Von Minckwitz Research Articles

Abstract P2-13-05: Central nervous system metastases as a site of first recurrence in adjuvant therapy trials of HER2+ early breast cancer (EBC)

Abstract Background: Among patients (pts) with HER2+ early breast cancer (EBC), the CNS continues to serve as a sanctuary for distant metastases following trastuzumab-based adjuvant treatment (von Minckwitz 2017, Piccart 2020, von Minckwitz 2019). Since the initial trastuzumab adjuvant trials, several other HER2-directed agents, including pertuzumab, lapatinib, ado-trastuzumab emtansine, and neratinib have been evaluated in EBC. We sought to describe the incidence of CNS metastases as a site of first recurrence in pts with HER2+ EBC who have received a HER2 directed agent, in order to evaluate whether there is any evidence of CNS prevention. Methods: A literature analysis was performed to identify controlled pivotal trials of HER2-directed adjuvant therapy in pts with HER2+ EBC and with or without prior neoadjuvant therapy. Data regarding CNS metastases as the first site of recurrence was extracted along with data from a meta-analysis of trastuzumab adjuvant trials. Due to differences in trial design, populations studied and differences in the use of neoadjuvant therapy, a descriptive summary of data is presented in lieu of statistical cross-trial comparisons. Results: Results from adjuvant trials of trastuzumab, lapatinib, neratinib, pertuzumab, and ado-trastuzumab emtansine in pts with HER2+ EBC (meta-analysis of trastuzumab trials, ALLTO, ExteNET, APHINITY and KATHERINE, respectively) are summarized (Table). In the trastuzumab adjuvant trials the incidence of CNS metastases was ~2.5% (Olson 2013). No pts had prior neoadjuvant therapy in APHINITY and neoadjuvant use was limited in ALLTO (8%). The addition of lapatinib, a reversible TKI, or pertuzumab, a HER2 monoclonal antibody, to trastuzumab had no impact on the incidence of CNS metastases. In the lapatinib and pertuzumab studies, the incidence of CNS metastases in all study groups was ~2%. The proportion of pts with CNS recurrence as a first site of metastasis among placebo pts in the ExteNET trial was similar to that reported in the other 3 trials (Table). Numerical improvements in the incidence of CNS as a site of first recurrence were seen in the intention-to-treat (ITT) population as well as in pts with hormone receptor positive (HR+) disease. The 5-year cumulative incidence of CNS metastases as a site of first recurrence in the ExteNET ITT population was 1.3% and in pts with HR+ disease who initiated neratinib ≤1 year post trastuzumab (HR+/≤1yr) was 0.7% (Table). The KATHERINE study, which enrolled higher risk patients, reported a higher incidence of CNS metastases as site of first recurrence, but without a reduction in the intervention arm (5.9% ado-trastuzumab emtansine and 4.3% trastuzumab). In a descriptive analysis of the subgroup of pts in ExteNET who were HR+/≤1yr and had residual disease after neoadjuvant therapy (n=295), the incidence of CNS metastases was 0.8% in the neratinib arm vs 3.6% in the placebo arm. Conclusions: The risk of developing a CNS metastasis as the site of first recurrence is generally low; however, it is higher in those with residual disease after neoadjuvant therapy. The ExteNET trial of neratinib is the only study to show a signal decrease in the incidence of CNS recurrence as the first site of relapse among HER2+ EBC pts. These data are consistent with other trials showing CNS activity with neratinib in the metastatic setting. CNS Recurrence as the First Site of Metastasis in Studies of Adjuvant Therapy in HER2+ EBCTrial and PopulationAnalysis TimepointNNeoadjuvant Population CNS Recurrence, %ComparatorTreatmentAdjuvant trast Meta-analysis1-9020N/A1.942.56ALLTO23 yr5190~822ExteNET3ITT5 yr284026%1.81.3HR+/≤1yr post trast.5 yr133427%2.10.7APHINITY4 node (+) or high-risk node ()3 yr480501.91.9No pCR Post Neoadjuvant TxKATHERINE5 high-risk3 yr1486N/A4.35.9ExteNET3 HR+/≤1yr post trast5 yr295N/A3.60.8HR+/≤1yr, hormone receptor positive with start of neratinib ≤1 year following trastuzumab adjuvant therapy; ITT, intent-to-treat; PLB, placebo; T-DM1, ado trastuzumab emtansine; trast, trastuzumab; pCR, pathologic complete responsea.Using all patients in the trials as a denominator1.Olson 2013; 2. Piccart-Gebhart 2015; 3. Chan 2021; 4. Von Minckwitz 2017; 5. Mamounas 2020 Citation Format: Nancy U Lin, Diana Lueftner, Adam M Brufsky, Sara M Tolaney, Michelle E Melisko, Frankie Ann Holmes, Ahmad Awada. Central nervous system metastases as a site of first recurrence in adjuvant therapy trials of HER2+ early breast cancer (EBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-05.

Abstract GS1-02: Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B

Abstract Background: About one third of patients with hormone-receptor-positive (HR+), HER2- primary breast cancer with residual invasive disease after neoadjuvant chemotherapy will relapse despite adjuvant endocrine therapy. The risk of relapse can be assessed more accurately using the CPS-EG scoring system (Mittendorf et al. JCO 2011). Therapeutic inhibition of cyclin-dependent kinase 4 and 6 (CDK 4/6) by palbociclib combined with endocrine therapy demonstrated highly relevant efficacy in metastatic breast cancer. Thus, we hypothesize that palbociclib may also be active in these high-risk patients with primary breast cancer. Methods: PENELOPE-B (NCT01864746) is a double-blind, placebo-controlled, phase III study in women with centrally confirmed HR+, HER2- primary breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy and at high-risk of relapse (CPS-EG score ≥3 or 2 and ypN+). After completion of neoadjuvant chemotherapy and locoregional therapy, patients were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 in a 28d cycle in addition to standard endocrine therapy. Randomization was stratified by lymph node status (at surgery), age, Ki-67, global region, and CPS-EG score. Primary endpoint is invasive disease-free survival (iDFS). Final analysis was planned after 290 iDFS events with efficacy boundary p<0.0463 due to 2 interim analyses. Main secondary endpoints include iDFS excluding second primary invasive non-breast cancers, overall survival, and safety. Results: A total of 1250 patients were randomized between 2/2014 and 12/2017. Median age was 49.7 years [range 19-79]; 96.8% had residual disease in the breast, 94.6% were ypN+; G3 was reported in 47.4%, Ki-67 >15% in 27.7 %; 54.7% of patients had risk status CPS-EG score ≥3. 1118 patients (89%) completed at least 7 cycles of therapy. 50.1% of patients received aromatase inhibitor (AI), 49.8% tamoxifen, 6.6% AI + gonadotropin-releasing hormone (GnRH) and 9.7% tamoxifen + GnRH. Most common related serious adverse events (SAEs) were infections and vascular disorders. 8 fatal SAEs were reported. Conclusions: PENELOPE-B evaluates the effect of palbociclib for 1 year compared to placebo in addition to endocrine therapy in high-risk primary breast cancer patients. The database was locked with 308 events on September 25th 2020. After breaking the blind for analysis, top line results will be available as of mid October 2020. Results of the final iDFS analysis will be presented at the meeting. Citation Format: Sibylle Loibl, Frederik Marmé, Miguel Martin, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Harry Bear, Nicole Mc Carthy, Mireia Melé Olivé, Karen Gelmon, José García Sáenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Sabine Seiler, Valentina Nekljudova, Carsten Denkert, Michael Gnant, Andreas Makris, Nicole Burchardi, Gunter von Minckwitz. Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B [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 GS1-02.

