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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:276-287 ispartof: location:England status: published

Introduction/Background* Recent and detailed data regarding treatment quality and outcome of patients with high grade AOC on a nationwide basis are largely unknown in Germany. Methodology All German hospitals treating patients with ovarian cancer were asked to document all patients with first diagnosis in the third quarter in 2012 and 2016. Details of tumor, treatment and outcome were documented. This analysis is focusing on patients with AOC FIGO III/IV and the endpoint PFS (progression free survival) (OS data immature for 2016 cohort). As response rates were not documented, we defined a subcohort of patients without progressive disease within 3 months after end of chemotherapy as potential candidates for an additional maintenance therapy. Result(s)* In total, 1010 patients with high grade AOC with a median age of 65 years were documented. 774/1010 (76.6%) were diagnosed with FIGO III disease and 947/1010 (93.8%) had high-grade serous histologic subtype. 915/1010 (90.6%) had primary cytoreductive surgery. Complete resection was achieved in 434/1010 (43.0%) at primary surgery and in 54/1010 (5.3%) at interval debulking surgery. Carboplatin/paclitaxel/bevacizumab (TCB) was the primary systemic therapy in 627/1010 (62.1%) and carboplatin/paclitaxel (TC) in 292/1010 (28.9%). Median PFS in patients with primary surgery and complete resection was 29.7 months (95% CI 27.4-34.2) compared to 17.2 months (95% CI 15.7-18.9) in all other patients (p Conclusion* Most patients in Germany with high grade AOC are treated with primary surgery followed by carboplatin/paclitaxel/bevacizumab. Depending on biomarker status most patients are potential candidates for a PARP-inhibitor maintenance therapy.

Background Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). Patients and methods This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). Results Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. Conclusions The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Different endogenous and exogenous mutational processes act over the evolutionary history of a malignant tumor, driven by abnormal DNA editing, mutagens or age-related DNA alterations, among others, to generate the specific mutational landscape of each individual tumor. The signatures of these mutational processes can be identified in large genomic datasets. We investigated the hypothesis that genomic patterns of mutational signatures are associated with the clinical behavior of breast cancer, in particular chemotherapy response and survival, with a particular focus on therapy-resistant disease.Whole exome sequencing was carried out in 405 pretherapeutic samples from the prospective neoadjuvant multicenter GeparSepto study. We analyzed 11 mutational signatures including biological processes such as APOBEC-mutagenesis, homologous recombination deficiency (HRD), mismatch repair deficiency and also age-related or tobacco-induced alterations.Different subgroups of breast carcinomas were defined mainly by differences in HRD-related and APOBEC-related mutational signatures and significant differences between hormone-receptor (HR)-negative and HR-positive tumors as well as correlations with age, Ki-67 and immunological parameters were observed. We could identify mutational processes that were linked to increased pathological complete response rates to neoadjuvant chemotherapy with high significance. In univariate analyses for HR-positive tumors signatures, S3 (HRD, P0.001) and S13 (APOBEC, P = 0.001) as well as exonic mutation rate (P = 0.002) were significantly correlated with increased pathological complete response rates. The signatures S3 (HRD, P = 0.006) and S4 (tobacco, P = 0.011) were prognostic for reduced disease-free survival of patients with chemotherapy-resistant tumors.The results of this investigation suggest that the clinical behavior of a tumor, in particular, response to neoadjuvant chemotherapy and disease-free survival of therapy-resistant tumors, could be predicted by the composition of mutational signatures as an indicator of the individual genomic history of a tumor. After additional validations, mutational signatures might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy and to define therapy-resistant subgroups for future therapeutic interventions.

