The randomised phase II NeoPAL study (NCT02400567) compared neoadjuvant letrozole-palbociclib (LP) to chemo (CT) in 103 patients with early high-risk PAM50-defined luminal BC. Clinical activity was similar in both arms. We report the pre-specified translational analysis. We compared baseline (BL) and surgical tumor samples expression of Ki67, cell cycle proteins and immune cell markers by central IHC, DNAseq, gene expression by the Nanostring nCounter BC360™ panel, and 3'mRNA sequencing (RNA-Seq) with BayesPrism cell type deconvolution. By IHC, BC360 signatures and RNA-Seq, no difference was observed between the BL samples of both arms. Median Ki67 was significantly reduced at surgery in both arms [LP: 27.5% (IQR 20-40) to 1% (IQR 0-5), p<.0001) and was lower in the LP than in the CT arm (median 1% (IQR 0-5) vs 5% (IQR 2-15), p=.0001). Similar reductions were seen in pRb and CCND1 Hscores in each arm. At surgery, the BC360 proliferation signature was reduced in both arms along most of the initially upregulated pathways, while the upregulated BC360 signatures were almost all immune-related (all p<.01). Active immune cell recruitment was confirmed by IHC after both therapies. No DNAseq changes were observed with LP therapy. Deconvolution of bulk RNA-Seq data using a finely annotated single-cell cellular atlas revealed enrichment of cancer cells, immunosuppressive cancer-associated fibroblasts, FOXP3+ CD4+ regulatory T cells and TREM2+ macrophages at BL. In contrast, myoepithelial cells, normal-like fibroblasts, FOLR2+ macrophages and SELL+ CD4+ T cells accumulate after treatment (p values: .046 to 7.2e-07). Strikingly, all these changes were almost identical between the LP and CT arms. Finally, a low ROR score was observed at surgery in 60% and 40% of patients in the LP and CT arms, respectively (p=.064). In these patients, no 3-year breast cancer-specific survival event was observed. This comprehensive analysis strongly suggests that LP has as profound an effect on luminal tumours as chemotherapy, with regard to proliferation decrease, immune attraction and stromal changes associated with tumor response. These results provide rationale for future chemo-sparing studies in high-risk luminal breast cancer.

Safety and effectiveness of T-DXd should be characterized in real world (RW) settings. We designed an observational study to address RW evidence gaps and highlight the first clinical experiences with T-DXd for HER2+ m/u BC pts. REALITY-01 is an ambispective phase IV study that includes HER2+ m/u BC pts who received T-DXd after ≥ 2 prior lines of anti-HER2+ treatments (tt) through an early access program or after marketing authorization. Interim analysis on safety and effectiveness data are presented. At data cut-off, 305 pts were enrolled in 56 centers (median follow-up of 17.7 months (mo)). At the start of T-DXd, median age was 59 years (17.7% pts were ≥ 70 years) and 22.1% (n=60) of pts had CNS metastasis (mCNS) including leptomeningeal disease. 69% (n=187) and 15.5% (n=42) of pts had ECOG 0-1 and ECOG 2-3. 51, 7% of pts received ≥4 lines before T-DXd. Median duration of T-DXd tt was 12.5 mo. Incidence and severity of T-DXd-related adverse drug reactions (ADR) of interest in general and a focus on interstitial lung disease (ILD) are presented in the table. Median progression free survival (mPFS) was 17.4 mo [95%CI: 15.6;19.6] and objective response rate was 49.7% [95%CI: 42.3;57.2], including 24.9% (n=46) of complete response (CR). For the study population, median overall survival (OS) was not reached. For pts with mCNS at inclusion, CNS response rate was 52.4% [36.4;68.0], including 19% (n=8) of CR.Table: 190PPrimary endpoint: Percentage of pts with at least one T-DXd related ADR of interest during the 2 years following the start of T-DXd administrationTotal n=305Total number of pts with any ADR n(%) [95%CI]240 (78.7) [73.7;83.1]Leading to T-DXdDose reduction44 (14.4)Discontinuation31 (10.2)Interruption66 (21.6)Any serious29 (9.5)Grades (worst grade)169 (22.6)266 (21.6)396 (31.5)44 (1.3)53 (1.0)Any ILD – no. (%)43 (14.1)114 (4.6)216 (5.2)37 (2.3)4053 (1.0) Open table in a new tab These first results from REALITY-01 confirm the safety and effectiveness of T-DXd in heavily pre-treated HER2+ m/u BC pts with or without mCNS and are consistent with DESTINY-Breast01/02 results.