P10 Clinical and pathologic tumor response following response-guided neoadjuvant chemotherapy for locally advanced breast cancer in the Philippine General Hospital – Breast Care Center

Background and purpose Neoadjuvant chemotherapy is recommended for locally advanced breast cancer (LABC) to improve surgical options and to provide an in-vivo assessment of response to treatment. The Philippine General Hospital (PGH) Breast Care Center has adopted a protocol of response-guided approach to allow for tailoring of the chemotherapy regimen being administered. This study aims to describe the clinical and pathologic tumor response of LABC patients after response-guided neoadjuvant chemotherapy. Methods This is a retrospective cohort of 128 patients with LABC who underwent neoadjuvant chemotherapy at the PGH Breast Care Center using sequential doxorubicin/cyclophosphamide-docetaxel (AC-T) regimen from July 2013 to June 2018. Clinical and pathologic response rates were obtained. Patients were categorized into either good or poor responders and were analyzed according to specific clinicopathologic factors. Results The mean clinical tumor response was at 80% with 14 patients (11%) achieving a pathologic complete response (PCR). The Her2 enriched subtype had the highest PCR rate (23.5%). Interestingly, 2 patients who initially had poor response to AC but had good response upon shifting to T attained PCR. A comparison of the clinicopathologic variables in patients with good or poor response to chemotherapy showed that there are significantly more patients with good response to the AC regimen if the patient is pre-menopausal (p=0.04), those with ductal histology (p=0.03), those with a triple negative subtype (p=0.002) and those with HR+HER2+ subtype (p=0.03). Intrinsic subtype did not appear to be a significant factor for a better response in those who received Docetaxel. A Spearman’s Rho score of 0.69 (p-value <0.0001) indicates a strong association between the pathologic and clinical responses. Conclusion Neoadjuvant chemotherapy allows direct and early evaluation of treatment response. This promotes personalized treatment and may justify early shifting to another chemotherapy regimen for non-responders as in response-guided neoadjuvant chemotherapy. 1. von Minckwitz, et. al. Response-Guided Neoadjuvant Chemotherapy for Breast Cancer. J Clin Oncol 31:3623-3630. DOI: 10.1200/JCO.2012.45.09402. Kim S.I, et. al. Molecular subtypes and Tumor Response to Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer. Oncology 2010;79:324-330. http://doi.org/10.1159/000322192

Abstract P5-06-02: Pathologic complete response (pCR) and prognosis following neoadjuvant chemotherapy plus anti-HER2 therapy of HER2-positive early breast cancer (EBC)

Abstract Background: The achievement of pCR (breast and axilla) is strongly prognostic for event-free (EFS) and overall survival (OS) in EBC (Cortazar 2014), and modulation of therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR (Von Minckwitz 2019). We sought to investigate prognostic factors for EFS and OS among patients with and without pCR following neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. Methods: We used individual data from 3,710 patients randomized in 11 neoadjuvant trials for HER2-positive EBC with N≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone-receptor (HR)-positive vs. HR-negative disease, and for patients who achieved pCR (pCR+; ypT0/is, ypN0) vs. patients who did not achieve pCR (pCR-). Results: The median follow-up overall was 61.2 months. The table shows hazard ratios and 5-year Kaplan-Meier estimates of OS (5yr OS) according to HR and pCR. Comparable results were observed for EFS. Both cT (1-2 vs. 3-4) and cN (cN- vs. cN+) were independent prognostic factors for OS in most subsets, including in pCR+ patients. Conclusions: These results confirm that patients achieving pCR have far better long-term outcomes than patients who do not, and that traditional poor prognostic features namely tumour size and nodal status remain important even after a pCR, with no clear evidence that the relative impact of unfavourable (cT3-4 or cN+) features is different in patients who achieve a pCR than in those who did not. Key words: neo-adjuvant therapy, HER2-targeted therapy, pathological complete response, prognostic factors, overall survival Funding: German Breast Group HR pCRBaseline cT/cN DeathsPatients5yr OS (%)Hazard ratio* [95% CI]HR+ pCR+cT1-2/cN-521298.6%1.0 (reference)(N= 637)cT3-4/cN-46592.9%0.49 [0.21-1.14]cT1-2/cN+720095.1%0.82 [0.34-1.99]cT3-4/cN+1016094.0%0.40 [0.13-1.25]HR+ pCR-cT1-2/cN-1737796.3%1.0 (reference)(N=1399)cT3-4/cN-2514381.8%0.51 [0.36-0.73]cT1-2/cN+4844888.9%0.71 [0.49-1.03]cT3-4/cN+6443184.9%0.36 [0.23-0.58]HR- pCR+cT1-2/cN-319698.1%1.0 (reference)(N=860)cT3-4/cN-89090.4%0.56 [0.32-0.98]cT1-2/cN+1928092.4%0.49 [0.24-0.98]cT3-4/cN+3029489.5%0.27 [0.12-0.64]HR- pCR-cT1-2/cN-2114083.2%1.0 (reference)(N=814)cT3-4/cN-207871.4%0.46 [0.34-0.64]cT1-2/cN+4225181.6%0.76 [0.53-1.09]cT3-4/cN+11634561.9%0.35 [0.22-0.56]*Hazard ratio cT1-2/cN- vs. higher risk cohorts Citation Format: Sibylle Loibl, Michael Untch, Marc Buyse, André Robidoux, Luca Gianni, Andreas Schneeweiss, Pierfranco Conte, Martine Piccart, Hervé Bonnefoi, Christian Jackisch, Valentina Nekljudova, Joseph Costantino, Pinuccia Valagussa, Colin Neate, Richard Gelber, Coralie Poncet, Pierre Squifflet, Everardo Saad, Dominik Heinzmann, Carsten Denkert, Charles E Geyer, Javier Cortes, Valentina Guarneri, Evandro de Azambuja, David Cameron, Gustavo Ismael, Gunter von Minckwitz, Norman Wolmark, Patricia Cortazar. Pathologic complete response (pCR) and prognosis following neoadjuvant chemotherapy plus anti-HER2 therapy of HER2-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-02.

LBA4 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

LBA4 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

LBA19 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

LBA19 - Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC)

Abstract P1-17-05: The impact of clinical risk assessment versus PAM-50 ROR score on prognosis and therapeutic decision making in patients with hormone-receptor positive early stage breast cancer

