Estrogen Receptor-positive HER2-negative Breast Research Articles

Use of Oncotype vs. Breast Cancer Index (BCI) for extended endocrine therapy decisions: A single center analysis in stage IA hormone receptor positive breast cancer.

e13083 Background: Extended Endocrine Therapy (EET) for hormone receptor positive HER-2 negative early-stage breast cancer reduces late recurrence risks but raises concerns about toxicity. Biomarker tests like the Breast Cancer Index (BCI) are vital for identifying patients who could benefit from continued ET, reassuring others against unnecessary extension. This study evaluates prognostic implications for both Oncotype Dx (Recurrence score, RS) and BCI amidst concerns about added testing costs in patients with early stage, estrogen receptor (ER) positive breast cancer. Methods: This is a single institution retrospective review of Stage IA ER positive HER-2 negative breast cancer patients who underwent both Oncotype Dx and BCI testing from January 2021 to December 2023. Pearson's correlation coefficient (r) was used to assess the linear relationship between the assays (p<0.05 for significance), analysis was performed with SAS software, version 9.4. Results: Fifty-eight patients with Stage IA ER positive HER-2 negative breast cancer who had both Oncotype and BCI results were identified (100% female; mean age 72.2 years [54-87]). After a median followed up of 72 months (63-75), no systemic or locoregional recurrences were reported. A low positive correlation between Oncotype and BCI was observed across the entire cohort (r=0.4058; p=0.0016). However, subgroup analysis showed no significant correlations: Oncotype <11 (n=17; r=0.2415; p=0.3504), Oncotype ≤18 (n=43; r=0.0914; p=0.5600), Oncotype <26 (n=51; r=0.2530; p=0.0733); Oncotype ≥26 (n=7; r=-0.5634; p=0.1878). Correlation was also not found in patients with Grade 1 tumor (n=16; r=0.3138; p=0.2365). Thirty-nine patients (67.24%) had their treatment recommendation changed based on BCI results. Side effects from ET affected 15 patients (25.86%) and included arthralgias (60%, n=9), hot flashes (26.67%, n=4), depression (13.33%, n=2), insomnia (6.67%, n=1), and others (53.3%, n=8). Twenty-two patients (37.93%) developed new osteopenia, and 6 (10.34%) new osteoporosis while on EET. Eight patients (13.79%) had ET interruption during their treatment course. Conclusions: Despite inclination towards cost-saving measures, Oncotype DX may be more useful to give prognosis in the early adjuvant period whereas BCI is more useful to evaluate late recurrence risk. Low or high Oncotype scores and tumor grade may not align with BCI findings. Considering the importance of managing toxicity against the risk of late recurrence, incorporating BCI testing can enhance EET recommendations, even for Stage I, node-negative, ER positive patients.

