Search

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 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.

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.

Background Pre-clinical data and initial results from clinical studies point to the added benefit of CDK4/6 inhibition when combined with anti-HER2 tx. The current study is designed to evaluate the added benefit of palbociclib when given in combination with anti-HER2 and endocrine tx maintenance in the 1st†line setting of metastatic HER2+HR+ breast cancer. Trial design PATINA is an international, open-label, pivotal Phase III study. Primary objective is to demonstrate that the combination of palbociclib with anti-HER2 plus endocrine tx is superior to anti-HER2 plus endocrine tx in prolonging PFS. Sample size is 496 pts. The study starts after completion of 6-8 cycles of chemotherapy-containing anti-HER2 tx for metastatic breast cancer in the 1st line setting. Pts are eligible provided they are without evidence of disease progression by local assessment (i.e. CR, PR or SD). To account for the need for less intense tx regimens for a subset of pts diagnosed with HER2+ER+ disease, clinicians may recommend the combination of trastuzumab with either a taxane or vinorelbine prior to study initiation. Clinicians might also choose a non-pertuzumab option for pts previously treated with pertuzumab in the neo(adjuvant) setting. Secondary objectives include measures of tumor control (OR, CBR, DOR), OS, safety and QOL. The translational science main objective is to compare PFS estimates according to PIK3CA mutation status assessed by cfDNA analysis. Endocrine tx options are AI or fulvestrant. Premenopausal pts must receive ovarian suppression. The study has a 90% power to detect a hazard ratio of 0.667 in favor of the palbociclib arm. Pts approached to participate in AFT-38 will be asked to indicate on the informed consent forms whether remaining biospecimens and clinical data from the control arm of the study can be shared with the Mastering Breast Cancer (MBC) Initiative. The overarching purpose of the MBC is to create a mechanism for understanding the natural history of metastatic breast cancer by cataloguing longitudinally studied tumor-specific markers and treatment effects. ClinicalTrials.gov Identifier: NCT02947685 Citation Format: Metzger-Filho O, Mandrekar S, Loibl S, Ciruelos E, Gianni L, Lim E, Miller K, Huang C, Koehler M, Francis P, Valagussa P, Goel S, Prat A, Goetz M, Loi S, Krop I, Carey L, Lanzillotti J, Winer E, Tripathy D, DeMichele A. PATINA: A randomized open label phase III trial to evaluate the efficacy and safety of palbociclib + anti HER2 therapy + endocrine therapy vs anti HER2 therapy + endocrine therapy after induction treatment for hormone receptor positive, HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-07.

Background: Cell cycle inhibition is a proven target for novel cancer therapeutics. Palbociclib (P) is an orally active inhibitor of CDK4/6, and arrests the cell cycle at the G1-S transition. P in combination with endocrine therapy (ET) has demonstrated efficacy in phase II and III randomized trials for patients with newly diagnosed and recurrent hormone receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancer (MBC), and is approved in these settings. Given confirmed benefits of P and ET for MBC, the PALLAS study was designed to determine if the addition of P to adjuvant ET improves outcomes over ET alone in HR+/HER2- early breast cancer. Trial Design: PALLAS is an international open-label phase III trial randomizing (1:1) patients (pts) to 2 years of P (125 mg daily, 21 days on 7 days off in a 28-day cycle) combined with at least 5 years of provider choice ET (AI, tamoxifen, +/- LHRH agonist), versus ET alone. The primary objective of the study is to compare invasive disease-free survival (iDFS) for the combination of P and ET, versus ET alone. Secondary objectives include comparison of iDFS excluding cancer of non-breast origin, DRFS, LRRFS, OS, as well as safety. The principal objective of the translational investigations is to determine the predictive or prognostic utility of defined genomic subgroups with respect to iDFS and OS. Additional objectives include evaluation of cfDNA and tissue biomarkers predictive of benefit or resistance, pharmacogenomics, adherence, and patient-reported QOL. Eligible pts are pre- or post-menopausal women or men with stage II-III, HR+/HER2- breast cancer. Patients may have already initiated ET, but must be randomized within 12 months of diagnosis and 6 months of initiation of adjuvant ET. Trial sample size is 4600 pts and stage IIA pts will be capped at a total accrual of 1000 pts. Interim analyses for safety, futility/efficacy and sample size re-estimation are planned. PALLAS opened in 9/2015 and accrual is ongoing. Contact information: emayer@partners.org Key words: palbociclib, CDK4/6 inhibition, HR+/HER2- early breast cancer, adjuvant endocrine therapy. Citation Format: Mayer E, DeMichele A, Gnant M, Barry W, Pfeiler G, Metzger O, Burstein H, Miller K, Rastogi P, Loibl S, Goulioti T, Zardavas D, Fesl C, Koehler M, Huang-Bartlett C, Huang X, Piccart M, Winer E, Wolff A. PALLAS: PALbociclib CoLlaborative Adjuvant Study: A randomized phase 3 trial of palbociclib with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone for HR+/HER2- early 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 OT3-05-08.