Background: Currently, patients with breast cancer (BC) with hormone receptor (HR) immunohistochemical expression between 1-9% are eligible to receive endocrine therapy. However, recent data suggest that these tumors express a basal-like molecular phenotype associated with triple negative BC (TNBC) rather than luminal phenotype associated with HR positive BC. Here, we aimed to determine the differences between strong HR positive, low HR positive and negative HR BC, in regard to responsiveness to neoadjuvant chemotherapy (NACT) and disease free survival (DFS) in large cohorts from GBG clinical trials. Methods: In this retrospective analysis of data from women with BC treated in the neoadjuvant GeparQuinto (n=2572), GeparSixto (n=588) and GeparSepto (n=1206) clinical trials, we compared patients with three HR phenotypes: low positive (ER and/or PR= 1-9%), strong positive (ER or PR= 10-100%), and negative (ER and PR= Results: Patients median age was 49 years, the majority had clinical tumor stage 2 (54.1%), negative nodal status (54.7%), and Her2 negative tumors (72.4%). 85.1% of women had BC classified as no special histological type. The pCR rate across the studies was 26.2%. 145 (3.4%) patients had low HR positive, 2417 (57.3%) strong HR positive and 1658 (39.3%) HR negative tumors. After NACT, 16.3% of patients with strong HR positive BC achieved a pCR, while among those with HR negative and low HR positive tumors, pCR rates were 40.2% and 37.9%, respectively (p Conclusions: Similarly to patients with negative HR tumors, patients with low HR positive tumors have a better responsiveness to NACT and worse survival rates, compared to patients with strongly HR positive BC. We suggest that studies on treatment options for basal-like/TNBC, should also consider including patients with low HR positive tumors. Citation Format: Villegas SL, Lederer B, Untch M, Holms F, Ulmer H-U, Diebold K, Fasching PA, Weber K, Schmitt WD, Tesch H, Rezai M, Marmé F, Sinn B, Hackmann J, Schneeweiss A, Tannapfel A, Nekljudova V, Denkert C, Loibl S. Similarities between low hormone receptor positive and hormone receptor negative breast cancer: An analysis of 4366 patients from multicenter clinical trials [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 P2-08-10.

Introduction Breast cancer diagnosed in young women who are 40 years (yrs) or younger is a relatively rare disease. However, it represents the most common cause of cancer-related deaths in this age-group. Furthermore, young age at diagnosis is associated with an increased risk of recurrence and worse survival. To date, general concepts concerning oncological cancer management should be driven by clinicopathological tumor characteristics and should adhere to standardized protocols for patients in general, but little is known about the oncological cancer treatment and outcome of this very young women in today's clinical practice. Patients and Methods The breast cancer in pregnancy registry study (BCP/GBG29/BIG 03-02) is a multicenter, international, observational study. BCP was established to investigate the oncological management and outcome of breast cancer in pregnancy. Since 2014 non-pregnant patients who are 40 yrs or younger are eligible if diagnosed with histological confirmed invasive breast cancer, independent of the type of treatment as control cohort. All patients received oncological treatment according to local standards. In this study the following endpoints will be analyzed descriptively for the young non-pregnant women cohort: breast cancer staging at diagnosis, biological characteristics of breast cancer at diagnosis, diagnostic procedures, treatment modalities, toxicity, pathological complete response after neoadjuvant chemotherapy, disease-free survival and overall survival. Results From February 2014 until June 2018, 969 non-pregnant patients ≤40 yrs have been registered. The median age at diagnosis was 35 yrs (range 19-40). Overall, 90.1% of patients had a stage T1-2 at diagnosis and 67.1% of patients had negative lymph nodes. 86.7% of tumors were invasive ductal carcinomas and 4.1% lobular carcinomas. Grading (G) 3 was reported in 55.5%. 26.6% of tumors were luminal A-like (ER- and/or PgR-positive, HER2-negative, G1-2), 40.0% luminal B-like (ER- and/or PgR-positive, HER2-negative, G3 or ER- and/or PgR-positive, HER2-positive, any G), 7.7% HER2 positive non-luminal-like, and 25.7% triple negative breast cancers. 3.8% of young non-pregnant patients had metastatic disease at primary diagnosis. Conclusion This registry comprises a large cohort of young non-pregnant patients with breast cancer diagnosed at the age of 40 yrs or younger and provides important data about a modern breast cancer treatment as well as oncological outcome in this setting of young women. Further results including oncological management, toxicity, and survival will be presented at the meeting. Citation Format: Seiler S, Schmatloch S, Reinisch M, Neunhöffer T, Schmidt M, Bechtner C, Marmé F, Wagner M, Möbus V, Reimer T, Kleine-Tebbe A, Sinn B, Stickeler E, Untch M, Janni W, Seither F, Loibl S. Cancer management and outcome of very young non-pregnant patients with breast cancer diagnosed at 40 years or younger– GBG 29 [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 P1-17-07.