Abstract Background: Therapeutic recommendations for adjuvant treatment of hormone-receptor positive breast cancer patients depend on the individual recurrence risk. A number of genomic assays introduced to achieve this goal, but it's still questioned if they actually offer superior risk assessment compared to traditional risk evaluation by experienced clinicians. This study was designed to compare the prognostic accuracy of PAM-50 to clinical judgment. Methods: Based on the real data of a large adjuvant trial cohort (ABCSG-8, postmenopausal HR positive breast cancer patients), we created online-questionnaires including demographic, histological, and local-therapy details, with and without results of PAM50 ROR score. Out of 14 international breast cancer experts asked for individual patient's risk evaluation (low, intermediate, high) and therapy recommendations, 9 completed the questionnaire. Patient data were described by Kaplan-Meier estimates of distant disease free survival (DDFS) stratified by risk group. Cox regression models were compared using the Akaike Information Criterion (AIC). Results: 10 years DDFS and hazard ratios for distant recurrences stratified by risk-group as estimated giving in Table 1: 10 years DDFS and hazard ratios for distant recurrences stratified by risk-group as estimated Low riskIntermediate riskHigh risk n (%)10y DDFS,%(95%CI)n (%)10y DDFS,%(95%CI)n (%)10y DDFS, %(95%CI) HR(95% CI) HR(95% CI) HR(95% CI)Clinical only: AIC 817.6269 (43)93.0(89.8-96.2)289 (46)89.7(85.9-93.5)73 (11)76.6(66.1-87.1) 0.68(0.39,1.20) 1 2.57(1.41,4.65)PAM50 ROR: AIC 804.8241 (34)96.5(93.1-99.1)210 (33)89.2(84.7-93.7)207 (33)82.5(76.9-88.2) 0.27(0.11,0.62) 1 1.66(0.99,2.78)Combined: AIC 813.4232 (37)95.7(93.0-98.5)282 (45)87.8(83.7-92.0)117 (18)81.7(74.2-89.2) 0.42(0.22,0.84) 1 1.90(1.11,3.24) Adding genomic information to clinical risk factors leads to escalation of therapeutic recommendations (i.e. additional chemotherapy, extended adjuvant endocrine) in 20% of patients, and de-escalation in 13% of patients. Conclusions: Clinical judgment accurately identified the patients at high risk of relapse, but was clearly inferior to multi-genomic testing using the PAM-50 ROR score in differentiating low from intermediate risk. Particularly when avoiding unnecessary escalated therapy is the strategic goal, the addition of PAM-50 testing to clinical judgment offers improved accuracy in predicting low vs. intermediate risk of breast cancer recurrence. Citation Format: Devyatko Y, Filipits M, Greil R, Balic M, Bago-Horvath Z, Singer C, Fitzal F, Steger G, Gray B, Ferree S, Fesl C, Soelkner L, von Minckwitz G, Gnant M. The impact of clinical risk assessment versus PAM-50 ROR score on prognosis and therapeutic decision making in patients with hormone-receptor positive early stage breast cancer [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 P1-17-05.

Abstract GS1-10: Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE

Abstract Background: Patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a high risk of recurrence and death. The current standard of care is continuation of the same HER2-targeted therapy in the adjuvant setting for one year. T-DM1 has shown activity and a favorable benefit-risk profile in metastatic patients with disease progression after prior chemotherapy plus HER2-targeted therapy. Thus, T-DM1 may also be active in patients with residual invasive disease after neoadjuvant HER2-targeted therapy. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed HER2-positive (IHC3+ or ISH+) primary breast cancer (T1–4, N0–3, M0) who received neoadjuvant chemotherapy plus HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg IV q3w) or trastuzumab (6 mg/kg IV q3w), for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single versus dual neoadjuvant HER2-targeted therapy, and pathological nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint is invasive disease-free survival (IDFS). A single interim analysis (IA) was planned after approximately 67% of the IDFS events required for the primary analysis had occurred, with an efficacy stopping boundary of HR?0.732 or p&amp;lt;0.0124. The statistical plan stipulated an IA of OS if the IDFS IA boundary was crossed. Secondary endpoints include IDFS including second primary non-breast cancer, disease-free survival, distant recurrence-free interval, overall survival, and safety. Results:After review of the pre-specified IA, the IDMC recommended full analysis and disclosure of the results. With 256 IDFS events reported, administration of T-DM1 significantly improved IDFS compared with trastuzumab (unstratified HR=0.50; 95% CI: 0.39 to 0.64; p&amp;lt;0.0001). IDFS events occurred in 91 patients (12.2%) in the T-DM1 arm compared with 165 patients (22.2%) in the trastuzumab arm. T-DM1 treatment increased estimated three-year IDFS rates (88.3% vs 77.0% with trastuzumab). A consistent benefit was shown across all stratification subgroups. With 98 deaths reported, the OS analysis is immature (HR=0.70; 95% CI: 0.47 to 1.05; p=0.085). The safety data were consistent with the known safety profile of T-DM1, with expected increases in AEs associated with T-DM1 compared to trastuzumab alone. One grade 5 AE (0.1%) occurred in each arm. Conclusions: Adjuvant T-DM1 substantially improved IDFS in patients with HER2-positive early breast cancer with residual disease after completion of neoadjuvant therapy. Citation Format: Geyer, Jr. CE, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Fischer HH, Redondo A, Jackisch C, Jacot W, Conlin AK, Schneeweiss A, Wapnir IL, Fasching PA, DiGiovanna MP, Wuelfing P, Arce-Salinas C, Crown JP, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, von Minckwitz G. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE [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 GS1-10.

Abstract PD5-05: Pre-therapeutic PD-L1 expression and dynamics of Ki-67 and gene expression during neoadjuvant immune-checkpoint blockade and chemotherapy to predict response within the GeparNuevo trial

Abstract Background In the GeparNuevo trial, the PD-L1 inhibitor durvalumab increased the rate of pathologic complete response (pCR; ypT0 ypN0) in triple-negative breast cancer if treatment started in a two-week window before neoadjuvant taxane/anthracycline chemotherapy (61 % pCR vs. 41%; p = 0.048; Loibl et al. ASCO 2018). Overall, pCR rates increased only numerically from 53 % to 44 % (p = 0.281). Herein, we aimed to evaluate the predictive value of PD-L1 immunohistochemistry in pre-therapeutic core biopsies. In addition, we identified dynamics in gene expression using repeated biopsies. Patients and Methods 174 patients were randomized to receive durvalumab or placebo with neoadjuvant chemotherapy. In the window part, 117 patients received a single dose of durvalumab (or placebo) before chemotherapy. Core biopsies were taken at three times: pre-treatment (“A”; N=174), after the window part (“B”; N=88) and after 12 weeks of nab-Paclitaxel (“C”; N=33). PD-L1 immunohistochemistry in A-biopsies (Ventana SP263 Assay) was recorded as percentage of cells with membranous staining in tumor cells and lymphocytes (TILs). We defined a tumor as PD-L1 high if ≥ 25 % of either compartment was stained. Ki-67 was stained on all available A, B and C biopsies (MIB-1, Dako, 1:100) and recorded as the percentage of tumor cells with nuclear staining. We profiled all available biopsies with targeted RNASeq using the HTG EdgeSeq platform (Oncology Biomarker panel, 2560 genes). Sequencing (IonTorrent S5) was successful in 162 A-, 79 B- and 31 C-biopsies. Results PD-L1 expression was high in 24 % of A-biopsies and was predictive for pCR in the complete cohort (OR 2.561; 1.183-5.554; p = 0.017). PD-L1 status of the TILs, but not of the tumor cells, was predictive (OR 1.313; 1.040-1.656; P= 0.022). The effect was not specific for durvalumab treatment. Higher levels of Ki-67 were predictive for pCR in B- biopsies in all patients (OR 1.399; 1.053-1.858; P =0.021) and in the placebo arm, but not in the durvalumab arm. Ki-67 levels in C-biopsies were not predictive; neither was the change in Ki-67 between pre-treatment and later time points (B vs. A or C vs. A). In a differential mRNA expression analysis (A vs. B), we found seven differentially expressed genes after one dose of durvalumab. We observed strong effects on gene expression after taxane treatment (A vs. C), but no significant difference according to treatment. These genes were associated with biological processes involved in therapy response. The pre-treatment levels of 12 of 69 markedly differentially expressed genes were associated with worse response to chemotherapy. Conclusion In A-biopsies, PD-L1 in TILs was predictive for response, and in B-biopsies, Ki-67 was predictive, but neither marker could specifically predict response to durvalumab. We observed limited effects of a single half-dose of durvalumab on global gene expression, but could identify substantial differential expression after taxane treatment. The evaluation of gene expression dynamic offers a promising approach for the identification of resistance-associated markers. The study was financially supported by AstraZeneca and Celgene Citation Format: Sinn BV, Loibl S, Karn T, Untch M, Kunze CA, Weber KE, Treue D, Wagner K, Hanusch CA, Klauschen F, Fasching PA, Huober J, Zahm D-M, Jackisch C, Thomalla J, Blohmer J-U, van Mackelenbergh M, Rhiem K, Felder B, von Minckwitz G, Burchardi N, Schneeweiss A, Denkert C. Pre-therapeutic PD-L1 expression and dynamics of Ki-67 and gene expression during neoadjuvant immune-checkpoint blockade and chemotherapy to predict response within the GeparNuevo trial [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 PD5-05.