Abstract 7653: Role of ITGB2 in patients with luminal B1 breast cancer

Abstract Purpose: Luminal-type breast cancers are the most commonly diagnosed in women. Among them, the luminal B1 subtype exhibits higher proliferation rates and a worse prognosis compared to the luminal A subtype. Despite significant advancements in detection and therapies, recurrence still occurs after primary treatment. In this study, our aim is to identify genomic alterations in early recurrent luminal B1 breast cancer. Experimental Design: In this VGHTPE cohort, we recruited a total of 42 patients diagnosed with stage I-III luminal B1 breast cancer, comprising 15 subjects who experienced recurrence within five years and 27 subjects who did not. Genomic DNA was extracted from formalin-fixed paraffin-embedded samples and subjected to targeted next-generation sequencing. We assessed cell aggressiveness through in vitro transwell migration, invasion, and sphere assays. Results: Luminal B1 breast cancer patients with advanced stage and poorly differentiated tumors were associated with recurrence within five years. Driver gene mutation analysis revealed that TP53 mutations were present in 46.7% of patients who experienced recurrence within five years, compared to 29.6% in the non-recurrence group. In the analysis of copy number variations, the most common amplifications/gains observed in luminal B1 breast cancer patients were in MCL1, MYC, and KLF6. Remarkably, patients who experienced recurrence within five years showed a higher occurrence of gain in ITGB2, the gene encoding the integrin β chain, compared to those who remained recurrence-free. Patients with ITGB2 amplifications/gains had a shorter 5-year recurrence-free survival compared to those with a neutral status. In vitro studies revealed that the knockdown of ITGB2 suppressed cell migration, invasion, and sphere formation in estrogen receptor-positive HER2-negative breast cancer cells. Conclusion: Our study has identified ITGB2 amplifications/gains as a potential biomarker for early recurrence in luminal B1 breast cancer. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Yi-Fang Tsai, Ta-Chung Chao, Wan-Lun Wang, Pei-Ju Lien, Chih-Yi Hsu, Jiun-I Lai, Chi-Cheng Huang, Jen-Hwey Chiu, Ling-Ming Tseng. Role of ITGB2 in patients with luminal B1 breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7653.

Intratumoral heterogeneity of Ki67 proliferation index outperforms conventional immunohistochemistry prognostic factors in estrogen receptor-positive HER2-negative breast cancer.

In breast cancer (BC), pathologists visually score ER, PR, HER2, and Ki67 biomarkers to assess tumor properties and predict patient outcomes. This does not systematically account for intratumoral heterogeneity (ITH) which has been reported to provide prognostic value. This study utilized digital image analysis (DIA) and computational pathology methods to investigate the prognostic value of ITH indicators in ER-positive (ER+) HER2-negative (HER2-) BC patients. Whole slide images (WSIs) of surgically excised specimens stained for ER, PR, Ki67, and HER2 from 254 patients were used. DIA with tumor tissue segmentation and detection of biomarker-positive cells was performed. The DIA-generated data were subsampled by a hexagonal grid to compute Haralick's texture indicators for ER, PR, and Ki67. Cox regression analyses were performed to assess the prognostic significance of the immunohistochemistry (IHC) and ITH indicators in the context of clinicopathologic variables. In multivariable analysis, the ITH of Ki67-positive cells, measured by Haralick's texture entropy, emerged as an independent predictor of worse BC-specific survival (BCSS) (hazard ratio (HR) = 2.64, p-value = 0.0049), along with lymph node involvement (HR = 2.26, p-value = 0.0195). Remarkably, the entropy representing the spatial disarrangement of tumor proliferation outperformed the proliferation rate per se established either by pathology reports or DIA. We conclude that the Ki67 entropy indicator enables a more comprehensive risk assessment with regard to BCSS, especially in cases with borderline Ki67 proliferation rates. The study further demonstrates the benefits of high-capacity DIA-generated data for quantifying the essentially subvisual ITH properties.

Liver metastasis in estrogen receptor-positive HER 2-negative breast cancer. Ribociclib as prognosis-changing therapy

The life expectancy of patients with metastatic luminal HER 2-negative breast cancer has stagnated at the level of 40 months for many years. The introduction of CDK4/6 inhibitors into practice has changed the standards of therapy, providing not only a significant increase in the time without progression while maintaining a high quality of life, but also significantly increasing overall survival. The presence of liver metastases determines an extremely unfavorable prognosis, with GH+HER 2-mBC reducing life expectancy to a median of 21 months. Endocrine therapy combined with ribociclib significantly increased overall survival rates on average per year, reaching medians of 36.1 and 46.5 months, depending on the line of treatment. This publication is devoted to liver metastases in breast cancer, in particular in the luminal HER 2-negative subtype. Epidemiological aspects are considered, the possibilities of modern systemic therapy are evaluated. A clinical case of successful therapy with ribociclib in a young patient with liver damage is presented.

