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Introduction: Previous studies have shown that HER2+ breast cancer is biologically heterogenous and intrinsic subtypes can be identified (luminal A, luminal B, HER2-enriched [HER2-E] and basal-like). HER2-E predominates and is associated with higher response rates following anti-HER2-based chemotherapy or dual HER2 blockade (only with lapatinib and trastuzumab). We explored the ability of intrinsic subtypes to predict pCR in pts treated with anti-HER2 neoadjuvant therapy. Methods: KRISTINE (NCT02131064) is an open-label, phase 3 study of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1+P) vs docetaxel + carboplatin + trastuzumab + pertuzumab (TCH+P) in pts with HER2+ EBC. Treatment-naive pts with stage II–IIIC HER2+ EBC were randomized to receive 6 cycles of T-DM1+P or TCH+P and assessed for the primary endpoint, pCR (ypT0/is, ypN0). HER2 and hormone receptor (HR) status were centrally assessed. Gene expression (RNA) was assessed by a custom 800-gene codeset on the nCounter platform. Intrinsic subtypes were assessed with the research-based PAM50 classifier. Results: KRISTINE randomized 444 pts (data cutoff, Dec 3, 2015; TCH+P, n=221; T-DM1+P, n=223). PAM50 results were available for 354 pts (79.7% of the intent-to-treat [ITT] population). Baseline characteristics and efficacy in the PAM50 population were similar to that of the ITT population. The HER2-E subtype represented 54.8% of the samples (Table 1). Differences were observed by HR status. Almost all luminal tumors (131/132) were identified within HR+ disease. Of HR+ tumors, 32% were identified as HER2-E. In the TCH+P arm, the pCR rate was 72.1% for HER2-E vs 32.8% in the other subtypes combined (Table 2.) In the T-DM1+P arm, the pCR rate was 62.2% for HER2-E vs 26.9% in the other subtypes combined. No major differences were observed in pCR rates within the HER2-E subtype according to HR status. Further multivariable analyses assessing differences between treatment arms and treatment benefit across subtypes is ongoing. Table 1. Intrinsic subtypesn (%)ITT (n=354)HR- (n=143)*HR+ (%) (n=200)*HER2-E194 (54.8)123 (86.0)64 (32.0)Luminal A60 (16.9)1 (0.7)57 (28.5)Luminal B74 (20.9)074 (37.0)Basal-like26 (7.3)19 (13.3)5 (2.5)*Central HR status unknown for n=11 Table 2. pCR by intrinsic subtype  TCH+PT-DM1+P npCR, n (%)npCR, n (%)pCR difference (95% CI)HER2-E10475 (72.1)9056 (62.2)-9.89 (-23.11, 3.32)HER2-E and HR+ *3724 (64.9)2715 (55.6)-9.31 (-33.56, 14.94)HER2-E and HR- *6448 (75.0)5937(62.7)-12.29 (-28.56, 3.98)Other subtypes combined6722 (32.8)9325 (26.9)-5.9 (-20.36, 8.45)Luminal A254 (16.0)3510 (28.6)12.57 (-8.18, 33.32)Luminal B3211 (34.4)4212 (28.6)-5.80 (-27.19, 15.58)Basal-like107 (70.0)163 (18.8)-51.25 (-85.49, -17.01)*Central HR status unknown for n=7 Conclusions: In this analysis from the KRISTINE study, HER2-E was the most common intrinsic subtype and was associated with the highest pCR rate with both regimens. Results are consistent with previous findings. The luminal A and B subtypes were well associated with HR+ status. A sizeable subgroup of the HER2-E subtype was HR+ (32%), and pCR rates within the HER2-E subtype seemed independent of HR status. Citation Format: Prat A, Slamon D, Hurvitz SA, Press MF, Lewis Phillips G, Lopez Valverde V, Kiermaier A, Helms H-J, Martin M, de Haas SL. Association of intrinsic subtypes with pathological complete response (pCR) in the KRISTINE neoadjuvant phase 3 clinical trial in HER2-positive early breast cancer (EBC) [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 PD3-06.

