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Kaplan-Meier curves stratified by endoxifen levels using a quartile split.

List of participating centres and number of patients included.

Comparison of olaparib (OLA) monotherapy versus chemotherapy in patients with platinum-sensitive (PSOC) or platinum-resistant ovarian cancer (PROC).Patients with measurable disease and ≥ 1 prior line of chemotherapy (CT) were randomized 2:1 to OLA (300 mg tablets, BID) or physician's choice CT.: for PSOC: Carboplatin-Pegylated-Liposomal-Doxorubicin (PLD) or Carboplatin-Gemcitabine; for PROC: PLD, Topotecan, Paclitaxel or Gemcitabine.160 patients (60 with PSOC and 100 with PROC) were randomized 2:1 to OLA (n = 107) or CT (n = 53). Baseline characteristics were similar between both arms. Overall objective response rate (ORR) for OLA and CT were similar (24.3% (26/107) and 28.3% (15/53), respectively). Clinical benefit rate (≥ 12 weeks) was similar with 54.2% (58/107) and 56.6% (30/53), respectively. In PSOC, ORR was 35.0% (14/40) and 65.0% (13/20) for OLA and CT (p = 0.053); in PROC, ORR was 17.9% (12/67) and 6.1% (2/33) for OLA and CT (p = 0.134). ORR in heavily pretreated PROC (4 prior lines) was 22.9% (8/35) with OLA versus 0% (0/14) for CT. ORR of 35.7% (5/14) and 13.2% (7/53) was observed in BRCA-mutated and -wildtype PROC cases, respectively. Median PFS in PROC was not significantly different with 2.9 months (95% CI 2.8-5.1 in the OLA group versus 3.8 months (95% CI 3.0-6.4) in the CT group (hazard ratio [HR] 1.11 [95% CI 0.72-1.78]; log-rank p = 0.600).OLA monotherapy showed overall an equal response rate in relapsed ovarian cancer compared with CT. In PROC, ORR and TFST tended to be higher with OLA than with CT. In heavily pretreated patients (four lines or more) with PROC disease, OLA treatment seemed to be more effective than CT.

Background The Regan Composite Risk Score (RCRS) is a web-based prognostic and predictive calculator to guide the use of adjuvant exemestane plus ovarian function suppression (AI + OFS) versus tamoxifen plus ovarian function suppression (TAM + OFS) or tamoxifen alone (TAM) for premenopausal women with hormone receptor-positive HER2-negative early breast cancer (HR+/HER2- EBC). We compared our adjuvant endocrine therapy policy based on the tumor board with the treatment guided by the RCRS during 2 time periods, one before and one after the acquaintance of the Tamoxifen and Exemestane Trial (TEXT) and Suppression and Ovarian Function Trial (SOFT) data. This allowed us to see a possible evolution in therapy policy. Methods A retrospective cohort study of 563 premenopausal patients with HR+/HER2- and HER2+ EBC diagnosed at the University Hospital of Leuven during 2 periods, 2010-2012 (cohort 1) and 2015-2017 (cohort 2), was conducted. For each patient with HER2- EBC, the RCRS was calculated by entering the requested characteristics in the online available tool. The primary outcome was to investigate how frequent our therapy differed from the therapy guided by the RCRS based on the estimated 8-yr distant relapse free interval (DRFI) with an arbitrary cut-off set at 3 %. If the received therapy was ≥ 3 % less efficient in 8-year DRFI compared to the optimal therapy according to RCRS, the patient was considered undertreated. If the received therapy differed by less than 3 % in 8-year DRFI compared to the optimal therapy according to RCRS and yet the most intensive therapy (AI + OFS > TAM + OFS > TAM) was administered, the patient was considered overtreated. In the other cases, the patient was considered to have been treated concordant with the RCRS. Secondarily, nonadherence of the HER2- and HER2+ patients towards the endocrine treatments leading to therapy switch because of intolerance was recorded at 6, 12, 24 and 36 months. Analyses were performed using SAS software and the comparison of both cohorts was performed by the chi-squared test for categorical variables. Results According to the RCRS, 43.2 % (89/206) of the HER2-negative patients of cohort 1 were undertreated compared to 22.1 % (43/194) in cohort 2 (chi- squared test, p-value < 0.001). The number of overtreated patients also differed significantly between the two cohorts (chi-squared test, p-value = 0.003) with 2.9 % (6/206) in the first cohort and 10.3 % (20/194) in the second cohort. Finally, the number of patients treated concordant with the guidance derived from the RCRS was 53.9 % (111/206) in cohort 1 and 67.5 % (131/194) in cohort 2 (chi-squared test, p-value = 0.005). Treatment intolerance and switch was observed in 34.8 %, 16.7 % and 12.4 % of the patients receiving AI + OFS, TAM + OFS or TAM as initial therapy respectively; this was numerically higher for all treatments in cohort 2 vs cohort 1, although the observed difference was only significant for TAM. Conclusion In our center, a recent cohort of premenopausal women was more likely to be treated with the adjuvant endocrine treatment concordant with the guidance derived from the RCRS when using an arbitrary cut-off of 3 % to define a relevant improvement in outcome. Citation Format: Charlotte Berteloot, Patrick Neven, Maja Vangoitsenhoven, Annouschka Laenen, Hans Wildiers, Kevin Punie, Ann Smeets, Ines Nevelsteen, Sileny Han, Thaïs Baert, Hilde Janssen, Eva Oldenburger, Adinda Baten, Patrick Berteloot, Rani Vanhoudt, Anne Deblander, Chantal Remmeriev, Christine Desmedt. Real world adjuvant endocrine treatment in premenopausal breast cancer patients compared with the proposed algorithm using the Regan Composite Risk Score [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-04.