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 (> 4) and variability (IQR > 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 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.

Background Over 90% of male breast cancer (BC) patients (pts) have hormone receptor (HR) positive disease. Until today tamoxifen is considered to be the standard of care in male BC pts. Due to the low incidence of male BC, there is a lack of data regarding efficacy and safety. Therapeutic strategies are extrapolated from the standard of care of female BC. However, no prospectively randomized study in male BC pts has been conducted so far. The Male-GBG54 study is the first prospective, randomized, multicenter trial evaluating the efficacy and safety of different endocrine treatment options in male BC patients. Patients and Methods In the phase II Male-GBG54 trial (NCT01638247), pts were randomized to receive either tamoxifen 20 mg/day per os (p.o.) or tamoxifen 20mg/day p.o. + GnRHa subcutaneous (s.c.) q3m or exemestane 25 mg/day p.o. + GnRHa s.c. for 6 months as (neo)adjuvant or metastatic therapy. Further treatment was conducted as per local guidelines. Primary objective was the suppression of oestradiol in the three treatment arms after 3 months of therapy. Secondary objectives comprised oestradiol suppression after six months, compliance and safety of the three therapies, the level of different steroidal hormones (testosterone, dihydrotestosterone, SHBG, FSH, LH) and osteocalcin in the three arms. Quality of Life was assessed using the Aging Male Symptom Score, International Index of Erectile function and International Prostate Symptom Score. Tissue and blood was collected for translational research. Male BC pts with a Karnofsky Index ≥60%, normal blood lipids, and no history or evidence of prostate cancer were eligible. 14 pts per group were needed for the F-test to have 80% power to detect a difference in mean oestradiol decrease between the three therapeutic groups at the 5% significance level. The final sample size was calculated as 48 patients, as a non-parametric test (Kruskal-Wallis) was chosen in case the oestradiol levels are not normally distributed within the study population. Results Between October 2012 and May 2017, 55 pts were randomized within 24 centers in Germany. 52 pts were included in the adjuvant and 2 pts in the metastatic setting of whom 48 pts were fully evaluable and comprised the analysis set. The median age was 62 years (range 37-83 years). The baseline characteristics were well balanced between the 3 treatment groups. Karnofsky Index ranged from 60%-100%, 36.4% had received prior chemotherapy and 12.7% had HER2-positive BC. The majority had a pT2 (52%), pN0 (58.0%) BC. 3 serious adverse events were reported, none was related to the study treatment. Conclusion This is the first prospective randomized trial worldwide evaluating the impact of three different endocrine treatments in male breast cancer. The therapy was well tolerated without safety signals. At the meeting, final results of the primary and secondary endpoints will be present. Citation Format: Reinisch M, Seiler S, Hauzenberger T, Schmatloch S, Strittmatter HJ, Zahm DM, Thode C, Jackisch C, Furlanetto J, Strik D, Stickeler E, Marmé F, Janni W, Schmidt M, Kamischke A, Rudlowski C, Nekljudova V, von Minckwitz G, Loibl S. Male-GBG54: A prospective, randomised multi-centre phase II study evaluating endocrine treatment with either tamoxifen +/- gonadotropin releasing hormone analogue (GnRHa) or an aromatase inhibitor + GnRHa in male breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-10.

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 >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.

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 < 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.