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.

Immune cell infiltration in breast cancer is important for the patient's prognosis and response to systemic therapies including immunotherapy. We sought to investigate the prevalence of tumour-infiltrating lymphocytes (TILs) and their association with immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in high-risk, node-positive breast cancer of the adjuvant German Adjuvant Intergroup Node-positive (GAIN-1) trial.We evaluated TILs by haematoxylin and eosin staining and PD-1 and PD-L1 (SP263 assay) expression by immunohistochemistry in 1318 formalin-fixed, paraffin-embedded breast carcinomas. The association of TILs with PD-1, PD-L1, molecular intrinsic subtypes, outcome and therapy regimens (dose-dense [dd] epirubicin, paclitaxel and cyclophosphamide [EPC] and dd epirubicin, cyclophosphamide, paclitaxel and capecitabine [EC-PwX]) was statistically tested.Overall TILs density was significantly associated with the expression of PD-1 and PD-L1 in immune cells (each p 0.0001) and PD-L1 in tumour cells (p = 0.0051). TILs were more common in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive tumours (each p 0.0001). On multivariate Cox regression analyses, patients with breast cancer without TILs had an unfavourable disease-free survival (DFS) in the EPC arm compared with the EC-PwX arm (hazard ratio [HR] = 0.69 [0.44-1.06], p = 0.0915); but no differences were seen in tumours with TILs (HR = 1.24 [0.92-1.67], p = 0.1566, interaction p = 0.0336). PD-1-positive immune cells in TNBC were associated with a significantly better DFS (HR = 0.50 [0.25-0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome.TILs predict the benefit of intensified ddEPC compared with ddEC-PwX therapy in node-positive, high-risk breast cancer. TILs, PD-1 and PD-L1 are linked to each other indicating tumour immunogenicity. Moreover, PD-1-positive immune cells have a positive prognostic impact in TNBC.NCT00196872.

Background Patients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer. Patients and methods Patients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival. Results After a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709–1.30, log rank P = 0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant ( P = 0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79–1.79; log rank P = 0.408). Zoledronate was well tolerated and no new toxicity signal was identified. Conclusion Postneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.

In treating HR+, HER2− metastatic breast cancer, novel agents that enhance endocrine therapy activity but do not worsen quality of life (QoL) are clinically desired. Patient-reported outcomes data from the PALOMA-3 study suggest palbociclib plus fulvestrant allow patients to maintain good QoL in the endocrine resistance setting while experiencing a substantially delayed disease progression., Background In the PALOMA-3 study, palbociclib plus fulvestrant demonstrated improved progression-free survival compared with fulvestrant plus placebo in hormone receptor-positive, HER2− endocrine-resistant metastatic breast cancer (MBC). This analysis compared patient-reported outcomes (PROs) between the two treatment groups. Patients and methods Patients were randomized 2 : 1 to receive palbociclib 125 mg/day orally for 3 weeks followed by 1 week off (n = 347) plus fulvestrant (500 mg i.m. per standard of care) or placebo plus fulvestrant (n = 174). PROs were assessed on day 1 of cycles 1–4 and of every other subsequent cycle starting with cycle 6 using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. High scores (range 0–100) could indicate better functioning/quality of life (QoL) or worse symptom severity. Repeated-measures mixed-effect analyses were carried out to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline. Between-group comparisons of time to deterioration in global QoL and pain were made using an unstratified log-rank test and Cox proportional hazards model. Results Questionnaire completion rates were high at baseline and during treatment (from baseline to cycle 14, ≥95.8% in each group completed ≥1 question on the EORTC QLQ-C30). On treatment, estimated overall global QoL scores significantly favored the palbociclib plus fulvestrant group [66.1, 95% confidence interval (CI) 64.5–67.7 versus 63.0, 95% CI 60.6–65.3; P = 0.0313]. Significantly greater improvement from baseline in pain was also observed in this group (−3.3, 95% CI −5.1 to −1.5 versus 2.0, 95% CI −0.6 to 4.6; P = 0.0011). No significant differences were observed for other QLQ-BR23 functioning domains, breast or arm symptoms. Treatment with palbociclib plus fulvestrant significantly delayed deterioration in global QoL (P < 0.025) and pain (P < 0.001) compared with fulvestrant alone. Conclusion Palbociclib plus fulvestrant allowed patients to maintain good QoL in the endocrine resistance setting while experiencing substantially delayed disease progression. Clinical Trial Registration NCT01942135.