Introduction Accurate information on cause of death is essential for correct breast cancer-specific mortality assessment. However, registration and coding of cause of death is prone to error since determining the exact underlying condition related to the death is challenging. In this study, an expert review of medical files was done to determine the principal cause of death for breast cancer patients of a Belgian tertiary hospital. The retrieved cause of death was compared to death certificate information to assess concordance between both sources. Secondly, the impact of discordant reporting on cause-specific survival (CSS) and other net survival approaches were examined. Methods Breast cancer patients diagnosed and treated at University Hospitals Leuven (UHL) between 2009 and 2014 with follow-up until December 31st, 2016, were included in the study. Information on cause of death was obtained from death certificates (following ICD-10 rules) and medical files. The latter were reviewed by a board of experts at UHL. Agreement was calculated using Cohen’s kappa coefficient, and reasons for discordant reporting were assessed. CSS was calculated based on cause of death information from both sources using the Kaplan-Meier method. These survival estimates were compared to the relative survival probability (RS) using the Ederer II and Pohar Perme method. Results A total of 2,862 patients were included, of whom 354 died after a median follow-up of 54.6 months. We found overall substantial agreement (kappa-value of 0.69 (95% C.I.: 0.62-0.77)) between cause of death reported by death certificates and medical files (Table 1). In 84.8% of cases, there was concordance between both methods. When comparing to medical files, misattribution of breast cancer-specific death in death certificates (4.5% of cases) was linked to the presence of comorbidities (43.7%), metastases (37.5%), or unspecified causes (18.8%). Five-year CSS based on medical files (93.1% (95% C.I.: 91.9-94.1)) was only slightly higher compared to CSS based on death certificates (92.3% (95% C.I.: 91.2-93.4)). RS measures using Ederer II and Pohar Perme were comparable to CSS measures. Conclusions Overall, substantial agreement of cause of death was seen between death certificates and medical files. Attribution of cause death to comorbidities was the most common reason for discordant reporting of breast cancer-specific death. Five-year breast cancer-specific survival was slightly higher based on cause of death information from medical files, compared to death certificates. Periodic reviews and implementation of ICD-10 guidelines for classification of cause of death could improve accuracy in cause of death annotation. Table 1: Discordance for the principal cause of death between medical files and death certificatesmedical filesother causesbreast cancerdeath certificatesother causes136 (38.4%)16 (4.5%)152 (42.9%)breast cancer38 (10.7%)164 (46.3%)202 (57.1%)174 (49.2%)180 (50.9%)354 (100%) Citation Format: Hava Izci, Tim Tambuyzer, Jessica Vandeven, Jérôme Xicluna, Hans Wildiers, Kevin Punie, Nynke Willers, Eva Oldenburger, Els Van Nieuwenhuysen, Patrick Berteloot, Ann Smeets, Ines Nevelsteen, Liesbet Van Eycken, Harlinde De Schutter, Patrick Neven, Geert Silversmit, Freija Verdoodt. Cause of death discordance between death certificates and medical files: Impact on cancer survival assessment in a Belgian case study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-63.

Purpose We studied presence of accompanying ductal adenoma in situ (accom-DCIS) in a consecutive series of primary operated TNBC for distant time-to-event outcome. Methods A retrospective cohort study (diagnosis 1/1/2000 - 31/12/2017) of prospectively registered primary operated TNBC patients in UZ Leuven. Only TNBC of no special type were included. We compared patient (age, BMI, symptomatic/screening-detected) and tumor related factors (Nottingham Prognostic Index (NPI), Lymphovascular Involvement (LVI)) for accom-DCIS and analyzed the effect of accom-DCIS on distant time to event outcome using the Cox proportional hazards model. Multivariate models were used to correct for possible confounders. Results We included 524 patients. Median follow-up was 102 months. Mean age of patient was 57.3 [26-90] years and 361 had accom-DCIS (68,9 %); demographics, clinical-pathological characteristics and postoperative chemo- and radiotherapy were similar in patients with and without accom-DCIS; only LVI was significantly more likely to be present in accom-DCIS cases (p= Citation Format: Jan Ardui, Hans Wildiers, Giuseppe Floris, Hava Izci, Kevin Punie, Tatjana Geukens, Els Van Nieuwenhuysen, Sileny Han, Patrick Berteloot, Annouschka Laenen, Hilde Janssens, Ann Smeets, Caroline Weltens, Ignace Vergote, Patrick Neven. Associated ductal carcinoma in situ in primary operated TNBC is associated with a longer time to distant event [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-13.

Background: Breast cancer is a disease that can recur even after 20 years of diagnosis. At the moment it remains difficult to predict which women will have a late relapse as most scientific research is conducted for relapse within 10 years following diagnosis. A recent meta-analysis by Pan et al was the first to look at risk factors for relapse in the second decade after diagnosis. However this paper mostly included patients that were treated before the year 2000, which makes the results less applicable to patients nowadays. Objective: We retrospectively explored known early relapse risk factors for late relapse in a population that was diagnosed between year 2000 and 2008, 10-year disease-free and treated in one center. Patients and methods: We included all patients, diagnosed with invasive breast cancer who remained disease-free for 10 years. We selected these from a prospectively managed database of consecutive treated patients in the University Hospitals Leuven for early breast cancer, diagnosed between 01-01-2000 and 01-08-2008. We analyzed the association of patient and tumor characteristics for relapse during the second decade after diagnosis. A disease-free survival event (invasive or in situ) was defined as local (ipsi- and contralateral breast), loco-regional (ipsi- and contralateral axillary, internal mammary and subclavian lymph nodes) or metastatic. For the statistical analysis we used Cox proportional hazard models, with time to recurrence as response variable. Furthermore, a multivariable model of independent predictors was constructed using backward selection. Results: 2757 patients were included with a median follow-up of 13.78 years since initial diagnosis (range=10.01-18.65). Out of this group, 179 patients (6,5%) had a disease-free survival event (6 were in situ carcinoma). The multivariate analysis showed a higher risk of relapse in patients with a younger age (HR=1.044, p=0.0002), higher BMI (HR=1.036, p=0.0243) and postmenopausal status at diagnosis (HR=2.266, p=0.0012), higher tumor grade (HR=1.943, p=0.0151), more lymph node involvement (HR=1.626, p Conclusion: Several patient and tumor related factors proved to be significant independent risk factors for late relapse (>10 years after diagnosis). Our findings may help to differentiate between patients with high and low risk of relapse beyond 10 years of treatment and in this way, provide them with a more personalized form of follow-up. Citation Format: Anne-Sophie Vertongen, Hans Wildiers, Kevin Punie, Floris Giuseppe, Vergote Ignace, Patrick Berteloot, Toon Van Gorp, Ann Smeets, Els Van Nieuwenhuysen, Han Sileny, Ines Nevelsteen, Annouschka Laenen, Caroline Weltens, Hilde Janssens, Patrick Neven. Risk of breast-cancer recurrence after a 10-year disease-free interval [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-18.

