Univariable Cox regression analyses indicated that PAI2 expression was associated with progression-free survival (PFS) and OS while UPA and PAI1 expression was only associated with OS with a p value < 0.3 (selected as the discovery limit). When carcinomas were sorted by biomarker levels, qPCR expression of RERG and NQO-1 were elevated in uPA- lesions while CD34 and EDG-1 were elevated in uPAR- cancers. However, ERBB4 expression was elevated in PAI-1+ carcinomas. Multivariate Cox regression, performed with backward conditional selection using microarray data with ER or PR status revealed clinically relevant genes for PFS and OS. SurvExpress, an online tool, validated gene subsets externally. Conclusions: Use of LCM-procured breast carcinoma cells in a nondestructive manner uncovered relationships between gene expression and either uPA, uPAR, PAI-1 or PAI-2 protein content of a lesion to reveal candidates for predicting clinical outcomes. Certain of these gene subsets appear related to patient prognosis when considered with ER/PR status of the carcinomas. Citation Format: Seth B. Sereff, Michael W. Daniels, James L. Wittliff. Expression of genes of the uPA system from LCM-procured breast carcinoma cells and their relationships with clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1610.

Background and objectives: Analysis of gene expression has identified various molecular subtypes. These molecular subtypes defined by immunohistochemistry expression of estrogen receptor (ER) or progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2) : luminal A, luminal B, basal cell-like and HER2-expresing. This study evaluates clinical and pathologic features and survival of the four molecular subtypes in premenopausal and postmenopausal women from northeast China. Methods: A retrospective analysis of 1214 women diagnosed with breast cancer from 2000 to 2007 in Breast Surgery Department, First Hospital of Jilin University. Four molecular breast cancer subtypes defined as: luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-), and HER2-expresing, (ER-, PR-, and HER2+). We examined the prevalence of breast cancer subtypes and analyzed the associations with patient clinicopathologic features: age, menopausal status, tumor size, lymph node status, stage of cancer at diagnosis, histological characteristics, and breast cancer-specific survival. Results: Among the all cases, the luminal A subtype was the most prevalent in our study sample (56.0%) compared with basal -like (18.5%), luminal B (13.7%), and HER2-expresing subtypes (11.8%). The four molecular subtypes differed significantly by menopausal status (P=0.011), age (P<0.001) and lymph node status (P<0.001). Luminal A subtype was more likely to with Stage II breast cancer (P<0.001) and most present with size of 2.1-5 cm (P<0.001). The luminal B and the HER2-expresing subtypes presented an increased association with more aggressive clinical course when compared with others subtypes. The estimated median follow-up period for all subjects was 54 months (range, 1 month to 120 months). The 8-year overall survival for all patients was 81.3% (95%CI, 79.4-83.7) and disease-free survival was 77.8% (95% CI, 75.4-79.9). The Kaplan-Meier curve showed breast cancer-specific survival differed significantly among the molecular subtypes (P < 0.03), with the luminal B and HER2-expresing subtypes having the poorest outcome. Conclusion: Luminal A breast tumor appeared the better outcome than the others three subtypes and the shortest survival was HER2-expresing subtype. The poor clinical outcomes of luminal B subtype with women from northeast China were different from those of Western women could contribute to the poor prognosis of breast cancer observed in this cohort of patients and some of them couldn't accept molecular targeted therapy with trastuzumab by poor economic situations. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-08.