Purpose: The BRCA1-like profile identifies tumors with a defect in homologous recombination due to inactivation of BRCA1. This profile has been shown to predict which stage III breast cancer patients benefit from myeloablative, DNA double-strand-break-inducing chemotherapy. We tested the predictive potential of the BRCA1-like profile for adjuvant non-myeloablative, intensified dose-dense chemotherapy in the GAIN trial. Methods: Lymph node positive breast cancer patients were randomized to 3 × 3 dose-dense cycles of intensified epirubicin, paclitaxel, and cyclophosphamide (ETC) or 4 cycles concurrent epirubicin and cyclophosphamide followed by 10 cycles of weekly paclitaxel combined with 4 cycles capecitabine (EC-TX). Only triple negative breast cancer patients (TNBC) for whom tissue was available were included in these planned analyses. BRCA1-like or non-BRCA1-like copy number profiles were derived from low coverage sequencing data. Results: 119 out of 163 TNBC patients (73%) had a BRCA1-like profile. After median follow-up of 83 months, disease free survival (DFS) was not significantly different between BRCA1-like and non-BRCA1-like patients [adjusted hazard ratio (adj.HR) 1.02; 95% confidence interval (CI) 0.55–1.86], neither was overall survival (OS; adj.HR 1.26; 95% CI 0.58–2.71). When split by BRCA1-like status, DFS and OS were not significantly different between treatments. However, EC-TX seemed to result in a trend to an improvement in DFS in patients with a BRCA1-like tumor, while the reverse accounted for ETC treatment in patients with a non-BRCA1-like tumor (p for interaction = 0.094). Conclusions: The BRCA1-like profile is not associated with survival benefit for a non-myeloablative, intensified regimen in this study population. Considering the limited cohort size, capecitabine might have additional benefit for TNBC patients.

Background: The GeparNuevo trial is a randomized, double-blind, multi-center phase II trial of neoadjuvant therapy in patients with early-stage triple negative breast cancer (TNBC) investigating the role of durvalumab, an anti-PD-L1 antibody, which blocks PD-L1 binding to PD1 and CD80, in addition to standard anthracycline/taxane based chemotherapy (Loibl S et al. ASCO 2018). Methods: In order to determine possible predictive and / or prognostic biomarkers, blood samples were taken before and during the different treatment phases (3 or 4 time points) and evaluated by multicolor flow cytometry by monitoring the absolute cell counts of T cells, B cells and NK cells as well as the frequency, composition and functionality of different immune cell populations using a panel of 35 distinct antibodies. Results: Overall 174 patients were randomized into the GeparNuevo study. 117 patients participated in the window phase of this study and 49 patients provided evaluable material for flow cytometric analyses for material at the above specified time points. Evaluation of the absolute cell count in the whole blood prior and after therapy highlighted a mixed behavior of the total leukocytes. Overall, there was a statistically significant reduction in the lymphocyte count, particularly during the last phase of the treatment (ECdd +/- durvalumab). Further dissection into the different immune populations highlighted an almost complete loss of B cells, which in some patients was also accompanied by a reduction of NK cells, mainly of the CD16+ subset. The loss of CD4+ and CD8+ T cells was less pronounced resulting overall in an enhancement of their percentages within the total lymphocytes. In addition, the different populations have also been evaluated for the expression of PD-L1 activation and exhaustion markers. A pre-specified analysis clearly demonstrated a specific effect of durvalumab during the window phase with mean decreases of 21.7% and 15.0 % in PDL1+ lymphocytes in the CD4+ and CD8+ subgroups, respectively (P Conclusion: Using this approach we hope to identify biomarkers, which will allow a better selection of TNBC patients undergoing specific immunotherapies. Final data will be presented at the meeting. The trial and this translational research project were funded by AstraZeneca and Celgene, Germany. Citation Format: Massa C, Schneeweiss A, Karn T, Hanusch CA, Blohmer J-U, Fasching PA, Jackisch C, van Mackelenbergh M, Marmé F, Müller V, Schem C, Stickeler E, Huober J, Weber KE, Untch M, Denkert C, Loibl S, Mueller A, Biehl K, Seliger B. Immunomonitoring of triple negative breast cancer patients undergoing neoadjuvant therapy with durvalumab - Results from the prospectively randomized 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 P4-06-01.