Spatial interplay of lymphocytes and fibroblasts in estrogen receptor-positive HER2-negative breast cancer

In estrogen-receptor-positive, HER2-negative (ER+HER2−) breast cancer, higher levels of tumor infiltrating lymphocytes (TILs) are often associated with a poor prognosis and this phenomenon is still poorly understood. Fibroblasts represent one of the most frequent cells in breast cancer and harbor immunomodulatory capabilities. Here, we evaluate the molecular and clinical impact of the spatial patterns of TILs and fibroblast in ER+HER2− breast cancer. We used a deep neural network to locate and identify tumor, TILs, and fibroblasts on hematoxylin and eosin-stained slides from 179 ER+HER2− breast tumors (ICGC cohort) together with a new density estimation analysis to measure the spatial patterns. We clustered tumors based on their spatial patterns and gene set enrichment analysis was performed to study their molecular characteristics. We independently assessed the spatial patterns in a second cohort of ER+HER2− breast cancer (N = 630, METABRIC) and studied their prognostic value. The spatial integration of fibroblasts, TILs, and tumor cells leads to a new reproducible spatial classification of ER+HER2− breast cancer and is linked to inflammation, fibroblast meddling, or immunosuppression. ER+HER2− patients with high TIL did not have a significant improved overall survival (HR = 0.76, P = 0.212), except when they had received chemotherapy (HR = 0.447). A poorer survival was observed for patients with high fibroblasts that did not show a high level of TILs (HR = 1.661, P = 0.0303). Especially spatial mixing of fibroblasts and TILs was associated with a good prognosis (HR = 0.464, P = 0.013). Our findings demonstrate a reproducible pipeline for the spatial profiling of TILs and fibroblasts in ER+HER2− breast cancer and suggest that this spatial interplay holds a decisive role in their cancer-immune interactions.

Abstract PS12-15: Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC)

Abstract RATIONALE: Addition of CDK 4/6 inhibitors to endocrine therapy has become standard for patients (pts) with ER+ and HER2- BC with improvements in overall survival. However, acquired resistance to front-line therapy is inevitable, and response to later-line therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα). H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα). A phase I-II study was conducted to explore the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics, and efficacy of this agent in advanced ER+ and Her2- breast cancer pts (NCT03250676). METHODS: PK samples in phase I were obtained at day 1 and day 15 of cycle 1 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose) and sparse PK samples were collected in the phase II part of the trial. For pts enrolled in the food effect sub-study of phase II, plasma samples were collected during cycle 1 on day 15 and day 22 (Predose, 0.5, 1, 2, 4, 6, 8, 10, and 24 h post dose). Nonlinear mixed effect model (NONMEM) was applied for development of population PK models to fit H3B-6545 plasma concentration data with NONMEM® version 7.4 software. R was used for data management, visualization and statistical summaries. RESULTS: This phase I-II trial enrolled 47 pts in phase I part and 83 pts in the phase II part at the recommended phase II dose of 450 mg QD as of May 15, 2020. The 1180 plasma concentrations of H3B-6545 from a total of 103 pts at doses of 100-600 mg available as of January 15, 2020 were included in this analysis, with the following characteristics [n or (median, min-max) unit]: race (n=91/5/1/6 for White/Black/Asian/others), age (62.5, 31-81) yrs, body weight (79.5, 49-140) Kg, BMI (26.9, 17.6-45.6) Kg/m2, albumin (40, 29-52) g/dL, ALP (88.5, 39-917) IU/L, ALT (28, 10-193) IU/L, AST (36.5, 13-259) IU/L, bilirubin (8.6, 1.7-25.7) µM and creatinine clearance (112, 49.5-389) mL/min. The median number of prior therapy in the metastatic setting was 3 (range: 1 - 10). Out of 103 patients, 32 pts received treatment with a single high-fat meal to test food effect on PK over a randomized crossover design. H3B-6545 plasma concentrations were best described with a one compartment disposition PK model, plus a combined first- and zero-order parallel absorption and lag time. The estimated apparent clearance (CL/F) and volume of distribution (V/F) were 31 L/h and 422 L, respectively, with a typical terminal half-life of about 10 hours. H3B-6545 was absorbed fast, with a typical tmax of about 4 hours. A moderate to high variability (40-60%) was identified in major PK parameters (CL/F, V/F, bioavailability [F1]). A high-fat meal increased bioavailability by approximately 45% and prolonged tmax, roughly from 4 hours to 6 hours post dose. No significant effect was identified from other covariates: age, body weight, race, albumin, AST, ALP, ALT, bilirubin and creatinine clearance. CONCLUSIONS: H3B-6545 PK profiles in breast cancer patients were well described by a one-compartment disposition model with no significant effect of demographics, liver and renal function. When administered with a high fat meal, H3B-6545 exposure was modestly increased. Citation Format: Oneeb Majid, Jianjun Alan Xiao, Tarek Sahmoud, Sanae Yasuda, Lisa Cantagallo, Erika P Hamilton, Timothy Pluard, Dejan Juric, Antonio Gualberto, Ziad Husseiin. Pharmacokinetics of H3B-6545 in patients with locally advanced or metastatic estrogen receptor-positive HER2 negative breast cancer (ER+ and HER2- BC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-15.