IntroductionAromatase inhibtors (AI) are recommended in the adjuvant management of oestrogen receptor positive (ER+) early breast cancer (EBC). With no consensus regarding the decision between starting AIs upfront or after an initial period of tamoxifen identifying factors that predict early recurrence on tamoxifen would help guide clinicians to choose the appropriate treatment strategy. HER2 overexpression and progesterone receptor (PR) negativity are poor prognostic factors in ER+ EBC. We aim to investigate whether these factors are particularly strong predictors of early recurrence.MethodsER, PR and HER2 receptor analysis was performed on a retrospective cohort of women with symptomatic early breast cancer diagnosed between 1980 – 2002 who received adjuvant tamoxifen. The primary endpoint was disease free survival (DFS) and recurrence was defined as invasive disease at any site as determined by histopathology or a high index of suspicion upon radiological investigation. Univariate and multivariate time dependent Cox regression analysis, using ≤2.5yrs as the time dependent term, were performed. The pattern of recurrence over the first five years was charted using an Epanechnikov smoothing function.ResultsA total of 402 tumours were confirmed as ER+ and therefore included in the analysis. The median age of the cohort was 63yrs with a median follow up of 6.1yrs. 241 (60.0%) of the tumours were PR+ and 51 (12.7%) were HER2 positive. On univariate analysis tumour size, grade, nodal status and PR status were significantly associated with DFS (p <0.001; except PR status, p = 0.002). In univariate time dependent analysis only HER2 status had a significant interaction with the time dependent term (p = 0.004) with a hazard ratio (HR) of 2.78 (95% CI 1.47-5.26) for DFS within the first 2.5yrs following diagnosis and a HR of 0.48 (0.18-1.34) beyond 2.5yrs. Following adjustment for pathology and PR status this interaction remained significant (p = 0.004; <2.5yrs HR 2.54 (1.21-5.32); >2.5yrs HR 0.33 (0.10-1.11)). Fig 1. clearly demonstrates a peak in the annual recurrence rate at 2yrs in the HER2 positive group.ConclusionsThis data shows that HER2 positive patients are at a significantly higher risk of recurrence within the first 2.5yrs following diagnosis of ER+ EBC. Whilst TransATAC and BIG 1-98 subgroup analysis demonstrate that HER2 is not predictive for response to AIs over tamoxifen, HER2 positive patients did show a significant reduction in recurrence on an AI in line with the remainder of the cohorts. We would therefore suggest that delaying initiation of AI therapy potentially leaves women at greater risk of early recurrence. Perhaps more importantly we should ensure that all ER positive HER2 positive patients receive trastuzumab along with their endocrine therapy as there is now significant in vitro and clinical evidence that inhibition of growth factor pathways is essential for endocrine sensitivity. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4045.

To investigate the clinicopathological characteristics and prognosis of breast cancer subtypes classified by quantitative estrogen receptor (ER), progesterone receptor (PR), and Her2. 923 patients with primary breast cancer having a median age of 53 years who were treated at the Cancer Hospital of Fudan University in Shanghai between January 2002 and June 2004 were retrospectively analyzed. Four molecular subtypes were constructed from the immunohistochemical results of quantitative hormone receptor (HR) and Her2 status. HR+ was defined as ER+ and PR+, HR+/- as ER/PR+ at lower levels or lacking either ER or PR, and HR- as both ER- and PR-. The four subtypes were HR+/Her2-, HR+/-/Her2-, HR-/Her2- (triple-negative), and Her2+. Clinical and pathological parameters, disease-free survival (DFS), and overall survival (OS) measurements were compared between patients with different molecular subtypes. The proportions of HR+/Her2-, HR+/-/Her2-, triple-negative, and Her2+ breast cancer were 36.6% (338/923), 22.9% (211/923), 20.6% (190/923), and 19.9% (194/923). The median follow-up was 49.0 months (4-77 months). In 145 cases disease recurrence or death occurred. In multivariate analysis with the HR+/Her2- subtype taken as the reference category, triple-negative and Her2+ subtypes were associated with increased recurrence and death with a hazard ratio (HR) of 2.05 (95% CI 1.31-3.20; P = 0.002) and 1.89 (95% CI 1.20-2.97, P = 0.006) for DFS and 2.84 (95% CI 1.45-5.55; P = 0.002) and 2.95 (95% CI 1.51-5.77, P = 0.002) for OS, respectively; the HR+/-/Her2- subtype was marginally associated with poor prognosis with HR 1.51 (95% CI 0.94-2.43; P = 0.088) and 1.90 (95% CI 0.92-3.94; P = 0.084) for DFS and OS, respectively. Breast cancer subtypes based on quantitative ER, PR, and Her2 may be predictive of prognosis. Patients whose tumors were not HR+/Her2- had a worse outcome in our study.