BACKGROUND:The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS:Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS:EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS:The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

Despite benefits of physical activity (PA) during breast cancer (BC) treatments, successful exercise strategies in routine BC care remain to be determined. The primary objective was to assess the efficacy of two 6-month PA interventions: connected PA program and therapeutic patient education (TPE), concomitant to adjuvant treatments. DISCO was a 2x2 factorial, multicenter, phase III, randomized controlled trial. Women with a localized invasive BC and eligible for any adjuvant treatment, were randomized in 1 of the 4 groups: web-based connected device (adaptative program of 2 walking and 1 muscle strengthening sessions/week in autonomy + a connected activity wristband); TPE (2 sessions); combination of both interventions; usual care. All patients received PA recommendations. Assessments (baseline, 6&12 months) included physical fitness, body composition and questionnaires. The primary endpoint was the proportion of patients who reached PA recommendations at 6 months based on the Recent Physical Activity Questionnaire, in each intervention compared to patients who did not receive it. Statistical analyses were performed in the ITT population. From 2018 to 2021, 436 patients were randomized: 108 patients received the connected device, 108 the TPE program, 110 both interventions, and 110 usual care. At baseline, 66% of patients reached PA recommendations. During the 6-month intervention, 96% of patients wore the connected device, the median number of PA sessions was 45 and 80% of patients attended the TPE program. Overall, 89,3% of patients who received the connected device reached PA recommendations at 6 months vs. 89,4% of patients without the device and 91,9% of patients who benefits from TPE reached PA recommendations vs. 87% of patients without TPE. For the primary endpoint, no statistically significant difference was found for both interventions. The findings provide new information on the efficacy of innovative interventions to practice PA during routine BC treatment. The 6-month major increase of PA, independently of patient group allocation, highlights the importance of providing PA recommendations and PA assessment to BC patients.

Conflicting results have been reported on the impact of HER2-low expression on the efficacy of CDK4/6 inhibitors in hormone receptor-positive (HR+) metastatic breast cancer. No data are yet available in the neoadjuvant setting. We investigated the efficacy of letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment according to HER2 expression in an exploratory analysis of the NeoPAL study (UCBG104, NCT02400567). NeoPAL was a randomised, parallel, non-comparative phase II study which assigned pts with HR+ HER2-, Prosigna®-defined luminal B or A and node-positive, stage II-III breast cancer to LETPAL or chemotherapy. Primary endpoint was residual cancer burden (RCB 0-I rate). Secondary endpoints included clinical response, proliferation-based markers, and safety. HER2 low status was centrally reviewed according to the ASCO/CAP guidelines. 40/53 patients treated in the LETPAL arm were evaluable for this substudy: HER2-low (n=20), HER2-0 (n=20). Luminal B molecular subtype was predominant in both groups (95% and 80% respectively) with a baseline high risk Prosigna® ROR score in 88.9% and 82.6% of patients, respectively. After 4 months of LETPAL, RCB 0-I was observed in one patient of each group and pathological complete response rates were 2.5% and 0% in the HER2-low and HER2-0 subgroups respectively. A 0-I PEPI score was observed in 4 patients in each group. Interestingly, the HER2 status switched (either way) in 7 out of 28 analysable matched samples (25%). LETPAL induced a decrease in the ROR score at surgery in a similar proportion in both groups: 68.4% and 60.0% of tumors switched from high or intermediate risk to low risk in the HER2-low and HER2-zero groups, respectively. All exploratory p values were >0.1. Strikingly similar results were observed in the chemotherapy arm. Neoadjuvant palbociclib activity in combination with letrozole does not seem to be influenced by the tumor's HER2 status (low versus zero).

SOLAR-1 and BYLieve trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA -mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP) opened to PIK3CA -mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant. Primary endpoint was PFS by local investigators using RECIST1.1. Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1–16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95% CI: 4.7–6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95% CI: 37.8–52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age < 60 years (HR = 1.5, 95% CI = 1.1–2.1), >5 lines of prior treatments (HR = 1.4, 95% CI = 1.0–2.0) and the C420R PI3KCA mutation (HR = 4.1, 95% CI = 1.3–13.6). N = 91 (39.1%) patients discontinued alpelisib due to adverse events. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.