Background: We previously reported that nab-paclitaxel (nP) increases the pathological complete response (pCR, ypT0 ypN0) rate when it replaces solvent-based paclitaxel (P) as part of a sequential taxane followed by epirubicin/cyclophosphamide (EC) neoadjuvant chemotherapy for patients with early breast cancer (Untch et al. SABCS 2014). Here, we report efficacy and safety of patients being treated either with 150 mg/m2 nab-paclitaxel (nP150) before an amendment or with 125 mg/m2 nab-paclitaxel (nP125) thereafter in comparison to solvent-formulated paclitaxel at 80 mg/m2 (P80). Methods: In the GeparSepto study (NCT01583426), 1207 patients were randomized to either nP150 or P80 q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E: 90mg/m2; C: 600 mg/m2) q3w. The primary objective of the study was to compare the pCR rate (pCR, ypT0 ypN0). Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. Patients with HER2+ tumors received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly to all chemotherapy cycles. After a safety analysis showed a higher rate of dose reductions and treatment discontinuations with nP150 compared to P80, weekly dose of nP was reduced to 125 mg/m2. Results: nP was given for the majority of cycles at a dose of 150 mg/m2 to 179 patients and at a dose of 125 mg/m2 to 426 patients. Treatment characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for HER2 status (HER2-positive: nP150 22%, nP125 37% and P80 33%) and Ki67 ( Conclusions: Risk-benefit ratio of nP125 was improved over nP150 with better drug adherence and RTDI, lower frequency of PNP but a higher pCR rate. It should therefore be considered as the preferred schedule when nP is used as neoadjuvant treatment for primary breast cancer. The trial was financially supported by Celgene and Roche. Citation Format: von Minckwitz G, Untch M, Jakisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Weibringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S. nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-11.

Background: The PI3K/Akt/mTOR pathway is frequently activated in breast cancer (BC) and is important for the oncogenic function of HER2. Buparlisib is an oral pan-PI3K inhibitor that targets all 4 isoforms of class I PI3K (a, b, g, d). Clinical activity was observed with buparlisib in patients (pts) with advanced BC as a single agent, and in combination with endocrine and anti-HER2 treatment. Methods: NeoPHOEBE (NCT01816594) is a phase II, randomized, double-blind, parallel-cohort study of neoadjuvant buparlisib/placebo plus trastuzumab and weekly paclitaxel in women with, untreated primary HER2-positive BC. Pts were stratified upfront into 2 independent cohorts according to PIK3CA mutation status. Other eligibility criteria: tumor size >2 cm; unilateral disease; available tumor tissue for central review of estrogen receptor (ER), HER2 status, and PIK3CA genotype; known PIK3CA mutation status; and ECOG PS ≤1. Pts in each cohort (PIK3CA mutant or wild-type [wt]) were randomized (1:1) to receive continuous daily buparlisib (100 mg) or placebo and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg) for 6 weeks, followed by continuous daily buparlisib (80 mg) or placebo with weekly trastuzumab (2 mg/kg) and weekly paclitaxel (80 mg/m2) for 12 weeks. Study treatment was followed by surgery. Stratification at randomization was based on PIK3CA (mutant vs wt) and ER (positive vs negative) status. The primary endpoint was pathologic complete response (pCR; ypT0) rate at time of surgery. The key secondary endpoint was objective response rate (ORR) at the end of week 6. Other secondary endpoints included pCR by other definitions, ORR prior to surgery, pCR and objective response by ER status, percent of pts with node-negative disease at surgery, rate of breast conserving surgery, and safety, as well as pCR by PTEN expression, Ki67 level, apoptosis rates, percentage of tumor infiltrating lymphocytes (TIL), and by phenotype of 50% TIL at baseline. The sample size is based on a minimax 2-stage randomized phase II design with a prospective control. This design allowed for early stopping if the desired efficacy was not observed after stage 1. Both cohorts were powered (80%) to detect a clinically meaningful increase in pCR of 18% at a one-sided significance level (α=0.15). Results: Between 9/2013 and 10/2014 50 pts were randomized in 38 sites in 4 countries. Recruitment was suspended due to toxicity in 10/2014. Median age was 50 years, 42 pts had a PIK3CA wt and 8 a PIK3CA mutant tumor, 62% of pts presented with HER2+/ER+, 90% with ductal or ductal-lobular invasive, and 62% with G3 tumors; 86% had Ki67 >20%; 9 pts reported a serious adverse event including 3 pts with hepatotoxicity. Overall 14/50 (28 %) pts developed grade 3-4 liver enzyme elevation, of whom 9 (64%) recovered to at least grade1. Final safety and efficacy data on the primary endpoint (pCR) and biomarker data will be presented at the meeting. Conclusions: The NeoPHOEBE study investigates for the first time the efficacy of adding a pan-PIK3 inhibitor to a taxane/trastuzumab-based neoadjuvant therapy in pts with primary HER2-positive BC with or without a PIK3CA mutation. Citation Format: Loibl S, de la Pena L, Nekljudova V, Zardavas D, Michiels S, Denkert C, Rezai M, Bermejo B, Lee S-C, Turri S, Urban P, Kümmel S, Lux M, Piccart M, von Minckwitz G, Baselga J, Loi S. Phase II, randomized, parallel-cohort study of neoadjuvant buparlisib (BKM120) in combination with trastuzumab and paclitaxel in women with HER2-positive, PIK3CA mutant and PIK3CA wild-type primary breast cancer – NeoPHOEBE. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-01.