Abstract P2-08-01: Factors predicting relapse in early breast cancer patients with a pathological complete response after neoadjuvant therapy – Results of a pooled analysis based on the GBG meta-database

Abstract Background Even though patients with a pCR following neoadjuvant chemotherapy have an excellent prognosis still some of these patients will eventually relapse. A better identification of pts with an increased risk of relapse despite a pCR would be helpful to select these patients for additional post-neoadjuvant treatment strategies. Thus, the rationale of this retrospective analysis was to identify factors predicting relapse despite a pCR. Methods This pooled retrospective analysis based on the GBG meta-database includes the neoadjuvant trials GeparTrio, GeparQuattro, GeparQuinto, GeparSixto and GeparSepto. In these trials 2188 (27%) of 7933 pts had a pCR according to ypT0/ypTis ypN0 Definition and were included. The primary endpoint was disease-free survival (DFS), secondary endpoints were distant DFS (DDFS) and overall survival (OS). A multivariate Cox proportional hazards model was used to report hazard ratios with 95% confidence interval (CI). The two-sided significance level was set to α=0.05. Endpoints were analysed for all pts and in subgroups defined by intrinsic subtypes. The potential risk factors intrinsic subtype (HER2 negative/hormone receptor (HR) positive, triple negative, HER2 positive/HR positive, HER2 positive/HR negative), histological tumor type (lobular vs other), grade (G1/G2 vs G3), KI67 (≤20% vs higher), initial cT and cN stadium (cT1 vs cT2 vs cT3/4; cN0 vs cN+), age (≤40 vs 41-59 vs ≥60), BMI (&amp;lt; 25 vs 25-29 vs ≥ 30), planned number of cycles of chemotherapy (≤6 vs &amp;gt; 6), menopausal status (pre- vs postmenopausal) and clinical response after 2-4 cycles (SD vs PR vs CR vs PD) were included as covariates in multivariate Cox regression models as well as study identification. Results From 2188 evaluable patients DFS, DDFS and OS events were observed in 290/197/130 pts respectively; the median follow-up over all studies was 59 months. In multivariate analysis including study and all potential risk factors DFS was significantly different with regard to the initial cN status (cN+ vs cN0, hazard ratio (HR) 1.70; 95% CI [1.2, 2.4], p=0.002). Of borderline significance was histological type (non-lobular vs lobular, HR 0.52 95% CI [0.3, 1.1]; p=0.076) and initial tumor stage (cT3/4 vs cT1, HR 1.61 95% CI [1.0, 2.7]; p=0.064). In terms of DDFS significant differences were seen for the initial cN status (cN+ vs cN0, HR 2.34; 95% CI [1.5, 3.6], p&amp;lt;0.001) and initial tumor stage (cT3/4 vs cT1, HR 1.83 95% CI [1.0, 3.3]; p=0.044); histological type was again close to significance (non-lobular vs lobular, HR 0.46 95% CI [0.2, 1.1]; p=0.067). Multivariate analysis showed significantly worse OS with initial cT3/4 tumors (cT3/4 vs cT1, HR 2.48 95%CI [1.1, 5.7]; p=0.030), and the lobular type (non-lobular vs lobular, HR 0.35 95% CI [0.1, 0.9]; p=0.026) and a trend for worse OS in pts with cN+ (cN+ vs cN0, HR 1.67 95% CI [1.0, 2.9]; p=0.067). Conclusions Initial tumor load before start of neoadjuvant chemotherapy (tumor stage and nodal status) and lobular subtype were predictors of long term outcome after a pCR following neoadjuvant chemotherapy. Intrinsic subtype, KI67, grade and planned number of cycles were not predictive for a relapse. Citation Format: Huober J, Schneeweiss A, Blohmer J-U, Denkert C, Tesch H, Hanusch CA, Salat C, Rhiem K, Rezai M, Solbach C, Fasching PA, Jackisch C, Mehta K, Nekljudova V, Seither F, von Minckwitz G, Loibl S, Untch M. Factors predicting relapse in early breast cancer patients with a pathological complete response after neoadjuvant therapy – Results of a pooled analysis based on the GBG meta-database [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 P2-08-01.

Abstract PD2-07: mRNA signatures predict response to durvalumab therapy in triple negative breast cancer (TNBC)– Results of the translational biomarker programme of the neoadjuvant double-blind placebo controlled GeparNuevo trial

Abstract Background: The GeparNuevo trial showed a numerical increase in the pCR rate to 53% vs 44%; p=0.281 compared to placebo in TNBC with the addition of the anti-PD-L1 antibody durvalumab to a neoadjuvant anthracycline-taxane containing chemotherapy (Loibl S et al. ASCO 2018). In a predefined subgroup analysis, a significant increase of the pCR rate was observed for patients that received durvalumab for 2 weeks alone prior to the start of chemotherapy in a window phase (61% vs 41%, p interaction=0.048), while the pCR rate was not increased for the subset of patients that did start durvalumab together with chemotherapy. Here we report the main results of the translational programme for GeparNuevo with a focus on mRNA signatures predictive for pCR in pretherapeutic core biopsies. Methods: A total of 162 baseline FFPE core biopsies were evaluable for expression of 2560 genes using the HTG EdgeSeq® system that combines a modified nuclease protection assay with next generation sequencing. Data was processed as recommended by the HTG and median transformed for further analyses. For differential gene expression analyses, the data was scale-normalized (TMM normalization; EdgeR package) and linear models were fit (limma package). Prior to these analyses, genes were filtered based on minimal expression (&amp;gt; 4) and variability (IQR &amp;gt; 1). As a first step, predefined immune-genes signature (TILs signature) (Denkert et al. JCO 2016) as well as IFN-gamma signatures were evaluated for correlation with pCR in logistic regression models. Subsequently, we performed a differential gene expression analysis according to therapy response for the durvalumab-arm and the placebo arm using the pre-filtered candidate genes. Gene names are not included in this abstract to allow filing of IP, but full gene names will be presented at the SABCS meeting. Results: The predefined TIL- and IFN-gamma signatures were associated with increased pCR rates in the complete cohort (TIL-signature: OR 1.44, 95% CI 1.15-1.82, p=0.002; IFN-Gamma-signature: OR 1.63, 95% CI 1.22-2.24, p=0.002) as well as in the durvalumab arm (p=0.012 and 0.042) and the placebo arm (p=0.050 and 0.011). These signatures were general pCR predictors without specificity for durvalumab response. Additional 44 genes were significantly (p&amp;lt;0.05) correlated with pCR in the durvalumab arm. Of those, 21 genes were upregulated and 23 genes were downregulated in pCR patients. 14 of the 21 upregulated genes are related to tumorbiologically relevant immune cell functions. A total of 6 of the 44 genes had a positive test for interaction (interaction p&amp;lt;0.05) with the therapy arm (durvalumab + NACT vs. placebo + NACT), suggesting that these genes might specifically predict response to durvalumab. Additional analyses investigating the role of molecular tumor subtypes, additional immune gene signatures and other subgroup analyses will be presented at the meeting. Conclusion: Our results show that specific immune-related gene expression signatures predict response to durvalumab in primary triple negative breast cancer. The trial was financially supported by Astra Zeneca and Celgene Citation Format: Loibl S, Sinn BV, Karn T, Untch M, Treue D, Sinn H-P, Weber KE, Hanusch CA, Fasching PA, Huober J, Zahm D-M, Jackisch C, Thomalla J, Blohmer J-U, Marmé F, Klauschen F, Rhiem K, Felder B, von Minckwitz G, Burchardi N, Schneeweiss A, Denkert C. mRNA signatures predict response to durvalumab therapy in triple negative breast cancer (TNBC)– Results of the translational biomarker programme of the neoadjuvant double-blind placebo controlled GeparNuevo trial [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 PD2-07.