Background: Classifying breast cancer into molecular subtypes (Luminal A/B, Her2-enriched, and Basal-like) has proven to be biologically and clinically informative. Recently, we developed a gene expression based protocol (PAM50) that provides reliable subtype classification as well as independent prognostic utility (Parker et al, J Clin Oncol 2009). In this study, we evaluated the ability of the PAM50 subtypes to predict pathological complete response (pCR) to anthracycline/taxane-based chemotherapy in the neoadjuvant setting.Methods: Gene expression data were combined from three independent neoadjuvant studies totaling 361 subjects. Complete clinical data (hormone receptor levels, tumor size, node status, and grade) were available for 186 subjects. The I-SPY cohort (n=129; fresh-frozen, Agilent) was treated with doxorubicin/cyclophosphamide (ACx4) followed by paclitaxel (Tx4). The NSABP B-27 cohort (n=103; FFPE, Affymetrix) was treated with ACx4 followed by docetaxel (4 cycles). The third cohort from MD Anderson Cancer Center (MDACC) (n=129; fresh-frozen tissue, Affymetrix) was treated with paclitaxel/T followed by sequential fluorouracil-AC (FAC). Subtype assignments and prognosis scores were generated as previously described (Parker et al., 2009). Univariate and multivariate testing for pCR was performed with Fisher's exact test and logistic regression. Statistical learning methods were also implemented in order to identify an improved predictor of pCR.Results: There was no difference between the cohorts/studies with respect to estrogen receptor (ER) status (p=0.23), subtype distribution (p=0.77), or pCR rate (p=0.95). ER, PR, HER2, grade, node status, and subtype were all associated with pCR in univariate analyses. Multivariable logistic regression indicated that molecular subtype is an independent predictor of pCR (p<0.01). We found that molecular subtype contains additional pCR-predictive information beyond that of ER status, and that adding ER status to models containing molecular subtype did not significantly improve the model's performance. This indicates that the information predictive of pCR represented by ER status is largely also present in molecular subtype. Among the subtypes, Basal-like and Her2-enriched tumors demonstrated the highest rate of pCR relative to Luminal A tumors (OR 7.4; 2.2-24.8; OR 6.4; 2.0-20.7). The Risk of Relapse based on the subtype (ROR-S) was also a strong predictor of pCR (auROC=0.74), but was improved when using a novel ridge regression model (auROC=0.77; p<0.01). ROR-S and the different pCR predictors evaluated were generally correlated, however, Luminal B samples were consistently classified as having a poor prognosis and a low likelihood of pCR.Conclusions: In this combined analysis, using ER, PR, HER2, node status, tumor size, and subtype, the intrinsic molecular subtype classification is the most significant predictor of pCR across three anthracycline/taxane-based neoadjuvant cohorts.Interestingly, hormone receptor status is no longer significant when subtype is included in the model. These results indicate robust predictive information provided by the subtype classification, and highlights the chemotherapy insensitivity of the poor prognosis luminal B breast cancer subtype. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2019.

Background: HER2-positive breast cancer consists of 4 intrinsic molecular subtypes (Luminal A, Luminal B, HER2-enriched [HER2-E], and Basal-like) and a Normal-like subtype, with the HER2-E subtype having the highest activation of the EGFR-HER2 pathway. Concordant with this, the HER2-E subtype was significantly associated with pathological complete response (pCR) following lapatinib and trastuzumab without chemotherapy on the PAMELA phase II neoadjuvant trial (Lancet Oncol 2017). Here, we aimed to further validate this observation in a different cohort using tumor samples from the TBCRC023 trial. Methods: TBCRC023 (NCT00999804) was a randomized phase II trial combining a Simon Phase 2 design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Ninety-seven women with HER2+ breast cancer measuring 2 cm or larger (median = 5 cm) were randomized in a 1:2 ratio to 12 vs. 