Background: The BRCA1-like copy number (CN) profile can be used as a biomarker to predict which stage III breast cancer patients benefit from myeloablative, DNA double-strand-break (DSB)-inducing chemotherapy. In addition, a BRCA1-like gene expression classifier, derived from the BRCA1-like CN profile, can predict which patient group will achieve an increased pathological complete remission rate on a standard neoadjuvant regimen complemented with carboplatin/veliparib. A non-myeloablative, dose-dense schedule of epirubicin, paclitaxel and cyclophosphamide (ETC) is used in the clinic to treat stage III patients. Since ETC contains an intensified dose of DNA DSB-inducing cyclophosphamide, we tested the BRCA1-like CN profile as a predictive biomarker for ETC benefit in the GAIN trial. Methods: The GAIN trial was a prospective, multi-center, non-blinded, randomized phase III trial. Eligibility comprised histologically confirmed invasive breast cancer with at least one positive axillary or internal mammary lymph node and no signs of distant metastases. The allocated adjuvant treatment was intensified chemotherapy with sequential E (150 mg/m2), T (225 mg/m2) and C (2500, after amendment 2000 mg/m2) each 3 cycles every 2 weeks (ETC) or concurrent E (112.5 mg/m2) and C (600 mg/m2) for 4 cycles every 2 weeks followed by 10 cycles of weekly T (67.5 mg/m2) combined with 4 cycles of capecitabine (2000mg/m2) on day 1-14 in a 3-weekly cycle (EC-TX). Only the triple negative patients were used for these analyses. For samples with good quality DNA extracted from formalin-fixed paraffin-embedded tumor tissue, a library was prepared and sequenced on an Illumina HiSeq2000 platform. Copy number estimates were extracted from the sequence data by normalizing GC-content and mappability corrected read counts to the average read count. These CN profiles were classified as either BRCA1-like or non-BRCA1-like using a previously established shrunken centroid classifier with an established cut-off. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method, the difference in survival was analysed using log-rank tests. Multivariate analyses were done by generating Cox regression models with important prognostic factors. Results: Out of 424 triple negative patients, 166 patients with available tissue and a tumour cell content of at least 60% were analysed for BRCA1-like status and included in the analyses (classified as BRCA1-like: n=122). Based on clinicopathological characteristics, these patients were similar to the total group of triple negative participants. In the BRCA1-like patients, there was no significant difference in DFS or OS between ETC and EC-TX (log-rank tests n.s.). In accordance, Cox regression models confirmed these findings. Conclusion: In contrast to the predictive value of the BRCA1-like profile in myeloablative chemotherapy, it could not predict survival benefit for a non-myeloablative, non-platinum-/veliparib-containing regimen in this study population. An intensified dose of cyclophosphamide resulted in similar outcomes in BRCA1-like patients as addition of capecitabine to standard chemotherapy. These results help to define the appropriate application of the BRCA1-like profile as a predictive biomarker. Citation Format: van Rossum AGJ, Schouten PC, Weber KE, Nekljudova V, Denkert C, von Minckwitz G, Karn T, Möbus VJ, Linn SC, Loibl S, Marmé F. BRCA1-like profile as predictive biomarker in non myeloablative chemotherapy (GAIN study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-28.