Background. High levels of sTIL have been associated with an increased pCR rate after NACT. Recent experimental and human data have demonstrated that obesity is associated with T-cell dysfunction (mediated by increased expression of checkpoints PD-1, LAG3 and TIM3), herewith reducing antitumor immune response. Here, we evaluated the value of sTIL in predicting pCR and prognosis in TNBC treated with NACT according to patient’s BMI. Patients and methods. We considered two institutional retrospective series of 452 TNBC patients treated with NACT (Leuven: n= 174, and, Curie: n= 278). Underweight patients ( Results. 236 (53%), 132 (30%) and 77 (17%) patients were lean, overweight and obese, respectively. pCR was achieved in 181/445 (41%) of the patients. Median sTIL was 11% and 99/445 (22%) tumors had high sTIL. Median follow-up time was 7.63 years. BMI was associated with menopausal status (33.8% lean and 50.4% overweight & obese patients were postmenopausal, p Conclusion. In this study, we demonstrated that in TNBC patients treated with NACT, high sTIL predict pCR and favorable prognosis only in lean patients. Table 1. Unadjusted and adjusted associations with pCR in TNBC.Unadjusted OR, 95% CIAdjusted OR (95% CI)sTIL (≥30 vs Citation Format: Christine Desmedt, François Richard, Lynn Jongen, Anne-Sophie Hamy-Petit, Hans Wildiers, Jan Ardui, Kevin Punie, Ann Smeets, Patrick Berteloot, Ignace Vergote, Maricl Lae, Diane Decroze, Didier Meseure, Fabien Reyal, Elia Biganzoli, Patrick Neven, Giuseppe Floris. Impact of body mass index (BMI) on the predictive and prognostic value of stromal tumor-infiltrating lymphocytes (sTIL) in triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy (NACT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-04.

Introduction Based on immunohistochemistry, triple-negative breast cancer (TNBC) lacks ER, PR and HER2, rendering them non-eligible for hormone or HER2 targeted therapy. Adjuvant chemotherapy (aCT) is often not initiated based on clinical decision making (low risk of relapse, comorbidities, older age), but sometimes because of patient refusal. We aimed to compare clinical-pathologic characteristics and outcome of patients with TNBC by reason to abstain from aCT (based on a clinical decision or patient refusal) with patients who did receive aCT. Methods In this retrospective study, we consecutively included patients with primary operable TNBC who received primary surgery, diagnosed and treated at University Hospitals Leuven between 2000-2017 (median follow-up of 9 years). The underlying reason for patients who did not receive aCT was obtained by performing a chart review: (1) by clinical decision for various different reasons: e.g. low risk of relapse (special histological subtypes e.g. adenoid cystic carcinoma, small pN0 lesions), comorbidities, older age or (2) by patient refusal. Distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS) were studied endpoints. Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals. All statistical tests are two-sided, a 5% significance level was assumed for all tests. Analyses have been performed using SAS software (version 9.4 of the SAS System for Windows). Results We included 673 patients with TNBC of whom 163 (24.2%) did not receive aCT; 141 (20.9%) due to a clinical decision, and 22 (3.3%) due to patient refusal. Mean age at diagnosis was 71.6 years and 68.7 years, respectively, compared to 52.3 years for those who received aCT. Patients who received aCT showed a tendency towards better DDFS when compared to the group of patients who refused aCT (HR=0.621 [0.217;1.774]; p=0.37), and when compared to the group who did not receive aCT due to a clinical decision (HR=0.545 [0.294;1.009]; p=0.05). The group of patients who did not receive aCT due to a clinical decision showed a tendency towards worse DDFS compared to the group of patients who refused aCT (HR=1.140 [0.390;3.30]; p=0.81), however this difference was not statistically significant. Interestingly, BCSS for patients who received aCT was better compared to patients who did not receive aCT due to a clinical decision (HR=0.484 [0.250;0.935]; p=0.03) and showed a tendency towards better survival when compared to the group of patients who refused aCT (HR= 0.582 [0.174;1.946]; p=0.38). Patients who did not receive aCT due to a clinical decision showed a tendency towards worse BCSS than patients refusing therapy (HR=1.204 [0.353;4.089]; p=0.77). Conclusion In this cohort, TNBC patients treated with primary surgery who refused aCT appeared to have worse DDFS and BCSS compared to patients who received aCT. Patients who did not receive aCT due to a clinical decision hade worse BCSS and a tendency towards worse DDFS, compared to patients who received aCT. These results suggest that chemotherapy is effective in reducing cancer-related mortality. Citation Format: Hava Izci, Jan Ardui, Annouschka Laenen, Freija Verdoodt, Giuseppe Floris, Laurence Slembrouck, Ignace Vergote, Ann Smeets, Els Van Nieuwenhuysen, Sileny Han, Ines Nevelsteen, Caroline Weltens, Patrick Berteloot, Kevin Punie, Hans Wildiers, Patrick Neven. Outcome of patients with triple-negative breast cancer who did not receive adjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-23.