Abstract P2-13-01: Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early-stage breast cancer: Subgroup analyses from the phase III ExteNET trial

Abstract Background: The international, randomized, placebo-controlled phase III ExteNET trial showed that 1 year (yr) of neratinib 240 mg/day after trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) in 2840 patients with early-stage HER2+ breast cancer at 2 yr (hazard ratio 0.67; 95% CI 0.50–0.91; p=0.009) [Chan 2016] and 5 yr (hazard ratio 0.73; 95% CI 0.57-0.92; p=0.008) [Martin 2017]. A prespecified subgroup analysis by hormone receptor (HR) status suggested enhanced efficacy with neratinib in patients with HR+ (2-yr hazard ratio 0.51; 95% CI 0.33–0.77) vs. HR– tumors (2-yr hazard ratio 0.93; 95% CI 0.60–1.43). The efficacy of neratinib was also greater in patients who initiated treatment within 1 yr of prior trastuzumab compared with those who started neratinib later. The European Medicines Agency's Committee for Medicinal Products for Human Use recently recommended neratinib for use in patients with HR+ tumors who initiate treatment within 1 yr of completing trastuzumab-based adjuvant therapy. Subgroup analyses from ExteNET examining iDFS benefits in this patient population are presented here. Methods: Patients with early-stage HER2+ breast cancer who completed trastuzumab-based (neo)adjuvant therapy were assigned to oral neratinib 240 mg/day or placebo for 1 yr. Randomization was stratified by HR status (determined locally before trial entry), nodal status, and trastuzumab regimen. Endocrine therapy was allowed in patients with HR+ disease. The primary endpoint, iDFS, was tested by 2-sided log-rank test and hazard ratios (95% CI) were estimated using Cox proportional hazards models. Kaplan-Meier methods were used to estimate iDFS rates. Secondary endpoints were DFS-DCIS, time to distant recurrence, distant DFS, and CNS recurrences. The primary analysis was conducted at 2 yr, and a sensitivity analysis conducted at 5 yr. Clinicaltrials.gov:NCT00878709. Results: Of the 2840 patients (neratinib, n=1420; placebo, n=1420), 1631 (57%) had HR+ disease (neratinib, n=816; placebo, n=815). Most (93%) HR+ patients were receiving endocrine therapy at baseline. 1334 of 1631 (82%) patients with HR+ tumors were randomized to start neratinib within 1 yr of last trastuzumab dose (neratinib, n=670; placebo, n=664). iDFS benefits from neratinib in this population are shown in the table. Secondary endpoints were also improved with neratinib vs. placebo in this population. Safety data in this subset will be presented at the meeting. Table. iDFS in patients with an interval between last trastuzumab dose and randomization of ≤1 yr HR+ population (N=1334)ITT population (N=2297) Hazard ratiob Hazard ratiob Δ, %a(95% CI)P-valueΔ, %a(95% CI)P-value2-yr analysisc+4.50.490.002+2.90.630.006 (0.30–0.78) (0.45–0.88) 5-yr analysisd+5.10.580.002+3.20.700.006 (0.41–0.82) (0.54–0.90) aDifference in iDFS rates between neratinib vs. placebo; bNeratinib vs. placebo; cData cut-off: July 2014; dData cut-off: March 2017 Conclusions: Neratinib may have enhanced and sustained efficacy in patients with HR+ disease who initiate treatment within 1 yr of trastuzumab-based adjuvant therapy. Citation Format: Gnant M, Martin M, Holmes F-A, Jackisch C, Chia SK, Iwata H, Moy B, Martinez N, Mansi J, Morales S, Ruiz-Borrego M, von Minckwitz G, Buyse M, Delaloge S, Bhandari M, Murias Rosales A, Galeano T, Fujita T, Luczak A, Barrios CH, Saura C, Rugo HS, Chien J, Johnston SR, Spencer M, Xu F, Barnett B, Chan A, Ejlertsen B. Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early-stage breast cancer: Subgroup analyses from the phase III ExteNET trial [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 P2-13-01.

Abstract P3-10-01: Single-cell profiling identifies hypoxic carcinoma cells as source of an immunosuppressive VEGFA metagene

Abstract Background: We have previously shown that expression of the IL8/VEGFA-metagene eliminates the good prognostic effect of TILs in TNBC (PMID 21978456, 28750120). We also showed that the VEGFA metagene predicted response to neoadjuvant bevacizumab in the GeparQuinto trial (Karn 2017 SABCS #851166). The main cellular sources of the transcripts that comprise the VEGFA metagene are unknown since mRNA profiling of bulk biopsies contains signals from different cell types. Methods: Individual genes that comprise the VEGFA metagene were measured in bulk tissue- and single cell-RNA-Seq from breast cancer subtypes and normal cells on different platforms (Affymetrix n=4915, Agilent n=597, Illumina n=2433, RNA-Seq n=1215, Exome Capture RNA-Seq n=226, HTG-Seq n=243, sc-RNA-Seq n=24710). For blinded, orthogonal validation we performed immunohistochemistry. Effect of neoadjuvant chemotherapy with or without bevacizumab was studied by RNA-Seq and IHC on samples from GeparQuinto trial. SWOG S0800 (GSE114403), PROMIX (GSE87455), and GeparSixto trials were used for validation. TCGA was mined for mutations and somatic CNA. RNA-Seq from GeparNuevo was used for correlation with checkpoint inhibitor treatment. Results: We identified a stable core of six genes (VEGFA, ANGPTL4, ADM, NDRG1, DDIT4, CSTB) in different cohorts. Strong expression of this signature was mainly restricted to TNBC subtype and associated with poor prognosis within this subgroup. Single cell RNA-Seq of breast epithelial cells from 4 reduction mammoplasties and 4 TNBC revealed that these genes are coexpressed in individual epithelial cells and not associated with endothelial cells. In line with their presumed functions in cellular stress and hypoxia, immunohistochemistry revealed strong para-necrotic expression in TNBC. Moreover, high gene expression in TNBC was associated with mutations in DNA damage control pathways, somatic copy number alterations, and lower TILs. While chemotherapy led to downregulation, bevacizumab increased expression. In multivariate analysis, high pretreatment values predict pCR to both bevacizumab and chemotherapy (OR 2.40, P=0.006), which may be explained by sensitivity of tumors which are already under cellular stress. On the other hand, expression of the VEGFA metagene seems to create an immunosuppressive environment that counteracts the positive prognostic effect of TILs. In pre-treatment biopsies from the GeparNuevo checkpoint inhibitor trial we found a negative correlation of VEGFA metagene expression with the amount of the recently identified tissue-resident memory T cell subset (CD8TRM, PMID 29942092; P=0.002), while the subsequent increase of CD8TRM during treatment was larger in tumors with high VEGFA (P=0.019). Conclusions: Perinecrotic carcinoma cells under stress from hypoxia and or chromosomal instability are the source of the VEGFA metagene signature. Its predictive value in TNBC suggests estimating and reporting the amount of necrosis in the pathology report may be helpful in predicting response to preoperative chemotherapy, and could be used as stratification factor in clinical trials. The signature indicates an immunosuppressive environment and should be further studied in the context of immune therapies in combinations with anti-angiogenic treatment. Citation Format: Karn T, Denkert C, Sinn BV, Weber K, Nekljudova V, Rody A, Meissner T, Hatzis C, El-Balat A, Becker S, Solbach C, Untch M, Schneeweiss A, von Minckwitz G, Loibl S, Pusztai L, Holtrich U. Single-cell profiling identifies hypoxic carcinoma cells as source of an immunosuppressive VEGFA metagene [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-01.