Introduction/Background Olaparib (50 mg hard capsules, HC) was the 1st PARPi approved in the EU in 12/2014 as monotherapy for maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (BRCAm) ovarian cancer (PSR-OC) who are in response to platinum-based chemotherapy. In addition, film-coated tablets (FT, 100/150 mg) were approved in 05/2018 regardless of BRCA status. Here, we report for the first time data on real-world olaparib treatment from patients who switched from HC to FT. Methodology The German prospective non-interventional study C-PATROL (NCT02503436) collects routine clinical and patient-reported outcome data in BRCAm PSR-OC patients treated according to label with olaparib with the recommended total daily dose of 800 mg (HC) or 600 mg (FT). The 3rd interim analysis (cut-off: 01APR2019) for patients treated with olaparib (HC/FT) reflects data on patient characteristics and safety by using descriptive statistics focussing on ‘switcher’ (here patients can be treated with FT since 08/2018). Results 252 olaparib-treated patients were analysed; 177 (70.2%) were treated with HC, 47 (18.7%) switched from HC to FT, and 28 (11.1%) were newly initiated with FT. Median therapy durations for the three subgroups were 9.0 months (HC), 17.4 months (switcher; 13.4 months before [HC] and 4.4 months after [FT] switch) and 9.2 months (FT). 44 switcher (93.6%) had adverse events (AEs); 41 (87.2%) before and 26 (55.3%) after switching. Treatment modifications due to AEs were more frequent prior to switching (i.e. during HC treatment). In total, 30 switcher had therapy modifications; 25 (83.3%) before and 11 (36.7%) after switching. Conclusion The 3rd interim analysis indicates that under routine conditions, olaparib is well tolerated in patients who switched from HC to FT. In fact, fewer AEs occurred after switching. The toxicity profile observed so far is in line with the results of the clinical trial program for olaparib in PSR-OC and 1st-line maintenance. Funding AstraZeneca. Disclosure F. Marme: honoraria received for speaker, consultancy or advisory role, travel, from AstraZeneca, Tesaro, Roche, Novartis, Pfizer, PharmaMar, GenomicHealth, CureVac, Amgen, Eisai, MSD,Celgene, Clovis. F. Hilpert: membership on advisory boards for AstraZeneca, Roche, Tesaro, Clovis, MSD, PharmaMar, receipt of honoraria from Astra Zeneca, Clovis, Roche, Tesaro, MSD, PharmaMar, Pfizer, Novartis. M. Welslau: No conflict of interest, nothing to disclose. J. P. Grabowski: Advisory, consultancy and speakers activities for AstraZeneca, Tesaro, Clovis, Riemser, honoraria from AstraZeneca, Tesaro, Roche, Clovis, Pfizer, Riemser. J. Seitz: no conflict of interest, nothing to disclose. A. El-Balat: membership on advisory councils, speaker’s activities for AstraZeneca, Roche, PharmaMar, Olympus. A. D. Hartkopf has received honoraria (speakers bureau and consulting fees) from AstraZeneca, Eisai, GenomicHealth, Lilly, MSD, Novartis, Pfizer, Roche, Tesaro, Teva. R. Glowik: employee of AstraZeneca. J. Sehouli: Advisory and expert activities for PharmaMar, Clovis, Tesaro, Roche, Roche Diagnostics, Astra Zeneca,Merck, Bayer,Eisei, Johnson and Johnson, MSD, Novocure, Amgen, Lilly; Receipt of professional fees from PharmaMar, Clovis, Tesaro, Roche, Astra Zeneca, receipt of research grant support (institution) from PharmaMar, Clovis, Tesaro, Roche, Astra Zeneca, Medimmune, Bristol Myers, Lilly.