Background: Phosphatidylinositol 3-kinase mutations (PIK3CA) are common in breast cancer (BC). Mutations are predominantly found in hot-spots located in the helical and kinase domains (exons 9 and 20). We recently demonstrated that PIK3CA mutations predict lower pathological complete response (pCR) to double blockade with trastuzumab/lapatinib in HER2+ve primary BC. Methods: We evaluated PIK3CA mutations in 293/403 HER2+ve tumors of participants of the neoadjuvant GeparSepto (G7) study (Untch et al. SABCS 2014). The G7 study investigated the effect of exchanging paclitaxel for nab-paclitaxel prior to EC. All patients received trastuzumab and pertuzumab. The G7 study showed a significantly higher pCR rate in patients receiving nab-paclitaxel. HER2, hormone receptors (HR), Ki67 and tumor infiltrating lymphocytes (TILs) were centrally assessed prior to randomization. PIK3CA mutations in exons 9 and 20 were evaluated in formalin-fixed, paraffin embedded core biopsies taken before therapy using deep targeted massive parallel sequencing with a minimum coverage of 500 and a mean coverage of 6520 and 6346 per amplicon, (exon9 and exon 20). Only non-synonymous mutations in the coding region that were called at variant allele frequency ≥10% were taken into consideration. Only cases with a tumor cell content of ≥20% were included. Results: In the G7 study, 396 patients with HER2+ve BC have been randomized from 06/2012 to 01/2014 and started treatment. From these 293 could be sequenced. Median age in the analyzed cohort was 49 years (range 22-75); most tumors were cT1-2 (89.9%); cN0 (54.4%); ductal invasive (88.7%), grade 3 (53.9%), HR+ve (69.6%), Ki67>20% (69.3%), LPBC-negative (83.2%). Overall, 22.2% of the tumors were found to have a PIK3CA mutation, 20.1% in HR+ve and 27.0% in HR-ve. Overall, the pCR rate was significantly lower in the PIK3CA mutant tumors compared to the wild type (wt) group (47.7% vs. 66.7%; p=0.009). This effect was seen both in the HR+ve (43.9% vs. 61.3%; p=0.052) and the HR-ve population (54.2% vs. 80.0%; p=0.029). There was also a significant difference in pCR according to PIK3CA mutation status dependant on the taxane. In the nab-paclitaxel group, pCR rates were significantly lower in patients with PIK3CA mutations compared to those without PIK3CA mutations (38.7% vs. 72.0%; p=0.001), whereas in the paclitaxel group, there was no significant difference between patients with and without a PIK3CA mutation (55.9% vs. 60.9%; p=0.690). The respective interaction could be demonstrated in univariate (p=0.039) as well as multivariate regression analysis (p=0.010) after adjusting for known baseline factors. Conclusion: Patients with PIK3CA mutant HER2+ve BC have a significantly lower pCR rate compared to patients with wt tumors. In contrast to the results with double anti-HER2 blockade consisting of trastuzumab/lapatinib, the effect was evident irrespective of the HR status. In addition, PIK3CA mutation status was significantly associated with higher pCR following nab-paclitaxel. The project has partly been funded within the EU-FP7 project RESPONSIFY No 278659 and the German Cancer Consortium (DKTK). Citation Format: Loibl S, Budczies J, Weichert W, Furlanetto J, Stenzinger A, Pfarr N, von Minckwitz G, Jackisch C, Schneeweiss A, Fasching P, Schmatloch S, Aktas B, Nekljudova V, Weber K, Untch M, Denkert C. PIK3CA mutations predict resistance to trastuzumab/pertuzumab and nab-paclitaxel in primary HER2-positive breast cancer – Massive parallel sequencing analysis of 293 pretherapeutic core biopsies of the GeparSepto study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-03.

Background: In routine clinical practice chemotherapy (CT) doses are frequently capped at a body surface area (BSA) of 2.0 m2 or adjusted to an ideal weight (i.e. [body length in cm - 10%] + 40% [current weight-ideal weight]) for obese patients (BMI>30 according to WHO) due to safety reasons. There are no data on CT dosing within intense dose-dense regimen for obese patients. Therefore, a retrospective analysis of the GAIN study population has been conducted. Methods: Between August 2004 and July 2008 a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense regimen. Patients were randomized to intense dose-dense ETC (Epirubicin 150 mg/m2, Paclitaxel 225 mg/m2, Cyclophosphamide 2500-2000 mg/m2, i.v. q15 for 3 cycles) or EC followed by T plus capecitabine (X) (EC-TX) (E 112.5 mg/m2 + C 600 mg/m2, i.v. q15 for 4 cycles followed by T 67.5 mg/m2 i.v. q8 for 10 weeks + X: 2000 mg/m2 p. o. day 1-14, q22 for 4 cycles). An adjustment of CT dose to an ideal weight for obese patients was implemented by a protocol amendment. Yet some patients received a dose adjustment by capping at 2.0 m2. We retrospectively evaluated a total of 543 patients with a BMI>30. Data on BSA and dose adjustment were collected from case report forms. Toxicities were compared between patients who received CT according to an unadjusted or adjusted BSA using the 2-sided exact test of Fisher. Disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method and the log-rank test. Results: Overall, 18.0% (n=543) of patients in the GAIN study were obese: 30.9% (n=168) of them received CT according to an unadjusted BSA. For the remainder BSA was adjusted to ideal weight or was capped at 2.0 m2 (69.1%; n=375). A total of 14.5% (n=24) of obese patients receiving full dose of chemotherapy vs 6.4% (n=24) of obese patients with an adjusted BSA experienced febrile neutropenia (p=0.005) and 9.6% (n=16) vs 2.9% (n=11) high grade thrombopenia (p=0.002). Overall, 16.7% (n=28) vs 10.1% (n=38) had a thromboembolic event (p=0.034), which was high grade in 12.5% (n=21) vs 6.4% (n=24), respectively (p=0.027) and 3.0% (n=5) vs 0.3% (n=1) experienced high grade hot flushes (p=0.012). The only significant differences in favor of the non-adjusted group were for dizziness (4.2% [n=7] vs 10.7% [n=40]; p=0.013), diarrhea (18.5% [n=31] vs 26.9% [n=101]; p=0.039) and an increase in serum creatinine (6.8% [n=11] vs 14.0% [n=52]; p=0.019). No differences in DFS and OS were observed between the two groups (5year DFS 81.9% [CI 74.9%-87.2%] vs 80.8% [76.3%-84.6%]; p=0.850; 5year OS 86.4% [79.9%-90.9%] vs 88.3% [84.4%-91.3%]; p=0.491). Conclusion: This analysis of patients treated with a dose-dense regimen showed that obese patients who received CT according to their real BSA have a higher risk of severe toxicities, in particular of febrile neutropenia, high grade thrombopenia and high grade thromboembolic events. Therefore, a dose adjustment of intense dose-dense CT should be performed for obese patients to avoid life-threatening complications. Citation Format: Furlanetto J, Eiermann W, Marmé F, Reimer T, Reinisch M, Schmatloch S, Stickeler E, Thomssen C, Untch M, Denkert C, von Minckwitz G, Nekljudova V, Loibl S, Möbus V. Higher rate of severe toxicities in obese patients receiving dose-dense chemotherapy according to unadjusted body mass index – Results of the prospectively randomized GAIN study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-04.

Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy regimens than TNBC patients whose tumors are HR non-deficient. We performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to better estimate the pCR rates amongst HR deficient and HR non-deficient tumors. Methods: Patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00148694/NCT00580333 (N=50), NCT01372579 (N=26), TBCRC 008 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Logistic regression models were used to adjust for study effects. The addition of data from the TNBC platinum-treated arm of GeparSixto (n=101) to this pooled analysis will be available at the time of presentation bringing the total sample size to 267. Results: pCR was achieved in 51 patients (31%) and 104 patients (63%) were HR deficient (31 with high HRD score and tBRCA mutation, 67 with high HRD score only, and 6 with tBRCA mutation only). Patients with HR deficient tumors were more likely to achieve a pCR than those with HR non-deficient tumors: 44% vs. 8% (p Likelihood of pCR adjusting for studyModel #Predictor VariablePopulation (n)Adjusted Odds RatioLower 95% CIUpper 95% CIP Value1HR DeficiancyAll (166)12.54.237.3 Conclusion: HR deficiency status is a robust predictor of pCR across different neoadjuvant platinum-based regimens. This pooled analysis suggests that HRD can be used to identify TNBC patients with a high probability of obtaining pCR with a platinum-based neoadjuvant chemotherapy regimen. Citation Format: Telli ML, McMillan A, Ford JM, Richardson AL, Silver DP, Isakoff SJ, Kaklamani VG, Gradishar W, Stearns V, Connolly RM, Loibl S, Elkin EP, Timms K, Hartman A-R, von Minckwitz G. Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-12.

Background: The incidence of brain metastases (BM) in breast cancer patients is rising and has become a major clinical challenge. So far, limited therapeutic options and insights into the biology of BM exist since only a few studies analyzed exclusively data of breast cancer patients. In order to improve this situation, our multicenter registry was initiated in 2014: Brain Metastases in Breast Cancer Network Germany (BMBC, GBG79). Materials and Methods: Patients with BM diagnosed since 2000, a history of breast cancer and no history of other malignant or neurologic disease can be included. Registration is allowed retrospectively as well as prospectively into a web–based database ("MedCodes"). Characteristics of the primary tumor, metastatic disease and BM as well as treatment details are documented. For this first analysis, 548 patients from 39 German centers were included. Results: Median age at first diagnosis of BM was 55 years (25 – 90 years). 43% of patients (233/548) were HER2 positive, 19% (n=105) were triple–negative and 25% (n= 138) had luminal primary tumors indicating a selection of patients with specific tumor biology who develop BM. 54 % of the patients (n=267) had up to three BM whereas 45% (n=223) had more than three BM. 19% of patients (n=106) had BM without evidence of extracranial disease. 27% of the patients (n=146) underwent surgery of the BM. Of these patients, 61% (n= 89) were treated with whole brain radiotherapy and 16% (n=23) with stereotactic radiotherapy. In patients without surgery (n=397), 73% (n=289) received whole brain radiotherapy and 7% (n=28) stereotactic radiotherapy. Median time from diagnosis of primary breast cancer to BM was 38.5 month for the entire cohort (CI95% 35.4 – 43.3). The time from first diagnosis to BM was shorter for triple–negative patients (20.9 month, CI95% 15.5 – 25.9) compared with patients with HER2–positive (37.0 month, CI95% 30.5 – 42.0) or luminal tumors (48.3 month, CI95% 38.2 – 54.0) (p Conclusion: This is so far the largest analysis of breast cancer patients with BM treated in Germany. In this cohort, triple–negative subtype or more than three BM were associated with shorter survival from the diagnosis of BM. HER2 positive patients with no HER2 directed therapy after the diagnosis of BM showed a shorter survival. The recruitment of the registry is ongoing and we aim to include more than 1000 patients by the end of 2015. Citation Format: Witzel I, Loibl S, Laakmann E, Augustin D, Flock F, Dohmen H-H, Durmus G, Frank M, Hesse T, Ignatov A, Kühn T, Neunhöffer T, Park-Simon T-W, Schmidt M, Stefek A, Weide R, Würschmidt F, Fehm T, Moebus V, von Minckwitz G, Burchardi N, Mueller V. Brain metastases in breast cancer network Germany (BMBC, GBG 79): First analysis of 548 patients from the multicenter registry. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-17-08.