Purpose Predictors for pathological Complete Response (pCR) in TNBC are very important given pCR is considered a surrogate marker for breast cancer-related survival. Associated DCIS in TNBC (accom-DCIS) as well as presence of microcalcifications on initial mammography (micro-MG) have been correlated with Androgen Receptor positive TNBC, known to achieve lower pCR rates. We aim to investigate the predictive impact of accom-DCIS and micro-MG on pCR. We also validated known clinico-pathological predictors for pCR. Long term outcome was analyzed for pCR and accom-DCIS. Methods A retrospective cohort study (diagnosed 1/1/2000 - 31/12/2017) of prospectively registered consecutively treated TNBC patients was performed. TNBC was defined as IHC-ER Citation Format: Jan Ardui, Sophie Vandamme, Chantal Van Ongeval, Giuseppe Floris, Hava Izci, Hans Wildiers, Kevin Punie, Tatjana Geukens, Ignace Vergote, Patrick Berteloot, Toon Van Gorp, Ann Smeets, Els Van Nieuwenhuysen, Sileny Han, Annouschka Laenen, Caroline Weltens, Hilde Janssens, Patrick Neven. The presence of ductal carcinoma in situ in core needle biopsy and microcalcifications on mammography in TNBC is associated with a lower pCR and worse long term outcome [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-07.

Purpose: Metaplastic Breast Cancer (mBC) is uncommon and often behaves aggressive with a high incidence of recurrence. Prognostic factors are poorly understood. We analyzed prognostic factors in a single center series of triple negative mBC and compared those to a patients with ductal TNBC of no special type (dTNBC-NST), treated during the same time period; Materials and methods: We retrospectively analyzed prognostic factors (demographic and clinical pathological features) and distant recurrence of all ER-negative mBC’s (primary operated and neoadjuvant chemotherapy (NAC-)) treated in the University Hospitals Leuven (UHL) between 1/1/2000 and 31/12/2016. TNBC was defined as IHC-ER Results: 49 mBC patients were identified; 11 treated with NAC and 38 primary operated. The dTNBC-NST group contained 662 patients; 194 treated with NAC and 468 primary operated. Median follow up was 8.35yrs [5.33 - 12.16] in the mBC and 9.48yrs [5.23-13.44] in the dTNBC-NST group. Median age was 52yr in the mBC and 53yr in the dTNBC-NST (p=0.482). There was a tendency for a higher BMI in the mBC group: median BMI was 26.4kg/m² in mBC and 24.7kg/m² in the dTNBC-NST group (p=0.09, univariate analysis). Tumors were significantly larger in the mBC group with the median size (mm) of 29.5 in mBC and 25.0 in dTNBC-NST (p=0.008). Nodal involvement was 17/49 (34.7%) in the mBC group and 205/662 (31.0%) in dTNBC-NST (p=0.345). LVI was significantly less present in mBC (7.9%) than in dTNBC-NST (24.4%) (p=0.026). A similar proportion in either group received adjuvant chemotherapy (76.3% in mBC and 80.8% in dTNBC-NST) but mBC received more often adjuvant radiotherapy (85.7% in mBC and 60.1% in dTNBC-NST, p Conclusion: mBC is larger at diagnosis and less often LVI-pos compared to dTNBC-NST. Adjuvant radiotherapy was more often given to mBC patients. The trend we observed of more distant relapse in mBC disappeared when corrected for tumor characteristics. Citation Format: Jan Ardui, Kevin Punie, Giuseppe Floris, Hava Izci, Hans Wildiers, Ignace Vergote, Patrick Berteloot, Toon Van Gorp, Annouschka Laenen, Ann Smeets, Caroline Weltens, Patrick Neven. Clinico-pathological characteristics of metaplastic breast cancer as compared to normal TNBC: A single center analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-26.

Background The introduction of multi-gene panel testing in the diagnosis of hereditary breast and ovarian cancer (HBOC) has led to an important increase in the detection of breast cancer predisposition genes other than BRCA1 and BRCA2. Methods All individuals who underwent HBOC-testing at our institution since the introduction of multi-gene panel testing were included (March 2016-August 2017). In this retrospective analysis, the BRCA Hereditary Cancer MASTR Plus® panel is used (Multiplicom, Belgium), with sequencing of BARD1, BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, TP53, MRE11A, RAD50, NBN, FAM175A, ATM, PALB2, STK11, MEN1, PTEN, CDH1, MUTYH, CHEK2, BLM, XRCC2, EPCAM, MLH1, MSH6, PMS2, MSH2. In breast cancer patients with a recurrent germline alteration, age and TNM stage at diagnosis, histological subtype, grade of differentiation and molecular surrogate subtype were recorded. Given the low numbers of TP53-carriers diagnosed by HBOC testing, also patients with a germline TP53-mutation diagnosed by targeted sequencing at our institution were included. Statistical analysis were performed with SPSS version 25. Results In 11.9 % of 2806 patients who underwent panel testing, a germline pathogenic alteration was detected. BRCA1 and BRCA2 were the most prevalent alterations, detected in respectively 3.35 and 2.92 % of patients. Germline alterations in CHEK2, ATM , PALB2 and TP53 were detected in respectively 2.5 %, 1.1 %, 0.5 % and 0.1 %. In 1 % of patients, germline alterations were retrieved that only contribute to ovarian cancer risk (BRIP, RAD51C, RAD51D). Germline DNA mismatch repair alterations were detected in 0.39 % of patients. The median age at onset of breast cancer in patients with germline CHEK2-, ATM-, PALB2- and TP53-mutations was 47, 53, 39 and 33 years respectively. The age of breast cancer diagnosis in patients with germline TP53-alterations was significantly younger compared to patients with CHEK2-mutations (p = 0.01), ATM-mutations (p = 0.01) and PALB2-mutations (p = 0.04). In situ carcinomas were diagnosed in respectively 9 %, 11 % and 11 % of patients with CHEK2-, PALB2- and TP53-mutations. Patients with CHEK2, ATM, PALB2 and TP53-alterations were diagnosed with ≥T3-tumors in respectively 13 %, 12 %, 33 % and 22 %. Nodal status at diagnosis was negative in 40-60 % in these 4 subgroups. Upfront metastatic disease was diagnosed only in 2/43 CHEK2-carriers. More than half of the breast cancer diagnoses were luminal tumors in CHEK2-, ATM- and PALB2-carriers, while cases with germline TP53-alterations only presented with luminal cancers in 22 % in our series. Conclusion Almost half of the pathogenic mutations detected in HBOC-genes are alterations in genes other than BRCA1 and BRCA2. CHEK2-mutations are by far the most prevalent, followed by ATM, PALB2 and TP53. The range of the CHEK2- and ATM-population was wider then expected at the lower-age boundary. The age of breast cancer diagnosis in patients with germline TP53-mutations was significantly younger compared to patients with CHEK2-, ATM- and PALB2-mutations. The distribution of the histological subtypes and grade of differentiation was not suggestive of a specific correlation with germline mutation status. Citation Format: Hoste G, D'Hoore P, Legius E, Van Buggenhout G, Floris G, Wildiers H, Han SN, Van Nieuwenhuysen E, Berteloot P, Smeets A, Nevelsteen I, Weltens C, Janssen H, Van Limbergen E, Neven P, Punie K. Hereditary breast cancer beyond BRCA: Clinical and histopathological characteristics in patients with germline CHEK2, ATM, PALB2 and TP53-mutations [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 P5-09-05.