Background The estrogen receptor (ER) as a nuclear transcription factor alters the transcription of estrogen sensitive genes to which the progesterone receptor gene belongs. The ER has also been described to exert non genomic effects by interacting with several cell signalling pathways that do not initially involve increases in gene transcription. These different patterns of action of the ER lead to the assumption that in tumors that utilize the non-genomic ER activity in order to stimulate tumorigenesis and proliferation progesterone receptor (PgR) expression would be decreased or absent. Therefore lack of PgR expression could be a surrogate marker of altered growth factor signalling. The aim of this study was to investigate if PgR expression may act as a predictive factor for response to neoadjuvant chemotherapy and long-term outcome in breast cancer patients. Methods 5613 patients with primary breast cancer, follow-up, positive ER expression; HER2+ and HER2- from overall 10 (n=9785) German neoadjuvant trials receiving an anthracycline and taxane based chemotherapy were included. The pathologic complete response (pCR)(ypT0, ypN0), long term survival data (disease free survival (DFS), distant disease free survival (DDFS), overall survival (OS) and local recurrence free survival (LRFS)) and early relapse, defined as DFS Results Tumors lacking PgR expression (1172 patients) were more often of grade 3 (38.4% v 26.3%; p pCR rates were significantly higher in PgR negative patients in the entire cohort (13.8% v 7.5%; p PgR negativity was also significantly associated with an early relapse overall (32.8% v 25.7%; p Patients with PgR negative disease had a significantly worse DFS, OS, DDFS and LRFS (p Conclusion This analysis demonstrates that ER positive and PgR negative tumors represent a specific subset in primary breast cancer patients associated with higher response but also worse long term outcome after neoadjuvant chemotherapy. Interestingly, PgR negativity served as an independent predictive factor for achieving a pCR after neoadjuvant chemotherapy and therefore its status should be considered when deciding on systemic treatment. Citation Format: van Mackelenberg M, Denkert C, Nekljudova V, Karn T, Schem C, Marme F, Stickeler E, Jackisch C, Hanusch C, Huober J, Fasching P, Blohmer J-U, Kümmel S, Müller V, Schneeweiss A, Untch M, von Minckwitz G, Weber K, Loibl S. Outcome after neoadjuvant chemotherapy in progesterone receptor negative breast cancer patients – A pooled analysis of individual patient data from ten prospectively randomized controlled neoadjuvant trials [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 P1-09-11.

Background Quantitative determination of estrogen receptor mRNA expression in luminal breast tumors is predictive for benefit from adjuvant tamoxifen compared to placebo treatment as has been shown in the large randomized NSABP B-14 trial, while protein determination by IHC or LBA is not (Kim et al JCO 2011). Interestingly, the ultrahigh expression of ESR1 mRNA (above ER score 10 by Oncotype test) has been indicative for tamoxifen benefit. This predictive cut-off value of mRNA expression is significantly higher than the diagnostic cut-off (at ER score 6.5). Here we tested wether the ultrahigh expression of ESR1 mRNA determined by commercial MammaTyper® testing is predictive for survival after neoadjuvant chemotherapy treatment of advanced breast cancer. Materials and Methods Pretreatment core cut biopsies from n=54 patients with PBC treated within a randomized phase II trial (2) of anthracyline/taxane based NAC with available clinical follow-up information were examined. RNA was extracted from the FFPE sections and ESR1 mRNA from each section was measured by commercial assays. For technical comparison of ESR1 mRNA values by Oncotype DX versus MammaTyper® from n=113 surgical samples were analyzed by both commercial assays in a blinded fashion. Statistical analysis was performed using the SAS JMP® 9.0.0 software. Results Quantification of ESR1 mRNA expression after RNA extraction from separate slices of 113 primary breast tumors and determination by different commercial RT-qPCR assays resulted in high correlation of continuous expression results (Spearman r=0,85; p Conclusion Previous data suggest that ultrahigh expression of ESR1 mRNA is predictive for improved overall survival and tamoxifen benefit (1). Here we show that ultrahigh expression of ESR1 mRNA is also prognostic in more advanced breast tumors after neoadjuvant chemotherapy. These findings validate the importance of quantitative determination of estrogen receptor expression and substantiate the understanding of receptor expression being a continuous determinant with indication specific cut-off values. Ultrahigh expression of ESR1 seems to identify a distinct subset of luminal breast tumors with superior prognosis and benefit from tamoxifen treatment. These findings warrant further investigation, which are currently being done in independent large breast cancer cohorts. Citation Format: Wirtz RM, Scheffen I, Marme F, Laible M, Sclombs K, Schumacher C, Schneeweiss A, Eidt S, Sinn H-P. Predictive value of ultra-high ESR1 mRNA expression in early breast cancer [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 P2-05-25.