Клиническое наблюдение применения перорального винорелбина при лечении диссеминированного эстроген- рецептор-позитивного, HER2-негативного рака молочной железы

Luminal B (HER2-negative) breast cancer is considered the most common type. The consistent prescription of hormone therapy lines for disseminated estrogen receptor-positive (ER+) HER2-negative breast cancer allows us to consider this variant of the tumor as a chronic disease with long-term oral therapy. Oral chemotherapy can improve the life quality of patients while ensuring the high efficiency of the treatment. If there is a standard for the first lines of hormone therapy, the optimal chemotherapy regimen of line 1 is not established and is determined individually in each case. The authors note that it is necessary to rely on the expected toxicity of therapy and the toxicity of previous treatment, as well as take into account the patient’s willingness to visit the clinic for intravenous infusions. The article presents a clinical case concerning a patient suffering from disseminated ER+ HER2-negative breast cancer. This clinical case shows how it is possible to postpone the prescription of intravenous chemotherapy as much as possible (with the rational use of hormone therapy regimens, as well as oral chemotherapy), thereby improving the patient’s life quality. In the context of the COVID-19 pandemic, which involves limiting visits to medical institutions, oral chemotherapy can be considered as the therapy of choice for such patients. KEYWORDS: chemotherapy, breast cancer, toxicity, vinorelbin, estrogen receptor-positive cancer, HER2-negative cancer. FOR CITATION: Glazkova E.V., Stenina M.B. Clinical case on the use of oral vinorelbine in the treatment of disseminated estrogen receptorpositive HER2-negative breast cancer. Russian Medical Inquiry. 2021;5(8):548–551 (in Russ.). DOI: 10.32364/2587-6821-2021-5-8-548-551.

ALTERNATE: Neoadjuvant endocrine treatment (NET) approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer (ER+ HER2- BC) in postmenopausal (PM) women: Alliance A011106.