Purpose: In stage IV breast cancer (BC), discordance in the human epidermal growth factor receptor 2 (HER2) amplification status between primary and metastatic BC might affect efficacy of HER2-targeted agents. We studied progression free (PFS) and overall survival (OS) dependent on HER2 concordance in patients treated with a first line taxane-trastuzumab combination and later line trastuzumab-emtansine (T-DM1). Patients and Methods: This retrospective monocentric study included 76 patients with metastatic BC under treatment with trastuzumab in which a biopsy from both the primary and metastatic site was available. HER2 amplification status, sex-steroid receptor status, Nottingham prognostic index, distant metastasis-free interval and consecutive lines of therapy were retrieved from patients' reports. The Kaplan-Meier method was used for estimating PFS/OS and log-rank test for analyzing between group differences. A Cox model is used for testing difference between groups while correcting for Pertuzumab. Multivariable Cox regression is used to model OS as a function group, correcting for possible confounders. Results: Discordance in HER2 amplification status was seen in 30 out of 76 patients (39%), 11 patients lost HER2 amplification in the metastatic lesion (HER2lost) while 19 acquired HER2 amplification (HER2acquired). The other 46 patients had a HER2 amplification on both primary and metastatic site (HER2stable). The HER2lost group had a significant lower median PFS (PFS= 5.5 months) for taxane-trastuzumab, after correcting for pertuzumab, compared to the HER2stable group (PFS= 9 months, corrected p= 0.0146) and HER2acquired group (PFS=14 months, corrected p=0.0121). For T-DM1 treatment, both discordant groups, HER2acquired (PFS=1.1 months, p=0.0373) and HER2lost (PFS=1.5 months, p=0.0116), had a significant lower PFS compared to the HER2stable group (PFS=6.0 months). After correcting for possible confounders, HER2lost had a significant worse OS compared to HER2stable (HR 0.187, 95% CI 0.079 – 0.439) and HER2acquired (HR 0.147, 95% 0.058-0.378). Conclusion: Loss of HER2 amplification in metastatic lesions seems to have a negative predictive value for PFS on HER2-targeted agents and negative prognostic impact on OS. Acquiring of HER2 amplification was predictive for lower PFS on T-DM1 but wasn't predictive for lower PFS on taxane-trastuzumab. Citation Format: Van Raemdonck E, Berteloot P, Laenen A, Han S, Van Nieuwenhuysen E, Salihi R, Concin N, Vergote I, Floris G, Wildiers H, Punie K, Neven P. Efficacy of HER2 inhibitors in metastatic breast cancer by discordance in HER2 amplification status between primary and metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-09.

PURPOSE: In stage IV breast cancer, the efficacy of human epidermal growth factor receptor 2 (HER2) targeted therapies in cases with discordance in HER2 expression between primary and metastatic site is not well known. We studied progression free (PFS) and overall survival (OS) by HER2 concordance when treating women with taxane-trastuzumab (± pertuzumab) in first or second line and trastuzumab-emtansine (T-DM1) or capecitabine-lapatinib in later lines. PATIENTS AND METHODS: Retrospective monocentric study including all breast cancer patients receiving trastuzumab between January 2002 and September 2017 at the University Hospital in Leuven; we selected metastatic patients with an available HER2 status in primary and metastatic site. The Kaplan-Meier method was used for estimating PFS/OS and log-rank test for analyzing between group differences. A Cox model is used for testing difference between groups while correcting for Pertuzumab. Multivariable Cox regression is used to model overall survival as a function group, correcting for possible confounders. RESULTS: We included 74 patients; 46 had an unchanged HER2 status (positive/positive), 9 lost HER2 (positive/negative), while 19 acquired HER2 amplification (negative/positive). 25 out of 28 cases with a discordant HER2 status were positive for ER and/or PgR in the primary site. HER2 positive/negative cases had a significantly lower PFS for taxane-trastuzumab-(pertuzumab) (PFS = 5.5 months), compared to HER2 positive/positive (PFS 9 months, p = 0.01) and HER2 negative/positive (PFS 14 months, p = 0.01) patients. PFS for later line T-DM1 (n = 30) was significantly higher for the HER2 positive/positive group (PFS 6.0 months) than for the discordant groups HER2 negative/positive (PFS 1.0 month, p = 0.04) and HER2 positive/negative (PFS 1.5 month, p = 0.01). After correcting for possible confounders, the HER2 positive/negative group had a significantly worse OS compared to HER2 positive/positive (HR 0.19, 95% CI 0.08-0.44) and negative/positive (HR 0.15, 95% 0.06-0.38). CONCLUSION: Conversion of HER2 status was seen in 28 out of 74 cases and was mostly observed in hormone receptor-positive tumors. In contrast to patients with HER2 loss, patients with a positive conversion of HER2 status derived substantial benefit from first line treatment with taxane-trastuzumab-(pertuzumab). This study highlights the importance of re-biopsying the metastatic lesion and changing treatment according to the last HER2 result. ispartof: Breast Cancer Research And Treatment vol:185 issue:1 pages:183-194 ispartof: location:Netherlands status: Published online