Background: Inhibition of HER2 and HER3 heterodimerisation is a novel treatment concept in HER2-”low” expressing breast cancer (BC). Lumretuzumab, a glycoengineered monoclonal anti-HER3 antibody, in combination with pertuzumab has demonstrated synergistic anti-tumor activity in preclinical HER2–low expressing preclinical BC models. Methods: This open-label, multicenter phase I study selectively enrolled metastatic BC patients (pts) expressing HER3 protein and low levels of HER2 (defined as IHC 1+ and 2+ and ISH-negative) in a formalin-fixed paraffin-embedded pretreatment tumor biopsy sample. Eligible pts were treated with a combination of paclitaxel (PA) qw plus lumretuzumab (L) and pertuzumab (P) q3w in three dose cohorts. The safety, antitumor activity and tumor biomarkers including protein expression (IHC, MS) and mutational data (NGS) in association with clinical activity were evaluated. Results: Overall, 35 pts were included in this study. The median age was 60 (range: 33 to 77) years. The median number of prior treatments for metastatic disease ranged from 0 to 5 with 23 pts (65.7%) without prior chemotherapy for metastatic disease. Cohort 1 was treated with PA at 80 mg/m2, L at 1000 mg and P at 840 mg for Cycle 1 followed by 420 mg for the following cycles. This cohort was stopped after two pts both experienced grade 3 diarrhea within the first treatment cycle which was considered a dose-limiting toxicity (DLT). For Cohort 2 the dose of L was reduced to 500 mg based on PK modelling and simulation data. No DLTs were seen for the first 6 pts. A total of 20 pts were recruited with an objective response rate (ORR) and disease control rate (DCR) of 30% and 75%, respectively, and 56% and 78%, respectively, for 1st-line pts (n=9) in this cohort. Diarrhea (≥G3) and hypokalemia (≥G3) occurred in 50% and 55% of pts, respectively, and all pts experienced chronic diarrhea throughout the course of treatment. For Cohort 3 the dose of L was maintained at 500 mg, PA at 80 mg/m2, and P was administered at 420 mg at all cycles. In addition, a prophylactic loperamide regimen was introduced. Altogether, 13 pts - all 1st-line for metastatic disease - were treated. No DLTs were seen for the first 6 pts. Diarrhea (≥G3) and hypokalemia (≥G3) were reduced to 31% and 15%, respectively, but chronic diarrhea was still observed throughout the treatment in all pts. The ORR and DCR were 31% and 77%, respectively. Preliminary mechanistic safety experiments revealed HER2/HER3-dependent chloride channels in the intestine as likely cause of diarrhea. Biomarker data will be presented along with updated clinical and safety data. Conclusions: The combination of L, P and PA was associated with high rates of persistent diarrhea. Dose modifications and prophylactic anti-diarrheal medication led to significantly reduced diarrhea intensity but did not change the incidence and persistence of diarrhea overall. Despite encouraging clinical activity especially in 1st line pts, the therapeutic window of this combination is too low to warrant further clinical development. Citation Format: Schneeweiss A, Park-Simon T-W, Albanell J, Lassen U, Cortes J, Dieras V, May M, Schindler C, Marmé F, Cejalvo JM, Martinez-Garcia M, Gonzalez I, Lopez-Martin J, Welt A, Joly F, Michielin F, Jacob W, Adessi C, Moisan A, Meneses-Lorente G, James I, Ceppi M, Hasmann M, Weisser M, Cervantes A. Phase Ib study evaluating the safety and clinical activity of lumretuzumab combined with pertuzumab and paclitaxel in HER2-low metastatic breast cancer [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 P6-11-13.