To investigate the clinicopathological characteristics and prognosis of breast cancer subtypes classified by quantitative estrogen receptor (ER), progesterone receptor (PR), and Her2. 923 patients with primary breast cancer having a median age of 53 years who were treated at the Cancer Hospital of Fudan University in Shanghai between January 2002 and June 2004 were retrospectively analyzed. Four molecular subtypes were constructed from the immunohistochemical results of quantitative hormone receptor (HR) and Her2 status. HR+ was defined as ER+ and PR+, HR+/- as ER/PR+ at lower levels or lacking either ER or PR, and HR- as both ER- and PR-. The four subtypes were HR+/Her2-, HR+/-/Her2-, HR-/Her2- (triple-negative), and Her2+. Clinical and pathological parameters, disease-free survival (DFS), and overall survival (OS) measurements were compared between patients with different molecular subtypes. The proportions of HR+/Her2-, HR+/-/Her2-, triple-negative, and Her2+ breast cancer were 36.6% (338/923), 22.9% (211/923), 20.6% (190/923), and 19.9% (194/923). The median follow-up was 49.0 months (4-77 months). In 145 cases disease recurrence or death occurred. In multivariate analysis with the HR+/Her2- subtype taken as the reference category, triple-negative and Her2+ subtypes were associated with increased recurrence and death with a hazard ratio (HR) of 2.05 (95% CI 1.31-3.20; P = 0.002) and 1.89 (95% CI 1.20-2.97, P = 0.006) for DFS and 2.84 (95% CI 1.45-5.55; P = 0.002) and 2.95 (95% CI 1.51-5.77, P = 0.002) for OS, respectively; the HR+/-/Her2- subtype was marginally associated with poor prognosis with HR 1.51 (95% CI 0.94-2.43; P = 0.088) and 1.90 (95% CI 0.92-3.94; P = 0.084) for DFS and OS, respectively. Breast cancer subtypes based on quantitative ER, PR, and Her2 may be predictive of prognosis. Patients whose tumors were not HR+/Her2- had a worse outcome in our study.

Background. According to the literature, BRCA1-associated breast cancer (BC) most often belongs to the triple negative (TNBC) molecular subtype. The data on the contribution of other molecular subtypes to this group of patients differ among different studies.The study objective is to evaluate the frequency of different tumor molecular subtypes in BC patients with BRCA1 gene mutation treated in N. N. Blokhin National Medical Research Center of Oncology in the period from 2017 to 2020.Materials and methods. The study included BC patients with a mutation in the BRCA1 gene (n = 209) identified as a result BRCA1 mutation screening of patients with BC. DNA diagnostics was carried out on blood samples of patients using the real-time polymerase chain reaction method. After analyzing the patients primary documentation clinical and morphological data were taken into account: the age of diagnosis, the stage of the disease, the results of immunohistochemical studies (estrogen receptor status, progesterone receptor status, HER2 expression, Ki-67 proliferation index). The assignment to the particular molecular tumour subtypes was performed according to estrogen receptor status, progesterone receptor status, HER2 status and Ki67 value.Results. Clinical and pathomorphological data of 209 patients with BRCA1-associated BC were analyzed. The age at diagnosis ranged from 23 to 72 years, the median age was 40 years, the mean age was 41.46 ± 9.82 years. BC associated with BRCA1 was found to be TNBC in 71.3 % and luminal B, HER2 negative (LumB–) in 19.1 % of the cases. Other tumour subtypes were much less common: luminal B, HER2 positive (LumB+) in 7.2 %, luminal A (LumA) in 1 % and HER2-positive (HER2+) in 1.4 % of the cases. The frequency of subtypes was estimated in different age groups (1st – patients 23–34 (n = 53), 2nd – 35–49 (n = 111), and 3rd – 50–72 (n = 45) years old). TNBC frequency was 81.1 % in the 1st group, 73.9 % in the 2nd and 53.4 % in the 3rd group; LumB– frequency was 15.1, 15.3 and 33.3 % respectively. Using the Fisher test it was shown that the differences in frequencies were statistically significant between groups 1st and 3 rd, as well as between groups 2 nd and 3 rd (p <0.05).Conclusion. TNBC was the main molecular subtype in all age groups of BC patients with BRCA1 germinal mutation, TNBC frequency was lower in the older age group. LumB– subtype was also common in BRCA1-associated tumors especially in older women.