504 Background: For PM patients (pts) with locally advanced ER+ HER2- BC, NET improves breast conservation surgery (BCS) rates, and modified preoperative endocrine prognostic index (mPEPI) 0, defined as pT1-2 pN0 Ki67< 2.7%, or pathologic complete response (pCR: no invasive disease in breast or lymph node) is associated with low risk of recurrence without adjuvant chemotherapy (CT). The ALTERNATE trial was initiated to assess if the endocrine-sensitive disease rate (ESDR: number of mPEPI 0 pts/number of eligible pts initiating NET) with fulvestrant (F) or F+anastrozole (A) is improved relative to A alone (reported here) and if the 5-year (yr) recurrence-free survival (RFS) rate for pts with mPEPI 0 on A alone without CT is ≥ 95% (awaits further follow-up). Methods: PM pts with clinical stage II/III ER+ HER2- BC were randomized 1:1:1 to 1 mg A po daily, 500 mg F IM every 4 week (wk)s after loading dose, or A+F for 6 months. Ki67 was tested centrally on biopsies acquired prior to NET, wk 4, wk 12 and at surgery. Pts with Ki67 >10% at wk 4 or 12 were recommended to go off protocol-directed ET and switch to CT. Pts with mPEPI 0 at surgery were recommended to continue assigned ET for 1.5 yrs followed by A for a total of 5 yrs ET (and not to receive CT). The primary endpoint of the neoadjuvant phase was ESDR. ESDR of each F arm was compared to that of the A alone arm. With 425 pts per arm, a one-tailed alpha = 0.025 chi-square test of two independent proportions has 84% power to detect an increase of ≥10% in ESDR for F or F+A compared to the A arm, assuming ESDR ≤30% in A. Results: 1362 pts (A 452; F 454; A+F 456) were enrolled Feb 2014 to Nov 2018. 63 pts were excluded (did not start NET). Of the remaining 1299 pts (A 434; F 431, A+F 434), 42% were cN1-3 and 73% were considered candidates for BCS. ESDR was 18.6% (95%CI: 15.1-22.7%) with A, 22.7% (95%CI: 18.9-27.0%) with F, and 20.5% (95%CI: 16.8-24.6%) with A+F. No significant difference in ESDR was found between A and F (p=0.15) or A and A+F (p=0.55). Among the 825 pts with wk 4 Ki67 < 10% who completed NET and surgery, ESDR and the BCS rate were 27.7% and 70.3% with A; 29.6% and 68.1% with F, and 26.8% and 69.9% with A+F, respectively. Conclusion: Neither F nor F+A significantly improved ESDR compared to A alone in PM pts with locally advanced ER+ HER2- BC. RFS data are awaited. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org ; NCI BIQSFP, BCRF, Genentech, AstraZeneca. Clinical trial information: NCT01953588 .

Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial)

BackgroundSingle-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer (ABC) non-responsive to hormone therapy and without visceral crisis. This phase II trial compared first-line oral vinorelbine versus weekly paclitaxel for ABC. MethodsEligible female patients had measurable locally recurrent/metastatic estrogen receptor-positive HER2-negative breast cancer and had received prior endocrine therapy (any setting) but no chemotherapy for ABC. Patients were stratified by prior taxane and visceral metastases and randomized to either oral vinorelbine 80 mg/m2 (first cycle at 60 mg/m2, escalated to 80 mg/m2 in the absence of grade 3/4 toxicity) or intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR; confirmed complete or partial response, or stable disease for ≥6 weeks). ResultsThe 131 randomized patients had received a median of 2 prior endocrine therapies; >70% had prior (neo)adjuvant chemotherapy and 79% visceral metastases. DCR was 75.8% (95% confidence interval: 63.6–85.5%) with vinorelbine and 75.4% (63.1–85.2%) with paclitaxel. The most common grade 3/4 adverse events were neutropenia (52%), fatigue (11%), and vomiting (5%) with vinorelbine, and neutropenia (17%), dyspnea (6%), hypertension (6%), and peripheral sensory neuropathy (5%) with paclitaxel. Grade 2 alopecia occurred in 2% of vinorelbine-treated and 34% of paclitaxel-treated patients. Neither arm showed relevant global health status changes. ConclusionOral vinorelbine and paclitaxel demonstrated similar DCRs (∼75%). Safety profiles differed and, together with administration route and convenience, may influence treatment choice (EudraCT number, 2012-003530-16).

The Prognostic Significance of the Oncotype DX Recurrence Score in T1-2N1M0 Estrogen Receptor-Positive HER2-Negative Breast Cancer Based on the Prognostic Stage in the Updated AJCC 8th Edition.