Everolimus (EVE) in combination with hormone therapy (HT) has been shown to improve progression free survival for advanced HR+/HER2- breast cancer (BC). The double blind randomized UNIRAD trial aimed to investigate the benefit of adjuvant EVE in combination with standard adjuvant HT versus HT alone for women with high-risk HR+/HER2- early BC. Women with high-risk HR+/HER2- early BC (≥4 N+ or 1-3 N+ and EPclin score ≥ 3.3) who had completed initial treatment and started adjuvant HT for ≤ 3 years were randomly allocated (1:1) to placebo (P-HT) or EVE (E-HT) for 2 years. HT treatment was investigator's choice. The primary endpoint was disease-free survival (DFS) from randomization. Secondary endpoints included metastasis free survival (MFS), overall survival (OS) and toxicity. UNIRAD is registered with ClinicalTrials.gov (NCT01805271). 1278 patients (pts) were randomized between June 2013 and March 2020 in 72 centers/3 countries; 641 in the P-HT arm, and 637 in the E-HT arm. The present final analysis was conducted after decision of stopping the study for futility at the first pre-planned interim analysis in March 2020. Median duration of HT before randomization was 15 months (IQR: 4.9-29.9). 700 (55%) and 544 pts (44%) received aromatase inhibitor and tamoxifen, respectively. After a median follow up of 35.7 months (range: 0.7-85), 147 events were recorded. Median 3 years DFS was 88% in both arms (HR=0.95; 95%CI: 0.69-1.32). MFS (HR=0.88; 95%CI: 0.62-1.25) and OS (HR=1.09, 95CI: 0.62-1.92) did neither differ. 187 pts (30%) vs 101 pts (16%) presented at least one grade 3-4 adverse event in the E-HT and P-HT arms, respectively. There was 1 toxic death in the E-HT arm. Dose reduction and early treatment discontinuation due to AEs respectively occurred in 34% and 35% of pts in the E-HT arm, vs 12% and 10% in the P-HT arm (p<0.001). Median duration of EVE exposition was 9.2 months (IQR=2.1-23.4). Everolimus given in combination with adjuvant HT for high risk early BC did not improve 3-year DFS compared with HT alone. Follow-up will continue to evaluate long-term outcomes.

The organisers regret that the abstract publication number was omitted from the title of the original publication of this abstract. The title with the abstract publication number is as follows: VP1-2021: Efficacy of everolimus in patients with HR+/HER2- high risk early stage breast cancer The organisers would like to apologise for any inconvenience caused. Efficacy of everolimus in patients with HR+/HER2- high risk early stage breast cancerAnnals of OncologyVol. 32Issue 4PreviewEverolimus (EVE) in combination with hormone therapy (HT) has been shown to improve progression free survival for advanced HR+/HER2- breast cancer (BC). The double blind randomized UNIRAD trial aimed to investigate the benefit of adjuvant EVE in combination with standard adjuvant HT versus HT alone for women with high-risk HR+/HER2- early BC. Full-Text PDF Open Archive

We have shown that neoadjuvant carboplatin and paclitaxel (NACP) increased tumor-infiltrating lymphocytes and PDL1 expression in OC pts. Combined PDL1/CTLA4 blockade is active in relapsed OC. INEOV is the 1st trial of neoadjuvant D +/- T with NACP in pts with unresectable OC. Main endpoints are feasibility and safety. 2° endpoints include macroscopically complete resection (CCO) and major pathological response rates after 3 cycles (C3).

The double blind randomized UNIRAD trial (NCT01805271) showed that adding Everolimus (EVE) to adjuvant endocrine therapy (ET) for high-risk early breast cancer (BC) does not improve 3-year disease-free survival (iDFS) compared with ET alone. We report the subgroup analysis focusing on the pre-specified stratification factors.

The COVID-19 pandemic has dramatically changed the Health Care System organization in many European countries. Many Oncology departments have rapidly implemented telehealth in their clinical practice. For breast cancer (BC) patients (pts), up to 80% of all in-person visits have been transformed in TV.

Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in ER+ HER2- metastatic breast cancer (MBC). While ESR1 mutations (ESR1mut) are a characterized mechanism of resistance to AI as single agent, it remains unknown how these mutations, when detected prior to treatment initiation, may affect the efficacy of Pal+AI. In a subsidiary analysis of the first line PADA-1 trial, we report the ESR1mut detection rate at baseline and, in patients with ESR1mut detected at baseline, how ESR1 circulating tumor DNA levels changed after the first cycle of AI-Pal therapy. Methods: PADA-1 (NCT03079011) is a randomized phase III trial testing the clinical utility of real time ESR1mut detection (baseline, at 1 month and then every 2 months) in the blood of patients treated with AI-Pal (first step). Patients with rising ESR1mut in circulating tumor DNA (i.e. increasing or appearing mutations during first line AI-Pal therapy) are randomized in a second step between keeping AI-Pal or switching to Fulvestrant-Pal. Main inclusion criteria are patients with ER+ HER2- MBC, who never received adjuvant AI or completed adjuvant AI for >12 months, with neither prior therapy for MBC nor visceral crisis. ESR1mut are tracked in circulating DNA from up to 4ml of plasma by a ddPCR-based assay targeting E380, L536, Y537 and D538 hotspots (i.e. #90% of known ESR1 activating mutations) with #0.1% sensitivity (Bidard et al, AACR 2018 #3867). Results: From 04/2017 to 05/2018, 803 MBC patients have been included in 80 centers. Among these patients, ESR1mut were detected at baseline, prior to any systemic therapy, in 17 patients (2.1%, 95%CI=[1.3;3.3%]). ESR1mut levels ranged from 6 to 3959 copies/ml of plasma (median: 30 copies/ml); allelic frequency ranged from 0.3% to 47% (median=3.5%). ESR1mut were not associated with any of the tumor pathological characteristics (including PR status, primary TNM stage, number and type of metastatic sites); a non-significant association was observed with primary tumor grade (1.7% vs 4.1% in grade I-II vs III, Fisher: p=0.15). Among patients who received a prior adjuvant endocrine therapy, ESR1mut detection rate was lower in patients treated with tamoxifen (0.9% with any tamoxifen exposure vs 5.7% with no tamoxifen exposure; Yates Chi2: p=0.01) and observed only in patients treated with AI (4.9% with any AI exposure vs 0% with no AI exposure, Yates Chi2: p=0.009). Among the 17 patients with ESR1mut detected at baseline, only 4 patients had residual detectable ESR1mut detected after 1 month of AI-Pal therapy (3 of these 4 had decreased levels of ESR1 mutation). Conclusion:ESR1mut is a rare event in untreated AI-sensitive, ER+ HER2- MBC patients. Such detection is primarily associated with prior use of AI in the adjuvant setting. Interestingly, in most MBC patients with ESR1mut detected at baseline, ESR1mut became undetectable after 1 month of AI-Pal therapy, suggesting that this combination may retain early antitumor efficacy. Funding: Pfizer Citation Format: Bidard F-C, Pistilli B, Dalenc F, De la Motte Rouge T, Sabatier R, Frenel J-S, Ladoire S, Dubot C, Ferrero J-M, Levy C, Lortholary A, Stefani L, Mouret-Reynier M-A, Hardy A-C, Jacquin J-P, Grenier J, Chakiba C, Teixeira L, Soulie P, Everhard S, Lemonnier J, Jeannot E, Bieche I, Berger F, Pierga J-Y, Bachelot T, Delaloge S. Circulating ESR1 mutation detection rate and early decrease under first line aromatase inhibitor and palbociclib in the PADA-1 trial (UCBG-GINECO) [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 PD2-06.

Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna(A (R))-defined luminal B, or luminal A and node-positive, stage II-III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2))x3 21-day courses followed by docetaxel 100 mg/m(2)x3 21-day courses. Primary end point was residual cancer burden (RCB 0-I rate). Secondary end points included clinical response, proliferation-based markers, and safety. Overall, 106 patients were randomised [median Prosigna(A (R)) ROR Score 71 (22-93)]. RCB 0-I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4-14.9)] and chemotherapy [15.7% (95% CI 5.7-25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna(A (R))-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. NCT02400567.