Abstract P1-08-29: Current status of clinical and pathological characteristics of breast cancer patients in Brazil: Results of the AMAZONA III study (GBECAM 0115)

Abstract BACKGROUND Breast cancer (BC) is the most common tumor in women in Brazil with about 60 thousand new cases estimated per year. In low and middle-income countries, patients with BC are diagnosed with more advanced stages as compared with high-income countries. In Brazil, disparities in access to new therapies are recognized; previous data suggests worse survival of BC patients treated in the public system. The aim of AMAZONA III study (GBECAM 0115) is to describe the current status of BC care in Brazil. Here we report patients data at baseline. METHODS The AMAZONA III is a prospective BC registry that included women 18 years or older with newly diagnosed stage I to IV BC from 22 sites in Brazil in the period of January 2016 to March 2018. All patients provided written informed consent; data was collected from interview and medical charts, comprising clinical-demographic variables, initial treatment and a planned follow-up for 5 years. BC subtypes were defined by hormone receptor (HR) expression, HER2 status and grade according to von Minckwitz G. et al 2012. Here we present a descriptive analysis of the patients' baseline characteristics. Continuous variables are shown as mean (standard-deviation) and categorical variables by its absolute and relative frequencies. The study is registered in clinicaltrials.gov NCT02663973. RESULTS A total of 2950 patients were included in the study. Median age at diagnosis was 53 years old (8.4% &amp;lt;= 35 years, 34.8% 36-50 years, 56.8% &amp;gt; 50 years), 58.6% were white, 34.4% had brown skin-color, 83% had children before BC diagnosis (median of 1 child/patient) and 63.1% had public health insurance. In terms of method of detection 34% were screen-detected whereas 66% were symptomatic, the last was even higher (70%) in patients in younger than 50 years. The distribution of BC stage at diagnosis was I (26.4%), II (41.6%), III (27%) and IV (5%). The most common histologies were ductal (80.9%) and lobular carcinoma (6.9%). The pathological characteristics were HR positive in 78.0%, HER-2 positive in 23.4% and grade 2 in 51%. BC subtypes were as follows: Luminal A 48%, Luminal B 12%, Luminal HER2 positive 17%, Non-luminal HER2 positive 7.3% and Triple negative 15.5%. DISCUSSION Breast cancer is diagnosed at an earlier age among Brazilian patients. The majority of patients were detected through symptomatic BC and therefore a significant proportion is still diagnosed in stages III and IV. Among other factors, these findings could have a significant impact in treatment outcomes. Further analysis of this large cohort of patients will help to identify other important elements and direct future strategies for breast cancer control. TRIAL REGISTRY: NCT02663973 KEYWORDS: Breast Cancer; Epidemiology; Treatment; Brazil Citation Format: Rosa D, Barrios C, Bines J, Werustky G, Cronemberger E, Queiroz GS, Lima VC, Freitas-Júnior R, Couto J, Emerenciano K, Resende H, Crocamo S, Reinert T, Van Eyil B, Néron Y, Dybal V, Lazaretti N, Costamilan RC, Andrade DA, Mathias C, Vacaro GZ, Borges G, Torres KL, Morelle A, Sampaio Filho CA, Mano M, Zaffaroni F, Simon S. Current status of clinical and pathological characteristics of breast cancer patients in Brazil: Results of the AMAZONA III study (GBECAM 0115) [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 P1-08-29.

Abstract LB-027: Mutational diversity and therapy response in breast cancer-a sequencing analysis in the neoadjuvant GeparSepto trial

Abstract Background: Targeted next-generation sequencing (NGS) enables investigation of key molecular events in breast cancer (BC) and driver genes. In this study we evaluated the relevance of mutations in 15 cancer genes and copy number amplifications in 8 cancer genes for response to neoadjuvant therapy in the GeparSepto cohort. The pCR rate was significantly higher in patients treated with nab-paclitaxel (nP) instead of paclitaxel (P). Methods: A total of 851 pretherapeutic formalin-fixed paraffin embedded (FFPE) core biopsies including luminal/HER2- (n=397), HER2+ (n=295) and TNBC (n=159) tumors from the neoadjuvant GeparSepto trial were analysed by targeted NGS. We used a panel of 21 genes including 15 genes selected for mutation analysis (AKT1, ATM, CCND1, CDH1, EGFR, ERBB2, FBXW7, FGFR2, HRAS, KRAS, NRAS, PIK3CA, PTEN, SF3B1, TP53) and 8 genes selected for amplifications (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, ZNF703). Results: The most prevalent mutations were in TP53 (38.4%), ATM (27.7%) and PIK3CA (21.5%) genes; the amplification frequencies were TOP2a (34.9%), ERBB2 (30.6%), ZNF703 (30.1%), PIK3CA (24.1%), TP53 (21.9%), CCND1 (17.7%), PAK1 (14.9%) and FGFR1 (12.6%). Amplification of ERBB2 was observed in 84.7% of HER2+ BC, but only in 1.5% of luminal/HER2- BC and 2.5% of TNBC (p&amp;lt;0.0005). In univariate analysis of the complete cohort, the two most important mutations (TP53 and PIK3CA) and 7 of 8 amplifications (CCND1, ERBB2, FGFR1, PAK1, TOP2A, TP53 and ZNF703) were significantly associated with the pCR rate. PIK3CA mutations overall predicted significantly lower pCR rate (23.0% mutant [mt] vs 38.3% wild-type [wt] group, OR 0.47 [0.32-0.69], p&amp;lt;0.0005). An increased pCR rate was only observed in the PIK3CA wt group treated with nP compared to P (43.5% vs 33.6%, OR 1.52 [1.11-2.08], p=0.009). Within the PIK3CA wt HER2+ group there was a significant interaction of the PIK3CA mutations with the response to taxane therapy in favour for nP (71.7% vs 60.7%, OR 1.64 [0.95-2.83], p=0.079; test for interaction p=0.039). Overall in the HER2+ cohort tumors with an additional ERBB2 amplification had a higher pCR rate than those without (65.6% vs 44.4%, OR 2.38 [1.25-4.53], p=0.008). An opposite effect was observed for PAK1 amplifications (47.2% vs 64.5%, OR 0.49 [0.24-1.00], p=0.048). Conclusion: NGS sequencing of FFPE samples from clinical trials is feasible, detects mutations and copy number alterations, and reveals high molecular heterogeneity indifferent BC types. Our results points to PIK3CA as a major mechanism of therapy resistance in BC, which might also be relevant for response to nP vs standard P. In general, NGS holds promise to identify markers of therapy resistance as a basis for individualized and new molecular-targeted BC therapies. Citation Format: Sibylle Loibl, Denise Treue, Jan Budczies, Karsten Weber, Albrecht Stenzinger, Wolfgang D. Schmitt, Wilko Weichert, Paul Jank, Jenny Furlanetto, Frederick Klauschen, Thomas Karn, Nicole Pfarr, Gunter von Minckwitz, Annika Lehmann, Christian Jackisch, Christine Sers, Andreas Schneeweiss, Peter A. Fasching, Christian Schem, Michael Hummel, Marion van Mackelenbergh, Valentina Nekljudova, Michael Untch, Carsten Denkert. Mutational diversity and therapy response in breast cancer-a sequencing analysis in the neoadjuvant GeparSepto trial [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 LB-027.