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was added in patients whose tumors were also estrogen receptor (ER)-positive. All evaluable patients were assessed for pCR, defined as no residual invasive carcinoma in the breast. Intrinsic molecular subtypes from tumor biopsy formalin-fixed, paraffin-embedded samples taken at baseline (day 0) were determined with the nCounter-based PAM50 predictor. Gene expression PAM50 data was performed at Hospital Clínic in Barcelona blinded from clinical data. The primary outcome was the association of the HER2-E subtype (vs. non-HER2-E) with pCR. A logistic regression model adjusted for tumor size, ER status, nodal status and treatment arm was performed. Results: A total of 85 of the 97 (87.6%) baseline tumor samples were available. Most patients had the HER2-E subtype (51 [60.0%]), followed by Normal-like (12 [14.1%]), Basal-like (11 [13.0%]), Luminal B (7 [8.2%]) and Luminal A (4 [4.7%]). The proportion of patients with HER2-E tumors within ER+ and ER-negative disease was 54.9% and 67.7%, respectively. At the time of surgery, 17 of 85 patients (20.0%; 95% confidence interval [CI] 0.13-0.30) had a pCR in the breast. Fourteen of 51 patients with the HER2-E subtype (27.5%; 95% CI 0.17 to 0.41) and 3 of 34 patients with non-HER2-E subtypes (8.8%; 95% CI 0.03 to 0.23) achieved a pCR at the time of surgery (adjusted odds ratio 4.33; 95% CI 1.08-17.41; P=0.039). No other clinical-pathological variable was found significantly associated with pCR in the multivariable model. Conclusions: In an independent validation study performed while blinded to clinical outcomes, HER2-E subtype confirms its ability to identify patients with HER2-positive breast cancer who are likely to benefit from dual HER2 blockade therapies without chemotherapy. Further studies should be performed to prospectively validate this biomarker, alone or in combination with other biomarkers. Citation Format: Prat A, De Angelis C, Pascual T, Gutierrez C, Wang T, Paré L, Rexer B, Cortes J, Forero A, Llombart A, Wolff AC, Krop I, Galván P, Pavlick AC, Villagrasa P, Hilsenbeck SG, Schiff R, Osborne CK, Rimawi MF. Independent validation of the HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive 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 P2-09-12.

Background: ALP is an a-specific PI3K-a inhibitor, that has shown to significantly abstracts Annals of Oncology Volume 32 -Issue S2 -2021 S77

Background: The efficacy of trastuzumab in different regimens and settings has been well established, including its benefit as neoadjuvant therapy for early HER2-positive disease. Combinations of two different anti-HER2 therapies without chemotherapy have generated great expectations. However, it is unclear which group of patients benefits the most from this strategy. Within HER2-positive breast cancer, the PAM50 assay identifies a HER2-Enriched (HER2-E) intrinsic subtype characterized by high activation of the EGFR/HER2 pathway and low expression of luminal-related genes, and therefore should obtain the greatest benefit from anti-HER2 therapy. Trial Design: This non-randomized, open-label, multicentric phase II translational research study will evaluate the ability of the PAM50 HER2-E subtype to predict pathological complete response (pCR) to dual HER2 blockade with lapatinib and trastuzumab for a total of 18 weeks. Patients with hormone receptor (HR)-positive disease will also receive endocrine therapy (letrozol or tamoxifen). Eligibility Criteria: Untreated, histologically confirmed invasive breast carcinoma eligible for definitive surgery (stage I-IIIA), HER2-positive invasive breast cancer by central assessment, premenopausal or postmenopausal, ECOG performance status of 0 or 1, adequate organ function and baseline LVEF >50% measured by echocardiography or MUGA scan. Specific Aims: The primary objective is to evaluate the ability of the PAM50 assay to predict pCR in the breast at the time of surgery. Secondary objectives are to (1) assess the correlation of HER2-E with pCR in the breast and axilla, (2) assess the correlation of HER2-E with Residual Cancer Burden (RCB) (3) evaluate the gene expression changes from Day 0 to Day 14 and the correlations with Ki67-IHC at Day 14, (4), identify additional gene expression signatures predictive of pCR, and (5) evaluate safety and tolerability. Statistical Methods: The statistical plan is based on the assumption that breast pCR rate will be 35.0% for HER2-E tumors and 8.0% for non-HER2E. The study will have a 95% power with a significance level of 5% (two-sided) and an assumed drop-out rate of 15%. Biomarker Analyses: Baseline, 14-day treated and post-treatment (surgical) formalin–fixed, paraffin–embedded tissues will be obtained. The expression of 547 genes will be explored with the nCounter platform. Subtype will be identified using the PAM50 predictor (Parker et al. J Clin Oncol 2009). Ki-67-IHC will also be evaluated on pre-treatment and Day-14 samples. Target Accrual: 150 patients with a maximum of 75 HR-positive patients across Spain and Portugal. Patient enrollment will begin in July 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-2-04.