PURPOSE: In metastatic breast cancer (MBC) population treated with capecitabine monotherapy, we investigated clinical-pathological features as possible biomarkers for the oncological outcome. METHODS: Retrospective study of consecutive MBC patients treated at University Hospitals Leuven starting capecitabine between 1999 and 2017. The primary endpoint was the durable response (DR), defined as non-progressive disease for > 52 weeks. Other main endpoints were objective response rate (ORR), time to progression (TTP) and overall survival (OS). RESULTS: We included 506 patients; mean age at primary breast cancer diagnosis was 51.2 years; 18.2% had de novo MBC; 98.8% were pre-treated with taxanes and/or anthracycline. DR was reached in 11.6%. Patients with DR, as compared to those without DR, were more likely oestrogen receptor (ER) positive (91.5% vs. 76.8%, p = 0.010) at first diagnosis, had a lower incidence of lymph node (LN) involvement (35.6% vs. 49.9%, p = 0.039) before starting capecitabine, were more likely to present with metastases limited to ≤ 2 involved sites (54.2% vs. 38.5%, p = 0.020) and time from metastasis to start of capecitabine was longer (mean 3.5 vs. 2.7 years, p = 0.020). ORR was 22%. Median TTP and OS were 28 and 58 weeks, respectively. In multivariate analysis (only performed for TTP), ER positivity (hazard ratio (HR) = 0.529, p

Background High levels of stromal tumor-infiltrating lymphocytes (sTIL) are associated with increased pathological complete response (pCR) rate and longer survival after neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients. Here, we evaluated the value of sTIL in predicting pCR and explored prognosis in TNBC patients treated with neoadjuvant chemotherapy according to body mass index (BMI). Methods sTIL were scored centrally on pretreatment biopsies from 2 retrospective series of nonunderweight TNBC patients (n = 445). sTIL and BMI were considered as binary (sTIL: Results 236 (53.0%) patients were lean and 209 (47.0%) overweight and obese. pCR was achieved in 181 of 445 (41.7%) patients. Median sTIL was 11.0%, and 99 of 445 (22.2%) tumors had high sTIL. A statistically significant interaction between sTIL and BMI, considered as categorical or continuous variables, for predicting pCR was observed in the multivariable analysis (Pinteraction = .03 and .04, respectively). High sTIL were statistically significantly associated with pCR in lean (odds ratio [OR] = 4.24, 95% confidence interval [CI] = 2.10 to 8.56; P < .001) but not in heavier patients (OR = 1.48, 95% CI = 0.75 to 2.91; P = .26) in the multivariable analysis. High sTIL were further associated with increased event-free survival in lean (hazard ratio [HR] = 0.22, 95% CI = 0.08 to 0.62; P = .004) but not in heavier patients (HR = 0.53, 95% CI = 0.26 to 1.08; P = .08). Similar results were obtained for overall survival. Conclusion BMI is modifying the effect of sTIL on pCR and prognosis in TNBC patients treated with neoadjuvant chemotherapy.

We aimed to investigate the role of palbociclib, a first-in-class cyclin-dependent kinase 4 and 6 inhibitor, in postmenopausal women with highly pretreated endocrine therapy-resistant metastatic breast cancer (MBC). Between 28 September 2015 and 14 March 2017, a compassionate use program was established in the University Hospitals Leuven in which 82 postmenopausal women with estrogen receptor-positive, HER2-negative MBC were included after at least four lines of systemic treatment. The efficacy and safety analysis was performed in 82 patients who had received at least one dose of palbociclib and who had at least 6-month follow-up at the data cut-off point. The primary objective was the evaluation of efficacy of the combination of palbociclib and endocrine therapy with clinical benefit as primary endpoint, defined as the absence of progressive disease and being on treatment for at least 6 months. Secondary objectives were the evaluation of toxicity and the identification of potential predictors for clinical benefit. The median age of the patients was 67.1 years (range 34.8–85.9) at the time of inclusion. The average duration of treatment was 5.6 months (range 1–19), with a median progression-free survival of 3.17 (95% CI 2.76–4.70) months. At the data cut-off point, 10 patients were still on treatment with palbociclib. In this highly pretreated setting, 34 patients experienced no progressive disease within 6 months, resulting in an overall clinical benefit rate (CBR) of 41.5%. 20.7% (17/82) showed stable disease for ≥ 9 months and 13.4% for ≥ 12 months. None of the investigated predicting factors were significantly associated with clinical benefit at 6 months. For 43.9% of the patients, treatment delay or dose reduction was indicated. Palbociclib in combination with endocrine therapy shows an unexpectedly high CBR and favorable safety profile in heavily pretreated endocrine-resistant estrogen receptor-positive, HER2-negative MBC patients.

In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women.We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing.Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [1%] vs seven [1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (1%) of 4851 patients died while on trial treatment (13 [1%] of 2417 patients in the intermittent letrozole group vs ten [1%] of 2411 in the continuous letrozole group).In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them.Novartis and the International Breast Cancer Study Group.