Patient (pt)-reported function and symptoms in APHINITY: A randomized comparison of chemotherapy (C) + trastuzumab (H) + placebo (Pla) versus C + H + pertuzumab (P) as adjuvant therapy in pts with HER2-positive early breast cancer (EBC).

521Background: In APHINITY (NCT01358877), adding P to H + C significantly improved invasive disease-free survival in pts with HER2-positive EBC (von Minckwitz, NEJM 2017). Pt-reported health-relate...

Abstract P5-20-09: Pharmacokinetic results of a subcutaneous injection of trastuzumab into the thigh versus into the abdominal wall in patients with HER2-positive primary breast cancer (BC) treated within the neo-/adjuvant GAIN-2 study

Abstract Background A new subcutaneous (s.c.) formulation of trastuzumab became available in 2013 based on equivalent efficacy, pharmacokinetic (PK) profile and safety with the standard intravenous (i.v.) administration, where the s.c. trastuzumab was administered only into the thigh. As an s.c. injection into the abdominal wall (abdw) might be more convenient for patients (pts) and health care professionals, the PK profile of s.c. trastuzumab injected into the thigh vs the abdw in pts with HER2+ early BC needs to be evaluated. Methods GAIN-2 study compared two intense dose-dense (idd) anthracycline/taxane containing regimens. After completion of the anthracycline and i.v. trastuzumab given concurrently with taxanes, HER2+ BC pts were randomized in a 1:1 ratio to continue adjuvant s.c. trastuzumab 600mg fixed dose injected every 3 weeks either into the thigh or the abdw. Randomization was stratified according to CT arm [(iddEnPC) vs tailored dd CT (dtEC-dtD)] and age (≤50 vs &amp;gt;50). Pts in the EnPC arm received 14 and in the dtEC-dtD arm 15 cycles of s.c. trastuzumab. For the PK profile of s.c. trastuzumab serum samples collected before cycle 7, on days 2, 4, 8, 15 and 21 of cycle 7 are evaluated. With a total sample size of 30 (15 per group), the simulated 90% two-sided CI for the area under the plasma concentration (AUC0-last) will be (0.79-1.27) and for the peak drug concentration (Cmax) will be (0.77-1.30). Allowing for a dropout rate of 15%, 18 pts per group will be included in the PK analysis. The primary objective was to assess the PK profile of s.c. trastuzumab injected into the thigh vs the abdw. The secondary objectives included safety and tolerability. Results The per-protocol (pp) set consists of 30 pts (17 in the thigh group and 13 in the abdw group). Baseline characteristics were well balanced between the groups. The log-transformed Geometric Least Square Means (GLSM) for Cmax were 11.77 and 11.52 in the thigh and the abdw group, respectively. The geo-mean ratio (on the original scale) for Cmax was 1.29 (90% CI 1.05-1.58). The log-transformed GLSM for AUC0-last were 14.54 and 14.28 in the thigh and the abdw group, respectively. The geo-mean ratio for AUC0-last was 1.29 (90% CI 1.02-1.63). Overall 29 pts (96.7%) reported any grade and 5 pts (16.7%) high grade adverse events (AEs). The incidence of any grade AEs was similar between the two groups. The most common AEs were anemia (70.6% for the thigh vs 61.5% for the abdw group, p=0.705), leukopenia (80.0% for both groups, p=1.000) and fatigue (47.1% for the thigh vs 76.9% for the abdw group, p=0.141). 6 serious AEs were reported (2 in the thigh vs 4 in the abdw group). The final PK results of s.c. trastuzumab will be presented at the meeting. Conclusions Bioavailability of s.c. trastuzumab as reflected by peak and total exposure measured in cycle 7 was approx. 30% higher if administered into the thigh than into the abdw in pts with HER2+ primary BC treated after dose-dense CT plus i.v. trastuzumab. However, no increased toxicity was observed. Study limitations were that no cross-over design was used and number of pts satisfying criteria for pp-set were different in the arms. Citation Format: Möbus V, Mahlberg R, Janni W, Tomé O, Marmé F, Forstbauer H, Reimer T, von der Assen A, Reinisch M, Lorenz R, Schmatloch S, Schmidt M, Sinn B, Klutinus N, Stickeler E, Untch M, Seiler S, Burchardi N, von Minckwitz G, Loibl S. Pharmacokinetic results of a subcutaneous injection of trastuzumab into the thigh versus into the abdominal wall in patients with HER2-positive primary breast cancer (BC) treated within the neo-/adjuvant GAIN-2 study [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 P5-20-09.

Abstract OT3-05-04: A randomized, open-label, multi-center phase IV study evaluating palbociclib plus endocrine treatment versus a chemotherapy-based treatment strategy in patients with hormone receptor-positive, HER2-negative metastatic breast cancer in a real world setting (PADMA)

Abstract Background: Although endocrine therapy (ET) is recommended as first-line therapy for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) up to 50% of patients receive chemotherapy in this setting. Meanwhile new targeted treatment options for combination with ET have been developed and endocrine-based therapy with the CDK4/6 inhibitor Palbociclib (P) improves the progression free survival (PFS) of ET alone by about 50%. So far, there is no data comparing chemotherapy with or without maintenance ET and ET in combination with P as first-line therapy. Patients included in clinical trials are often criticized not to mirror the general breast cancer population and every-day clinical practice due to rigid inclusion and exclusion criteria, limited number of treatment options, strict monitoring intervals and study assessments. Methods: PADMA trial is a so called low intervention trial with no rigid inclusion and exclusion criteria, and study assessments.Patients with first-line HR+/HER2- MBC who are candidate for mono-chemotherapy will be eligible to receive either P plus ET per label or mono-chemotherapy per investigator´s choice with or without maintenance ET (1:1 randomization). Primary objective is to compare the time-to-treatment failure (TTF) for patients randomized to receive the mono-chemotherapy treatment strategy versus those randomized to receive P and ET. TTF is defined as time from randomization to discontinuation of treatment due to disease progression, treatment toxicity, patient's preference, or death. Main secondary objectives are progression free survival, overall survival at 36 months, amongst other time to event endpoints as well as toxicity and compliance. All patients receive a specific mobile device (PADMA-Phone) and a validated wearable device (ActiWatch) in order to collect data regarding sleep and activity levels, patient well-being and health care utilization (number and duration of phone calls, and patient visits to investigator site) for assessment of daily monitoring treatment impact (DMTI). Results: Overall, 360 patients will be accrued to show an improved TTF for P in combination with ET compared to mono-chemotherapy of investigator´s choice with or without maintenance ET. Recruitment will start in QIII/2017 and is planned for approximately 18 months in 100 sites in Germany, Spain, Poland, Italy, France, UK and Canada. Conclusions: The aim of PADMA is to demonstrate that an endocrine-based strategy consisting of ET plus P is superior to a chemotherapy-based strategy as first-line therapy in women with HR+/HER2- MBC in a real world setting. Assessment of patient-reported outcome, health care utilization, and sleep and activity levels will deliver important information on the differences between endocrine-based and chemotherapy-based treatment. Citation Format: Loibl S, Barinoff J, Seiler S, Decker T, Denkert C, Hardy-Bessard A-C, Senkus-Konefka E, Cognetti F, Palmieri C, Gelmon K, Luebbe K, Furlanetto J, Mueller V, Mundhenke C, Schmidt M, von Minckwitz G, Uhlig M, Burchardi N, Thill M. A randomized, open-label, multi-center phase IV study evaluating palbociclib plus endocrine treatment versus a chemotherapy-based treatment strategy in patients with hormone receptor-positive, HER2-negative metastatic breast cancer in a real world setting (PADMA) [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 OT3-05-04.