Background: The epigenetic profile of triple-negative breast cancer (TNBC) showed a wide prevalence of MGMT promoter methylation.Aberrant methylation of MGMT seems to be an independent predictor of poor survival in patients with basal-like breast cancer. Moreover, patients with MGMT-negative basal-like tumors who received cyclophosphamide had asignificantly improved DFS and OS compared with MGMT-positive tumors.However, the impact of MGMT methylation in the context of modern therapy concepts is not clear. Methods: We retrospectively evaluated 174 TNBC tumors of patients enrolled into the neoadjuvantGeparSixtotrial from 08/2011 to 12/2012. Patients were randomized to receive 18 weeks of neoadjuvant treatment with paclitaxel (80mg/m2/week) and non-pegylated liposomal doxorubicin (20mg/m2/week) with or without addition of carboplatin (AUC 2.0-1.5/week).Hormone-receptor status, HER2status, and Ki67 were centrally confirmed prior to randomization. We defined pathological complete response (pCR)as ypT0/is ypN0. MGMT promoter methylation status was determined by PCR using EZ DNA Methylation Kit™ (Zymo Research); TNBCtumors were considered to be methylated if they had an average methylation ≥10%, some tumors were considered borderline due to high heterogeneity among GpC islands.We investigated the effect of MGMT methylation on pCR and its correlation with baseline characteristics. Results: A total of210 tumors from the TNBC cohort of the GeparSixtotrial(n=315) were available with a tumor content >20%. In 174 tumors the methylation assay was performed successfully. The number of tumorswith methylated MGMT was similar in carboplatin vs. non-carboplatin treated cohorts. In the carboplatin group 19.3% (17/88) of TNBC were methylated, 65.5% (58/88)unmethylated, and 14.8% (13/88) borderline.In the non-carboplatin group 20.9% (18/86) of TNBC were methylated, 62.8% (54/86)unmethylated, and 16.3% (14/86) borderline.In the entire cohort,there was no association between MGMT methylation status and pCR (p=0.522).Non-carboplatin cohort: 33.3% (6/18) of patients with methylated MGMT achieved pCR vs. 51.9% (28/54) of unmethylatedand 21.4% (3/14) of borderline (p=0.079).Carboplatin cohort: 52.9% (9/17) of patients with methylated MGMT achieved pCR vs. 55.2% (32/58) of unmethylatedand 76.9% (10/13) of borderline (p=0.320). In TNBC patients with methylated MGMT, the addition of carboplatin resulted in a 20% increased pCR rate (p=0.241). Conclusion: In this study no statistically significant association between MGMT methylation andpCR was found.Patients with MGMT methylation seemed to have a lower possibility to achieve a pCR and the addition of carboplatin seemed to reverse this effect. However, a clear classification of the borderline MGMT samples and further studies in larger series of TNBC are warranted. Citation Format: Fontanella C, Gehlhaar C, Denkert C, Schneeweiss A, Heppner B-I, Koch I, Blohmer J-U, Jackisch C, Lederer B, Fasching PA, Müller V, Untch M, Aprile G, Puglisi F, Nekljudova V, Heppner F, von Minckwitz G, Loibl S. Predictive value of O6-methylguanine-DNA methyltransferase (MGMT) promoter gene methylation in triple-negative breast cancer patients receiving carboplatin. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-55.