Osteonecrosis of the jaw (ONJ) is a serious adverse event of bone resorption inhibitors (BRIs), such as bisphosphonates and denosumab. Bisphosphonates and denosumab inhibit osteoclast function through different pharmacological effects and bisphosphonates are retained in bone for several months to years. Sequential treatment with bisphosphonates and denosumab might lead to an overlapping treatment effect, due to the addition of the effect of denosumab on the residual bisphosphonate effect. Therefore, the aim of our study was to investigate if switching from denosumab to bisphosphonates is associated with a higher incidence of ONJ.We retrospectively reviewed records of patients with solid tumors and bone metastases treated with denosumab after prior treatment with bisphosphonates at the University Hospitals Leuven (sequential group). Patients treated with denosumab or bisphosphonates alone were used as control groups.We identified 110 patients sequentially treated with bisphosphonates and denosumab with a median total BRI exposure of 36 months (sequential group). Median bisphosphonates exposure was 16 months and median denosumab exposure was 13 months. About 299 patients were included in the bisphosphonates control group with a median bisphosphonate exposure 19 months. About 6.7% (20/299) of patients developed ONJ. About 240 patients were included in the denosumab control group with a median denosumab exposure 17.5 months. About 10.0% of patients (24/240) developed ONJ. In the sequential group, 15.5% of patients (17/110) developed ONJ. The incidence of ONJ was 1.8% (2/110), 6.3% (6/99), 4.9% (4/82), 5.6% (3/54), and 3.4% (1/29), respectively in the first, second, third, fourth, and fifth year of BRI exposure, an ONJ-incidence similar to ONJ-incidence in the denosumab control group. In a time-to-ONJ-analysis, the curves of the sequential group and the denosumab control group were overlapping. In the sequential group, most of the ONJs occurred in the first year of denosumab exposure and in a matched control group analysis, with correction for median BRI-exposure, ONJ cases tend to occur earlier in the sequential group compared to ONJ cases in the bisphosphonates group.Cancer patients with bone metastases treated with BRIs seem to have a slightly higher risk of ONJ early after switching from bisphosphonates to denosumab compared to patients remaining on bisphosphonates. Nevertheless, based on the global ONJ-incidence, the switch from bisphosphonates to denosumab can be considered as safe as an equivalent exposure to denosumab from the start on.

Background: The last EBCTCG-overview reported, in general, a significant better breast cancer outcome if adjuvant chemotherapy was added to surgery and endocrine therapy in ER-pos breast cancers, but the precise indication for adjuvant chemotherapy in this population remains controversial. We study the effect of adjuvant chemotherapy on breast cancer outcome in consecutive patients with an ER-pos HER-2 negative breast cancer treated with adjuvant antihormonal therapy. Methods: Data were collected prospectively from consecutive patients with non-metastatic breast cancer that were primary operated between 2000 and 2012 at the University Hospitals Leuven (Belgium). A Propensity Score (PS) weighted analysis was performed to estimate the average treatment effect (ATE). The primary endpoint was recurrence free interval (RFI). Secondary endpoints were distant recurrence free interval (D-RFI) and breast cancer specific survival (BCSS). Covariates used to generate the propensity score and to include in the PS weighted analysis were age at diagnosis, body mass index, tumor size, grade, pN, lymph vessel invasion, PR, and radiotherapy. Cause-specific hazard models were fitted, using death not from breast cancer as competing risk. Treatment heterogeneity was examined by evaluating interactions of each covariate with adjuvant chemotherapy, using the Bonferroni-Holm method to correct for multiple testing. Results: In the total cohort of 5609 patients, 4282 had a hormone sensitive HER-2 neg breast cancer and 4121 (96.2%) of these received adjuvant antihormonal therapy. Adjuvant chemotherapy was given in 1179/4121 patients (29%). Median follow-up was 8.5 years. Due to very strong differences between patients with and without adjuvant chemotherapy, a restricted PS weighted analysis was used according to a recent recommendation in the statistical literature. This analysis is based on 1750 patients with a PS between 0.1 and 0.9. In this group, 807 (46%) received adjuvant chemotherapy, 211 (12%) observed an event for RFI, 167 (10%) for D-RFI, and 108 (6%) for BCSS. Adjuvant chemotherapy was associated with better prognosis: the adjusted cumulative incidence of recurrence within 5 years was 9.7% without and 5.3% with adjuvant chemotherapy. The adjusted hazard ratio for RFI was 0.50 (95% CI 0.33-0.74). There were no strong interactions with adjuvant chemotherapy. Results for D-RFI and BCSS were similar. Conclusion: Based on PS analysis to reduce confounding and chemotherapy indication bias, we observed clear benefit from adjuvant chemotherapy in ER-pos HER-2 negative breast cancers. Citation Format: Van Calster B, Neven P, Wildiers H, Punie K, Jongen L, Han S, Berteloot P, Van Nieuwenhuysen E, Nevelsteen I, Smeets A, Floris G. The effect of adjuvant chemotherapy in a large consecutive series of ER-pos HER-2 negative early breast cancers [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 P5-14-06.

Despite excellent per-lesion performance for peritoneal staging, the additional clinical value of diffusion-weighted magnetic resonance imaging (DWI/MRI) compared to computed tomography (CT) remains to be established in ovarian cancer. Our purpose was to evaluate whole body (WB)-DWI/MRI for diagnosis, staging and operability assessment of patients suspected for ovarian cancer compared to CT. One hundred and sixty-one patients suspected for ovarian carcinoma underwent 3 T WB-DWI/MRI and contrast-enhanced CT. WB-DWI/MRI and CT were compared for confirmation of the malignant nature and primary origin of the ovarian mass, Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) staging and prediction of incomplete resection using institutional operability criteria. Interobserver agreement between two readers was determined for WB-DWI/MRI and CT. WB-DWI/MRI showed a significantly higher accuracy than CT (93 versus 82%, p = 0.001) to confirm the malignant nature of the ovarian mass and correctly identified 26 of 32 (81%) cancers of non-ovarian origin compared to 10/32 (31%) for CT (p < 0.001). WB-DWI/MRI assigned more ovarian carcinoma patients to the correct FIGO stage (82/94, 87%) compared with CT (33/94, 35%). For prediction of incomplete resection, WB-DWI/MRI showed significantly higher sensitivity (94 versus 66%), specificity (97.7 versus 77.3%) and accuracy (95.7 versus 71.3%) compared to CT (p < 0.001). Interobserver agreement was almost perfect (κ = 0.90) for WB-DWI/MRI and moderate (κ = 0.52) for CT for prediction of incomplete resection. WB-DWI/MRI was superior to CT for primary tumour characterisation, staging and prediction of incomplete resection in patients suspected for ovarian cancer