the next follow-up visit and the filled-in TFU form was attached to the clinical chart. When a suspected disease relapse was found, an ambulatory visit was performed.Results: There were 547 pts previously scheduled for in-hospital follow-up visit between March 9th and May 4th, 2020. 82 of 547 pts (15%) were considered not eligible for TFU according to the pre-screening assessment. 465 pts out of 547 (85%) were included in the TFU program. All these pts accepted calls with a compliance rate of 100%.The median age was 73 years (34-95); 152 male (33%) and 313 female (67%). The distribution by tumor type was: 179 breast cancer (38%), 86 colorectal (18%), 55 urinary tract (12%), 39 melanoma and skin (9%), 31 gynecologic (6%), 26 lung cancer(6%), 16 GEP (3%), 15 head and neck (3%), and 18 other tumors (4%). Ten patients with signs/symptoms of tumor recurrence were detected at TFU: 1 had clinical symptoms, 3 abnormal blood tests and 6 suspicious radiological findings. These patients were called for live visit and tumor relapse/progression was confirmed in 10 out of 10 cases. Medical or surgical treatment was started, or planned to start, in all 10 patients.Conclusions: TFU proved to be feasible with an eligibility rate of 85% and 100% patients' compliance. The detection rate for tumor recurrence was 2.1%.Legal entity responsible for the study: The authors.

Background: Resistance to endocrine therapy remains an important clinical problem in hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer (BC), necessitating alternative treatment options. The insulin-like growth factor (IGF) axis and cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathway have been implicated in the pathogenesis and resistance mechanisms of a variety of cancers, including BC. Binding of IGF-I and -II to the IGF receptor results in upregulation of cyclin D1, and subsequent progression through the cell cycle, thus providing rationale for the simultaneous inhibition of IGF-I and -II and CDK4/6. This Phase Ib trial assesses the maximum-tolerated dose (MTD)/recommended phase II dose (RP2D), safety and preliminary efficacy of the IGF-ligand-neutralizing antibody, xentuzumab, in combination with abemaciclib, a selective, small-molecule inhibitor of both CDK4 and 6, in patients (pts) with solid tumors. The trial includes four dose finding cohorts followed by two expansion cohorts. Only those cohorts that will include pts with postmenopausal HR+, HER2- BC will be presented here. Trial design: In this phase Ib multicenter, non-randomized, open-label, dose escalation trial (BI 1280.18 [NCT03099174]), the key aims in the BC cohorts (Cohorts B–D, F) are to define the MTD or recommended phase 2 dose (RP2D), and to evaluate the preliminary efficacy, safety and tolerability of xentuzumab plus abemaciclib in combination with endocrine therapies. Eligible pts include adults ≥18 yrs (≥20 for Japan), with measurable or evaluable disease, adequate organ function, ECOG PS ≤1, and postmenopausal locally advanced or metastatic HR+, HER2- BC (Cohorts B–D, F). CDK4/6 inhibitor-naïve pts (Cohorts B–D) and pts who have received prior CDK4/6 inhibitors (palbociclib or ribociclib) plus aromatase inhibitors (Cohort F) are included. The MTD/RP2D of xentuzumab plus abemaciclib to be used in Cohorts B–D will be established in pts with solid tumors (Cohort A) who will receive xentuzumab (starting dose 1000mg weekly iv) plus abemaciclib (starting dose 150mg every 12 hours). CDK4/6 inhibitor-naïve pts with BC will receive xentuzumab plus abemaciclib at the RP2D determined in Cohort A in combination with letrozole (2.5mg/day; Cohort B), anastrozole (1mg/day; Cohort C), or fulvestrant (500mg/month; Cohort D). CDK4/6 inhibitor pre-treated pts with BC (Cohort F) will receive xentuzumab plus abemaciclib and fulvestrant at the RP2D determined in Cohort D. Primary endpoints in the BC cohorts are the MTD and/or RP2D of xentuzumab plus abemaciclib in combination with endocrine therapies, and the objective response (OR) in CDK4/6 inhibitor pre-treated pts with advanced BC (Cohort F); disease control (DC), duration of DC, time to OR, duration of OR, and progression-free survival (PFS) in Cohort F are secondary endpoints. Additionally, PK outcomes, safety and tolerability will be assessed in all cohorts. This study will be conducted in the US, Europe and Japan. Pt screening started in May 2017. Target enrolment is ˜88 pts, including ˜56 pts with advanced HR+, HER2- BC, of whom ˜20 had previously been treated with CDK 4/6 inhibitors. Citation Format: Yee D, Sablin MP, Iwata H, Johnston EL, Bogenrieder T, Serra J, Hua H, Lo Russo P, Prat A. A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, including hormone receptor-positive, HER2-negative breast cancer (plus endocrine therapy) [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 OT3-06-02.