Background: GAIN-2 compares the effectiveness and safety of a predefined intense dose-dense regimen (EnPC) vs. a dose-dense regimen with modification of single doses depending on individual hematological and non-hematological toxicities (dtEC-dtD) (NCT01690702). Moreover, the Trastuzumab substudy compares the subcutaneous administration of the drug to the abdominal wall vs. thigh. Methods: The primary objective of the GAIN-2 trial is to compare the invasive disease-free survival (iDFS) in patients with high-risk primary breast cancer (luminal A ≥4 N+; luminal B N+; HER2+ and TNBC N0/N+). Patients are randomized between EnPC (epirubicin 150 mg/m2 q2w x 3, nab-Paclitaxel 330 mg/m2 q2w x 3, cyclophosphamide 2000 mg/m2 q2w x 3) or dtEC-dtD (dd/tailored epirubicin/cyclophosphamide q2w x 4 followed by dd/tailored docetaxel q2w x 4) Two safety interim analyses after 200 (Noeding et al. Ann Oncol 2014) and 900 patients who have completed chemotherapy were planned. We present the results of the second safety analysis. In addition to the standard analyses for hematological and non-hematological toxicities, any affections of the cranial nerves as well as the rate of macula degenerations and anaphylactic reactions are of special interest. Results: Between 09/2012 and 05/2015 a total of 1473 patients have been randomized (EnPC n=734; dtEC-dtD n=739). Among those, 84 patients have been included in the trastuzumab substudy. No safety data are currently available for the substudy. Median age was 52 years and median body-mass-index 26. In terms of hematological adverse events, the rate of febrile neutropenia grade 3-4 (12% vs. 8%) and thrombopenia grade 3-4 (12% vs. 5%) was significantly increased in the EnPC arm. As for non-hematological side effects, there were significantly more patients developing an increase in alkaline phosphatase (59% vs. 40%), ALAT (69% vs. 59%), peripheral sensory neuropathy (83% vs. 68%), arthralgia (63% vs. 49%), myalgia (48% vs. 41%) and bone pain (25% vs. 17%) in the EnPC arm, whereas nosebleed (10% vs. 25%), edema (13% vs. 26%) and hand-foot syndrome (12% vs. 28%) were more common in the dtEC-dtD arm. We observed two treatment related deaths, both in the dtEC-dtD arm (cause of death: acute respiratory distress syndrome and pneumonia). There were no differences between the treatment arms for the toxicities of special interest. In the EnPC arm, overall 30% of the patients required dose-reductions due to hematological toxicities compared with only 10% in the dtEC-dtD arm (p Conclusion: This interim safety analysis from a prospectively randomized trial investigating iddEnPC with predefined doses and a toxicity adapted idd/tailored strategy (dtEC-dtD) showed no additional or unexpected safety signals in the iddEnPC or dtEC-dtD arm. Therefore, no modifications in the conduction of the study are necessary and the study continues as expected. Citation Format: Möbus V, Lück H-J, Forstbauer H, Wachsmann G, Ober A, Schneeweiss A, Christensen B, von Abel E, Grischke E-M, Höffkes H-G, Klare P, Yon-Dschun K, Schmatloch S, Furlanetto J, Burchardi N, von Minckwitz G, Loibl S. GAIN-2: Adjuvant phase III trial to compare intense dose-dense (idd) treatment with EnPC to tailored dose-dense (dt) therapy with dtEC-dtD for patients with high-risk early breast cancer: Results of the second safety interim analyses. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-05.

There is clear evidence that the immune system plays an essential role in tumor defense. By determining tumor-infiltrating lymphocytes (TILs), the individual immunological response becomes more apparent and measurable. In breast cancer, high levels of TILs are associated with a more favorable clinical course. In this review, we describe how TILs are determined with emphasis on daily routine diagnostics. We further discuss their impact as a prognostic and predictive biomarker in the neoadjuvant and adjuvant therapy setting as well as in residual disease. We also discuss their potential future implications on further stratifying prognostic subgroups of breast cancer, thereby possibly influencing future therapy considerations.

Background: Currently, axillary surgery for breast cancer is considered as staging procedure that does not seem to influence breast cancer mortality, since the risk of developing metastasis depends mainly on the biological behaviour of the primary. Based on this, the postsurgical therapy should be considered on the basis of biologic tumor characteristics rather than nodal involvement. Trial design: The goal of INSEMA is to show that early-stage breast cancer patients with reduced extent of axillary surgery are not inferior regarding invasive disease-free survival (IDFS) outcome. Patients with planned breast-conserving surgery (BCS) will be first randomized (1:4 ratio) to either no axillary surgery or axillary sentinel lymph node biopsy (SLNB). Patients with SLNB and pN+(sn) status will be secondly randomized (1:1 ratio) to either SLNB alone or completion axillary lymph node dissection (ALND) in cases with less than three involved nodes (one or two macrometastases). Primary objective: -IDFS after BCS (non-inferiority question) Inclusion criteria: -Written informed consent -Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy) -Age at least 35 years -Preoperative imaging techniques with estimated tumor size of maximal 5 cm (iT1/iT2 irrespective of hormone sensitivity or HER2 status) -Clinically and sonographically tumor-free axilla prior to core biopsy -In cases with cN0 and iN+, a negative core biopsy or fine needle aspiration biopsy of the suspected lymph node is required -No clinical evidence for distant metastasis (M0) -Planned breast-conserving surgery (R0 resection) with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation) Statistics: The calculated total case number for per-protocol analyses is 6,740 (5,940 German and 800 Austrian patients), the expected total number of randomized patients is 7,095. Time lines: -First patient in: September 2015 -Last patient in: August 2019 -Final analysis: End of 2024 Present accrural: In June 2016, more than 1.000 patients were recruited in Germany and Austria. Citation Format: Reimer T, von Minckwitz G, Loibl S, Hildebrandt G, Nekljudova V, Schneider-Schranz C, Gerber B. Comparison of axillary sentinel lymph node biopsy versus no axillary surgery in patients with early-stage invasive breast cancer and breast-conserving surgery: A randomized prospective surgical trial. The Intergroup-Sentinel-Mamma (INSEMA)-trial [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 OT2-04-02.

Tumor-infiltrating lymphocytes (TILs) have been identified as prognostic parameter in breast cancer.The aim of this review article is to provide an overview on the clinical and analytical validation of TILs in breast cancer.Summary of international guidelines of the TIL working group as well as clinical and translational studies.Breast carcinomas with a high TIL level have an improved response to neoadjuvant chemotherapy. Triple-negative and HER2-positive carcinomas with increased TIL levels have improved survival. TILs are a new prognostic biomarker for routine histopathological diagnosis.