Abstract Background: Resistance to endocrine therapy remains a major clinical challenge with aberrant PI3K/ mTOR pathway activation being one of the main drivers. Randomised clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Vistusertib (AZD2014), a dual inhibitor of mTORC1 and mTORC2, has shown a broader range of activity in preclinical ER+ breast cancer models, showing superior activity to everolimus (EVE) both in hormone-sensitive and resistant models. The MANTA trial was desgined to evaluate the safety and efficacy of vistusertib (VIS) in combination with fulvestrant (FULV) relative to FULV alone or FULV + EVE. In addition to a continuous (cont) daily schedule of VIS, the study also explored an intermittent (int) schedule to assess the potential of short-term, maximum target inhibition. Methods: MANTA is an investigator-led, randomised, open-label phase II trial. Postmenopausal women with estrogen-receptor (ER)-positive breast cancer were eligible if they had disease recurrence while on or within 12 months of end of adjuvant treatment with an aromatase inhibitor (AI), or progression while on or within one month of end of AI treatment for locally advanced or metastatic breast cancer. Patients were randomly assigned (2:3:3:2) to receive either FULV (500 mg intramuscular injection on day 1, followed by 500 mg doses on days 15 and 29, and then every 28 days); FULV + daily VIS (50mg BD), FULV + intermittent VIS (2 days on, 5 days off; 125mg BD); or FULV + EVE (10mg OD). Treatment was given until disease progression (RECIST 1.1) or intolerable toxicity. Patients were stratified by disease measurability and response to prior endocrine therapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary objectives included objective response, clinical benefit rate, duration of response and clinical benefit, overall survival and safety. Results: Between 04/2014 and 10/2016, a total of 333 patients were randomised at 88 sites in 9 countries. 66 patients were assigned to receive FULV; 101 to FULV+VIS (cont), 95 to FULV+VIS (int); and 64 to FULV+EVE. Median PFS was 4.6 months (95% CI 3.4–6.9) in patients assigned to FULV; 7.5 months (95% CI 5.6–9.4) in those assigned to FULV+VIS (cont); 7.6 months (95% CI 5.5–9.6) in those assigned to FULV+VIS (int); and 12.2 months (95% CI 7.5–14.3) in those assigned to FULV+EVE. No significant difference was recorded between the patients assigned to FULV+VIS (cont) and FULV (hazard ratio 0.87, 95% CI 0.62-1.23; log-rank p=0.42); FULV+VIS (int) and FULV (HR 0.78, 95% CI 0.55-1.12; log-rank p=0.16); and FULV+VIS (cont) and FULV+VIS (int) (HR 1.11, 95% CI 0.81-1.52; log-rank p=0.52). PFS was significantly longer in patients assigned to FULV+EVE compared to FULV+VIS (cont) (HR 0.64, 95% CI 0.45-0.91; log-rank p=0.01) and FULV+EVE compared to FULV (HR 0.64, 95% CI 0.43-0.94; log-rank p=0.02). Conclusion: The trial failed to demonstrate a benefit of adding the TORC1/2 inhibitor vistusertib (AZD2014) to FULV. The combination FULV+EVE demonstrated significantly longer PFS compared to FULV+VIS or FULV. Citation Format: Schmid P, Zaiss M, Harper-Wynne C, Ferreira M, Dubey S, Chan S, Makris A, Nemsadze G, Brunt AM, Kuemmel S, Ruiz Cabrero I, Perelló A, Kendall A, Brown J, Kristeleit H, Conibear J, Saura C, Grenier J, Máhr K, Schenker M, Sohn JH, Lee KS, Sarker S-J, Coetzee C, Mousa K, Cortes Castan J. MANTA - A randomized phase II study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic 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 GS2-07.