Abstract P1-07-01: HLA class I expression is associated with tumor-infiltrating lymphocytes and response and survival after neoadjuvant chemotherapy in hormone receptor-positive, HER2-negative breast cancer

Abstract Background: Interactions between cancer cells and the host immune system influence tumor biology, response to therapy and patient survival and their modulation offers promising new approaches for cancer therapy. The downregulation or loss of HLA class I expression in breast cancer cells might be an effective mechanism to evade the recognition by the immune system facilitating malignant behavior. Aim: To evaluate the association of tumor-infiltrating lymphocytes (TILs) with HLA class I expression and its theranostic value for therapy response and survival after neoadjuvant chemotherapy. Methods: HLA class I expression was evaluated by immunohistochemistry in a cohort of 732 pre-therapeutic core biopsies from breast cancer patients treated within the neoadjuvant GeparTrio trial. Patients received anthracycline- and taxane-based neoadjuvant therapy and adjuvant endocrine treatment if hormone receptor-positive (HR+). A publicly available microarray dataset of pre-therapeutic core biopsies from 508 breast cancer patients that received neoadjuvant chemotherapy and endocrine treatment if HR+ was used for validation of the results. The association of HLA class I expression with predefined genomic signatures for immune cell populations was evaluated in publicly available data from the cancer genome atlas. Results: HLA class I expression was associated with TILs (p &amp;lt; 0.001) and was predictive of better response to neoadjuvant chemotherapy in the subgroup of patients with HR+/HER2- breast cancer (14 % in tumors with high HLA vs. 7 % in tumors with low HLA, p = 0.029). Interestingly, high HLA was also predictive for shorter progression-free survival in univariate analysis (HR 1.590, 95 % CI 1.062—2.380; p = 0.024) and after adjustment to clinical and pathological parameters (HR 1.701, 95 % CI 1.105—2.618; p = 0.016). The results could be validated in the independent microarray-based dataset (HR 1.521, 95% CI 1.088 – 2.129; p = 0.0142). HLA class I was not associated with therapy response or survival in hormone receptor-negative breast cancer. HLA class I was associated with a predefined signature for T-cells and cytotoxic T- cells in the cancer genome atlas dataset (rho = 0.546). Conclusion: HLA class I expression is associated with better response but shorter progression-free survival in HR+/HER2- breast cancer following neoadjuvant chemotherapy. The underlying mechanisms warrant further investigation. Citation Format: Sinn BV, Weber K, Denkert C, Fasching PA, Schmitt WD, Thomas K, Ingold-Heppner B, van Mackelenbergh M, Symmans WF, Marmé F, Taube E, Müller V, Kunze CA, Schem C, Pfitzner BM, Stickeler E, von Minckwitz G, Loibl S. HLA class I expression is associated with tumor-infiltrating lymphocytes and response and survival after neoadjuvant chemotherapy in hormone receptor-positive, HER2-negative 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 P1-07-01.

Abstract GS3-05: Survival analysis of the prospectively randomized phase III GeparSepto trial comparing neoadjuvant chemotherapy with weekly nab-paclitaxel with solvent-based paclitaxel followed by anthracycline/cyclophosphamide for patients with early breast cancer – GBG69

Abstract Introduction The GeparSepto study showed that the substitution of paclitaxel (P) with nab-paclitaxel (nP) followed by epirubicin/cyclophosphamide (EC) as neoadjuvant chemotherapy increased the rate of pathological complete response (pCR) from 29% to 38% (p&amp;lt;0.001). A pronounced improvement of pCR from 26% to 48% (OR: p&amp;lt;0.001) was achieved in patients with triple-negative BC (TNBC) (Untch et al. Lancet Oncology 2016). It has not yet been shown whether these effects on pCR will be translated into a survival benefit. We here report the survival analysis of the GeparSepto trial. Patients and Methods In the GeparSepto trial (NCT01583426) patients were randomized in a 1:1 ratio to receive either nP 125mg/m2 or P 80 mg/m2 q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E: 90mg/m2; C: 600 mg/m2) q3w (Furlanetto et al. Annals Oncol 2016). Patients with HER2+ tumors received trastuzumab 6(8)mg/kg q3w and pertuzumab 420(840)mg q3w concomitantly to all chemotherapy cycles (Loibl et al. Annals Oncol 2016). Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d breast carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. Primary objective was pCR rate (ypT0 ypN0). Secondary objectives were invasive disease-free survival (IDFS), and overall survival (OS) overall and according to stratified subpopulations, amongst other time to event endpoints, quality of life focusing on peripheral sensory neuropathy (PNP), treatment of PNP, and cardiac toxicity, detection of circulating tumor (ct) DNA at the time of surgery and during follow up and correlation with pCR and early relapses. The IDFS analysis is planned after 248 events have occurred. The log-rank test will have 80% power to detect an improvement of the 5 year IDFS from 75% to 81.8% (HR=0.70) at a 2-sided significance level of α=0.05. Results In 69 German centers, 1229 patients were randomly assigned (07/2012 – 12/2013) to receive either nP (606) or P (600). nP was given for the majority of cycles at a dose of 150mg/m2 to 179 patients and at a dose of 125mg/m2 to 426 patients. Follow-up is still ongoing. The expected number of events will be awaited for October 2017. Conclusion Neoadjuvant GeparSepto study demonstrated a significantly higher pCR rate when patients received nP instead of P as part of an anthracycline/taxane based sequential chemotherapy. The expected long-term results will help to assess the overall benefit of nP in BC and the surrogate value of pCR for survival endpoints. Citation Format: Schneeweiss A, Jackisch C, Schmatloch S, Aktas B, Denkert C, Schem C, Wiebringhaus H, Kümmel S, Rhiem K, Warm M, Fasching PA, Just M, Hanusch C, Hackmann J, Blohmer JU, Gerber B, Furlanetto J, von Minckwitz G, Nekljudova V, Loibl S, Untch M. Survival analysis of the prospectively randomized phase III GeparSepto trial comparing neoadjuvant chemotherapy with weekly nab-paclitaxel with solvent-based paclitaxel followed by anthracycline/cyclophosphamide for patients with early breast cancer – GBG69 [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 GS3-05.