Background During the last decade, neoadjuvant chemotherapy (NACT) of early breast cancer (EBC) evolved from a therapy intended to enable operability to a standard treatment option aiming for increasing cure rates equivalent to adjuvant chemotherapy (ACT). In parallel, improvements in the quality control of breast cancer care have been established in specialized breast care units. Patients and methods This study analyzed chemotherapy usage in patients with EBC treated at the Heidelberg University Breast Unit between January 2003 and December 2014. Results Overall, 5703 patients were included in the analysis of whom 2222 (39 %) received chemotherapy, 817 (37 %) as NACT, and 1405 (63 %) as ACT. The chemotherapy usage declined from 48 % in 2003 to 34 % in 2014 of the cohort. Further, the proportion of NACT raised from 42 to 65 % irrespective of tumor subtype. In addition, frequency of pathologic complete response (pCR) defined as no tumor residues in breast and axilla (ypT0 ypN0) at surgery following NACT increased from 12 % in 2003 to 35 % in 2014. The greatest effect was observed in HER2+ breast cancer with an increase in patients achieving pCR from 24 to 68 %. Conclusions The results mirror the refined indication for chemotherapy in EBC and its preferred usage as NACT in Germany. The increase in pCR rate over time suggests improvement in outcome accomplished by a multidisciplinary decision-making process and stringent measures for quality control. Electronic supplementary material The online version of this article (doi:10.1007/s10549-016-4016-4) contains supplementary material, which is available to authorized users.

Background: We previously demonstrated that the majority of women ≤45 years experienced chemotherapy-induced ovarian failure (CIOF) after CT for EBC. Age, CT regimen, duration and dose-density influenced the rate of CIOF. The regain of premenopausal Follicle-Stimulating Hormone (FSH) and Estradiol (E2) levels after chemotherapy is not equivalent to fertility restoration. The Anti-Muellerian Hormone (AMH) assessment seems to be more accurate than other hormones in predicting the ovarian reserve. FSH, E2 and AMH have been prospectively assessed in young patients receiving (neo)adjuvant CT. Methods: 740 patients (pts) aged ≤45yrs treated with anthracycline or taxane-based CT for EBC from 4 German neoadjuvant/adjuvant trials were included. Blood samples were collected at baseline before CT (N=740), end of treatment (EOT n=740), 6 (n=177), 12 (n=113), 18 (n=69), 24 (n=47) months (m) after EOT. Only the full set of samples of a given patient was included. FSH, E2 and AMH were centrally assessed. Postmenopausal hormone levels of FSH and E2 according to the central laboratory were defined as FSH>12.4IU/l and E2 Results: Median age was 40yrs (range 21-45); 57.2% had BMI 18.5- Conclusion: Nearly 70% of women regain premenopausal hormone levels of FSH and E2 within 2 years after end of CT. Despite that, only less than one third maintain their fertility potential as predicted by AMH. AMH is a very sensitive marker for the prediction of fertility function after CT for EBC. Table 1 Median and range of FSH, E2 and AMH levels per time pointsTimepointFSH,IU/lE2, ng/mLAMH, ng/ml% of pts with AMH levels above dtBaseline6.0 [dt-142.7]88.0 [dt-2375.0]0.96 [dt-16.18]95.4EOT76.1 [1.9-225.0]dt [dt-632.0]dt [dt -3.11]15.66 m41.4 [1.1-190.6]10.0 [dt-929.0]dt [dt -3.11]26.112 m28.7 [1.1-146.0]11.0 [dt-947.0]dt [dt -2.81]29.218 m20.6 [0.8-172.3]19.0 [dt-624.0]dt [dt -1.89]34.824 m16.30 [dt-93.9]44.0 [dt-11795.0]dt [dt -1.75]38.3Abbreviations: dt, detectable threshold, EOT, end of treatment; m, month; pts, patients. Detectable threshold: FSH Citation Format: Furlanetto J, Thode C, Huober J, Denkert C, Bassy M, Hanusch C, Jackisch C, Kümmel S, Schneeweiss A, Untch M, Fasching PA, Karn T, Marmé F, van Mackelenbergh M, Müller V, Schem C, von Minckwitz G, Strik D, Nekljudova V, Loibl S. Changes in hormone levels (E2, FSH, AMH) and fertility of young women treated with neoadjuvant chemotherapy (CT) for 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 PD7-09.