This study aimed to evaluate the prognostic significance of the Oncotype DX recurrence score (RS) in T1-2N1M0 estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer based on the prognostic stage in the updated American Joint Commission on Cancer, 8th edition. The Surveillance, Epidemiology, and End Results database was searched to identify ER-positive invasive ductal breast cancer in T1-2N1M0 with RS results diagnosed between 2004 and 2012. Patients with RS were categorized into low-risk (RS < 11), intermediate-risk (RS 11-25), and high-risk (RS > 25) groups. The distributions of clinical-pathological characteristics were compared among the RS risk groups using Pearson's Chi square. Breast cancer-specific survival (BCSS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared across RS groups using the log-rank statistic. Cox models were fitted to assess the factors independently associated with survival. The study enrolled 4059 cases categorized into prognostic stages IA to IIB. The RS risk groups were positively correlated with pathological prognostic stages (P < 0.001). The RS risk groups differed significantly in terms of BCSS and OS (P < 0.001). According to the multivariate analysis, RS risk group was an independent prognostic factor for BCSS and OS together with the pathological prognostic stage. The subgroup analysis showed similar survival rates across pathological prognostic stages in the RS low-risk group but significant differences in survival rates among pathological prognostic stages in the RS intermediate-risk group. The survival rates among the RS risk groups also differed significantly in pathological prognostic stage IA. Oncotype DX RS provided independent prognostic significance to complement the prognostic staging system.

Erratum to: Post-relapse survival in patients with the early and late distant recurrence in estrogen receptor-positive HER2-negative breast cancer.

Erratum to: Post-relapse survival in patients with the early and late distant recurrence in estrogen receptor-positive HER2-negative breast cancer.

Limitations in predicting PAM50 intrinsic subtype and risk of relapse score with Ki67 in estrogen receptor-positive HER2-negative breast cancer.

PAM50/Prosigna gene expression-based assay identifies three categorical risk of relapse groups (ROR-low, ROR-intermediate and ROR-high) in post-menopausal patients with estrogen receptor estrogen receptor-positive (ER+)/ HER2-negative (HER2-) early breast cancer. Low risk patients might not need adjuvant chemotherapy since their risk of distant relapse at 10-years is below 10% with endocrine therapy only. In this study, 517 consecutive patients with ER+/HER2- and node-negative disease were evaluated for Ki67 and Prosigna. Most of Luminal A tumors (65.6%) and ROR-low tumors (70.9%) had low Ki67 values (0-10%); however, the percentage of patients with ROR-medium or ROR-high disease within the Ki67 0-10% group was 42.7% (with tumor sizes ≤2 cm) and 33.9% (with tumor sizes > 2 cm). Finally, we found that the optimal Ki67 cutoff for identifying Luminal A or ROR-low tumors was 14%. Ki67 as a surrogate biomarker in identifying Prosigna low-risk outcome patients or Luminal A disease in the clinical setting is unreliable. In the absence of a well-validated prognostic gene expression-based assay, the optimal Ki67 cutoff for identifying low-risk outcome patients or Luminal A disease remains at 14%.

Post-relapse survival in patients with the early and late distant recurrence in estrogen receptor-positive HER2-negative breast cancer

Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer. A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed. Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6months than in those with a duration ≤6months. Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

A short-term neoadjuvant pilot study comparing exemestane and letrozole in postmenopausal women with estrogen receptor-positive HER2-negative breast cancer.