Background: Dual blockade with P plus T is highly active as 1st-line treatment in patients (pts) with HER2+ MBC. In 2nd line therapy T-DM1 is considered standard of care. We hypothesize that a strategy with dual blockade with T+P without chemotherapy followed by T-DM1 at progression could be less toxic with similar efficacy in terms of overall survival (OS). Methods: Pts with centrally confirmed HER2+ MBC were randomized 1:1 to receive either P+T alone (arm A) or P+T combined with weekly paclitaxel or vinorelbine (arm B), followed by maintenance treatment with T+P until progression. After progression, T-DM1 was given as second line therapy in both arms. The primary endpoint was OS at 24 months (mo), described by the proportion of successes, along with the exact Clopper-Pearson confidence interval (CI). Secondary endpoints included progression free survival (PFS) and time to failure of strategy (TFS: PD after having received both 1st and 2nd-line treatment or death to any reason). Results: Between 05/13 and 01/16, 210 pts were enrolled. Median age was 58 years, 63% of pts had lung or liver metastases, 36% of tumors were hormone receptor negative, paclitaxel / vinorelbine was given in 46/59 pts. In both arms, 2-year OS was the same. 61/44 of pts of arm A/B proceeded to 2nd line treatment with T-DM1. There were more hematologic, gastrointestinal, neurological toxicities and more alopecia in arm B. Efficacy results.Table: 288PDKaplan-Meier estimatorsP+TP+T with chemo[%/median (95% CI)][%/median (95% CI)]2-year OS (%)*Binomial with 90% CI reported;76.2 (68.4-82.9)*Binomial with 90% CI reported;76.2 (68.4-82.9)*Binomial with 90% CI reported;3-year OS (%)73.0 (62.8-80.8)73.1 (62.3-81.2)1st line PFS (median - mo)#1st CNS metastasis was ignored for this endpoint.8.4 (7.7-12.0)23.3 (17.6-32.6)2nd line PFS (T-DM1, median - mo)7.0 (4.3-11.3)5.3 (4.0-10.3)TFS (median - mo)33.6 (23.2-not reached)48.6 (39.5-not reached)* Binomial with 90% CI reported;# 1st CNS metastasis was ignored for this endpoint. Open table in a new tab Conclusions: P+T alone as first line treatment followed by T-DM1 is a reasonable therapeutic strategy in HER2+MBC. Despite shorter PFS and TFS survival at 2 and 3 years was not affected and side effects were less frequently seen in the chemotherapy free arm. T-DM1 as second line therapy is active and safe after dual blockade with T+P. Clinical trial identification: EudraCT: 2012-002556-17. Legal entity responsible for the study: Sakk-Swiss Group for Clinical Cancer Research. Funding: Roche. Disclosure: J. Huober: Travel grants, advisory board: Novartis, Roche, Pfizer, Celgene. P. Weder: Consultant, advisory board: MSD, Roche. B. Thürlimann: Stock ownership (Roche) and advisory board (Roche). E. Brain: Honoraria or consultation fees (Roche). All other authors have declared no conflicts of interest.

Abstract Background: Genomic tests can identify ER-positive Her2-negative localized breast cancer (BC) patients (pts) who may not drive any benefit from adjuvant chemotherapy (CT). Several genomic tests have reached a high level of analytical and clinical validity, as well as clinical utility in such situation. Recent results suggest that the safe de–escalation of adjuvant chemotherapy may be most beneficial in pts with clinical high or indetermediate risk, as assessed by classical variables or online tools, through the use of a genomic test. The clinical risk though remains quite uncertain with variable definition and grey zones. The present study aimed at determining if EPclin clinico-genomic test had a significant impact on treatment decision making among pts with predefined intermediate /borderline clinical risk. Patients and methods: Women were eligible for the present study if they had complete surgical removal of a localized ER+ Her2- pN0 or pN1mi BC, and were considered by the multidisciplinary team meeting (MTM) of the center as being in a "grey zone" of uncertain CT benefit based on classical clinic-pathological assessment. The MTM1 proposed a decision (chemo/no chemo). After informed consent, an EPclin signature classified the tumor as low risk (EPclin Score < 3.3, no chemo advised) or high risk (> 3.3, a theoretical indication for adjuvant chemo). Primary end point was the proportion of change between initial adjuvant CT decision at MTM1 and final administration of CT (yes/no). A 5 steps Fleming design was planned, considering that a change rate of 15% or less was not acceptable (low clinical utility). A one-step design was used (unilateral α = 2.5% and β = 1%). Results: 203 pts were included, of whom 198 are evaluable for the main end point. 74% of the tumors were grade 2, 72% T1 , 25% T2, 3% T3; 16% were pN1mi and 84% pN0. Median age was 57. EpClin® was low risk in 67% and high risk in 33% of the cases. The global rate of decision change between MTM1 and final administration of CT was 70/198 (35.4% IC-95% = [28.7-42.1]), with 55 (27.7%) decreases and 15 (7.6%) increases in CT indication. 27% instead of 47% of all pts finally received CT (43% decrease in CT prescription). In the multivariate analysis, the factors associated to decrease for less CT were EPclin score (OR 0.11 [0.03-0.35]), proliferation (OR 1.08 [1.03-1.13]) and higher grades (OR 5.22 [1.04-26.08]); while EPclin score was positively (OR 76.6 [7.11-824.8]), but higher grades inversely (OR 0.06 [0-0.86]) associated to an increase in CT administration. Of note, the change in final decision occurred after the MTM2 and after report of the results and discussion with the patient in 9 of the 70 cases (12% of changes; 4.5% of the whole population)(8 decreases and 1 increase in CT administration). Conclusion: Adendom met its primary objective, with 35% of intermediate clinico-pathological risk pts getting significant therapeutic changes upon the receipt of an EPclin gene expression profile. 43% of these "intermediate risk" pts planned for CT avoided it. 12% of the changes were discrepant with the test's results and occurred after discussion with the patient. Citation Format: Penault-Llorca F, Kwiatkovski F, Grenier J, Levy C, Leheurteur M, Uwer L, Derbel O, Le Rol A, Jacquin J-P, Jouannaud C, Quenel-Tueux N, Girre V, Foa C, Guardiola E, Lortholary A, Catala S, Lemonnier J, Delaloge S. UCBG 2-14: A prospective multicenter non-randomized trial evaluating the effect of EndoPredict® (EPclin®) clinico-genomic test on treatment decision making among patients with intermediate clinical risk [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-10.