591 Background: Current approaches of neoadjuvant endocrine therapy (NAET) are focusing on biomarker analysis of the diagnostic specimens. One of the important things in neoadjuvant treatment is to determine the in-vivo responsiveness to the agent. Little is known regarding biomarker changes in specific agents and the association with biomarker changes and treatment duration. A pilot study was conducted to investigate the differences of biomarker changes in short-term NAET (letrozole vs. exemestane) and also the difference in treatment durations of each AI. Methods: Totally 120 samples from 60 postmenopausal women with ER positive HER2 negative stage 1-3 breast cancers in NAET comparing letrozole (LET) and exemestane (EXE) were analyzed with pre- and post-treatment mRNA expression of ERα, ERβ, PR, HER2, Ki67, PIK3CA, and MAPK using QuantiGene Assay. Thirty-one patients took letrozole 2.5mg daily and 29 did exemestane 25mg daily until the surgery (median duration 22 days). Statistical tests were two-sided. Results: Clinical characteristics were well balanced between the two treatment arms. Median % changes of Ki67 were -58%, ERα -44%, ERβ +93%, and PR -69% in LET and Ki67 -59%, ERα -30%, ERβ +135%, PR -72% in EXE. There were no significant differences of these marker changes between two agents. Dividing into 4 groups in treatment duration, 10-14 days (q1), 15-21 days (q2), 22-28 days (q3), and over 29 days (q4), LET had 2 peaks in Ki67 decreases (-69% (q1), -28% (q2), -78% (q3), -59% (q4)), whereas EXE had a peak in q2 (-62%, -77%, -49%, -26%). Ki67 increasing cases including primary resistance and tachyphylaxis were 5 (16%) in LET (3 in q2 and 2 in q4) and 3 (10%) in EXE (one of each in q2-4). All 8 cases had increases of ERβ, PIK3CA, and MAPK. Conclusions: Although both LET and EXE for short duration had significantly decreased Ki67 mRNA level irrespective of treatment duration, no significant differences was found between two agents. Tumor resistance with AIs may be associated with the other pathways.

ASTER 70s: Benefit of adjuvant chemotherapy for estrogen receptor-positive HER2-negative breast cancer in women over 70 according to genomic grade—A French GERICO/UCBG UNICANCER multicenter phase III trial.

TPS667 Background: The benefit of adjuvant chemotherapy (CT) is highly controversial for elderly breast cancer (BC) women presenting with an oestrogen receptor-positive (ER+) HER2-negative (HER2-) phenotype. Conversely to hormonal treatment (HT) that remains the cornerstone of adjuvant treatment for such luminal tumours, CT may severely decompensate comorbidities and alter quality of life in elderly patients. As disappointing as it is in drug development, elderly have been constantly excluded from trials evaluating new modern prognosis classifiers. This prospective multicentre trial funded by a French national grant (PHRC 2011) is the first phase III trial to investigate the impact on overall survival (OS) of adjuvant CT in elderly ER+ HER2- BC patients selected with a modern prognosis classifier and taking into account competing risks for mortality (EudraCT 2011-004744-22). Methods: Following surgery, 2,000 women 70+ with ER+ HER2- BC (any pT/pN), will have a genomic grade (GG, derived from frozen MapQuantDx™, Ipsogen) centrally assessed on formalin-fixed paraffin-embedded samples. Only those with a high GG (estimation~700) will be randomized between HT alone vs CT followed by HT. CT regimen is left to the choice of investigators amongst 3 regimen of same duration [4 q3w cycles, docetaxel+cyclophosphamide, doxorubicin or non pegylated liposomal doxorubicin (Myocet)+cyclophosphamide, all with G-CSF], as well as HT (aromatase inhibitor±tamoxifen). Those with low GG or not included for other reasons (estimation~1,300) will be followed as an observational parallel cohort with HT alone. Sample size is based on 4-year OS as primary endpoint (87.5 vs 80%), bilateral α=0.05, β=0.20 and HR= 0.60. Secondary endpoints include assessment of competing risks for mortality, cost-effectiveness and Q-TWiST analysis, geriatric items (e.g. Lee’s 4-year mortality score and G8 screening tool), acceptability, quality of life (QLQ-C30 and specific elderly scale ELD15), and translational research on ageing/prognostic biomarkers and pharmacogenetic. The trial has been just opened to inclusion in February 2012.