Background: Benefit of neoadjuvant chemotherapy in patients (pts) with luminal breast cancer (LBC) is limited. Palbociclib combined with endocrine treatment has shown impressive results in advanced LBC. We conducted a randomized parallel phase II study, assessing letrozole + palbociclib (LP) as neoadjuvant treatment in LBC. Methods: Postmenopausal women were eligible if they had a stage II-III ER-positive HER2-negative BC, not candidate for breast conserving surgery (BCS), with either a PAM50 luminal B, or a PAM50 luminal A profile with proven lymph node involvement (N+). A parallel 1:1 randomization proposed 6 courses of 3rd generation chemotherapy (FEC100 x 3 - docetaxel 100 x 3), or 19 weeks (wks) of L 2.5 mg/day plus P 125 mg/day, 3 wks/4. Surgery was performed at wk 20. Primary endpoint was locally assessed Residual Cancer Burden (RCB) rate. Main secondary endpoints included safety, response rate, positive and negative predictive values of PAM50 ROR (risk of recurrence)-defined status, centrally reviewed RCB, and BCS rates. The protocol planned that the trial should be stopped for futility if ≤ 5 local RCB 0-I events (16.7%) were observed in the first 30 pts in the LP arm. Results: Out of 184 screened pts, 106 women with Stage II-IIIA, PAM50-ascertained LBC were randomized. Pts had T1-2 (73%) or T3 (27%); N + (26.5%); luminal B (89%) tumors. Median ROR score was 68 (22-93). At interim analysis, RCB 0-I was observed in 1 pt in the LP arm and inclusions were stopped. At final analysis, local RCB 0/I/II/III was observed in 3.8%/3.8%/52%/40.4% of pts in the LP arm, and in 5.9%/9.8%/37.3%/47.1% in the chemo arm, respectively. Central and local RCB results were identical. ROR score was not predictive of RCB 0/1. Clinical objective response rates were 74.5% and 76%, and BCS rates 69.2% and 68.6%, in the LP and chemo arms, respectively. Ki67 final median value was significantly lower in the LP arm [3% (range 1-40) vs 8% (2-15), p=.017). Of 19 serious adverse events, 2 occurred in the LP arm and 17 in the chemo arm (p < 0.001). Conclusions: Neoadjuvant LP led to a slightly lower pCR/RCB 0-I rate than chemo, however clinical response and BCS rates were similar in both arms and LP had a much better safety profile. Extensive analyses are ongoing. Clinical trial identification: NCT02400567 Legal entity responsible for the study: UNICANCER R&D Funding: Pfizer - Nanostring Disclosure: P. Cottu: Consulting Fees (e.g. advisory boards): Pfizer, Roche, Novartis. Travel: Pfizer, Roche, Novartis. F. Duhoux: Consulting Fees (e.g. advisory boards): Pfizer, Roche. Travel: Amgen, Pfizer, Roche, Teva. All other authors have declared no conflicts of interest.