Purpose: Extended adjuvant hormone therapy improves estrogen receptor (ER)-positive breast cancer outcome. The total duration of endocrine therapy is still a subject for debate. The CTS5 score, developed by Dowsett et al1., predicts late distant recurrence (LDR) between years 5 and 10 after diagnosis in ER-positive invasive breast cancers in postmenopausal women. This LDR risk might be used to select patients for extended endocrine therapy. The CTS5 score is calculated using age at the start of endocrine therapy, tumor size, grade, and lymph node status. The aim of this study is the validation of this tool in a series of women from the UZ Leuven. Methods: This retrospective cohort study included 1125 postmenopausal women consecutively diagnosed with invasive estrogen receptor (ER) positive breast cancer who stopped endocrine therapy after 4.5 to 5.5 years. Tissue was tested for ER positivity and considered positive if >1% of tumor nuclei were stained. HER2 status was defined according to ASCO guidelines. Statistical analysis was performed by Cox proportional hazards models which determined the prognostic performance of the CTS5 score for LDR. Results: A total of 1125 patients were included in this analysis, of which 1097 had a known HER2 status and 1023 were negative. 62 of 1125 (5.5%) developed an LDR between years 5 and 10. The continuous CTS5 was a significant predictor for LDR (HR =2.69 (1.99-3.60), p Conclusion: In our series of postmenopausal women, CTS5 accurately predicts late distant recurrence in ER-positive, HER2-negative early invasive breast cancers. The CTS5-score, identifying a patient group with LDR risk of ≥5%, might be used to discuss the benefits of extended endocrine therapy for individual patients. However, the exact predictive value for the benefit of prolonged therapy can only be based on a randomized controlled trial (RCT) using the LDR risk as a stratification factor. It would be of great value to expand the study population, especially HER2-positive tumors, and define the prognostic performance of the CTS5 score in premenopausal women. Further research is needed. 1. Dowsett, M. et al. Integration of Clinical Variables for the Prediction of Late Distant Recurrence in Patients With Estrogen Receptor-Positive Breast Cancer Treated With 5 Years of Endocrine Therapy: CTS5. J. Clin. Oncol. 36, 1941-1948 (2018). Citation Format: Josephine Van Cauwenberge, Ivana Sestak, Kevin Punie, Hans Wildiers, Giuseppe Floris, Ignace Vergote, Patrick Berteloot, Toon Van Gorp, Ann Smeets, Els Van Nieuwenhuysen, Sileny Han, Ines Nevelsteen, Caroline Weltens, Hilde Janssen, Patrick Neven. Predicting distant recurrence of ER+ HER2- breast cancer after 5 years of endocrine therapy: The CTS5-tool validation in real life [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-08.

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published

To assess clinical pathological characteristics and outcome of triple-negative breast cancers (TNBC) by androgen receptor (AR) protein expression. We retrospectively evaluated AR by immunohistochemistry on core-needle biopsy, (CNB) and residual disease (RD) in a consecutive institutional series of TNBC patients treated with neo-adjuvant chemotherapy (NACT) between 2000 and 2017. We investigated univariate associations between AR-expression on CNB (using different cut-offs), clinical pathological variables, and pathologic complete response (pCR). Next, we used multiple correspondence analysis (MCA) to investigate the relationships between AR on CNB and standard clinical and pathological variables, including stromal tumor infiltrating lymphocytes (sTILs). Finally, we investigated the prognostic value of AR-expression on CNB and RD using the Fine and Gray model. We included 71 patients; median follow-up was 6.7 years. Considering the ≥ 1% cut-off, AR was present in 32% on the CNB and 14% on RD. AR-low (1-34% positive tumor cells) patients were associated with younger (premenopausal) age and AR-high (≥ 34% positive tumor cells) with older (postmenopausal) age. AR on CNB did not correlate with other features nor was it predictive for pCR or prognostic for metastatic outcome, regardless of the used cut-off. The MCA suggested that body mass index (BMI) affects the predictive role of AR-low and -high for pCR differently. AR-loss on RD was prognostic for a better 5-year distant disease-free survival (DDFS) as compared to RD with retained AR-expression (61.6% (95% CI 44.26–79.14) and 25.0% (95% CI 3.94–87.21), respectively; p = 0.01). Low and high AR-expression on CNB of TNBC were correlated with age and menopausal status but qualitative AR was not predictive for pCR. AR-loss on RD was prognostic for DDFS in TNBC patients treated with NACT.

BackgroundEverolimus in combination with exemestane is indicated for the treatment of hormone receptor-positive, HER 2-neg endocrine resistant advanced breast cancer in postmenopausal women. This study investigated treatment adherence, tolerability, satisfaction and efficacy. MethodsA prospective, non-interventional, non-controlled, multicentric observational study assessed adherence by means of a validated questionnaire (‘Morisky Medication Adherence Scale’) and ‘Medication Event Monitoring System’ (MEMS®) data. The level of adherence was calculated per patient as percentage of days on which the medicine was taken as prescribed during the total treatment period, referred to as ‘unadjusted adherence rate’ (UAR). Second, MEMS® data were adjusted for treatment interruptions according to the CRF and questionnaire data, approved by the treating physician (‘adjusted adherence rate’ (AAR)). Successful adherence was defined as ≥ 95% – ≤ 105%. Validated questionnaires (‘Patient Satisfaction with Cancer Treatment Education’, ‘Cancer Treatment Satisfaction Questionnaire’ (CTSQ) and ‘Functional Assessment of Cancer Therapy – General’ (FACT-G) were used to report patients experience and satisfaction with the treatment and perceived care, questioned at initial visit and after approximately 1, 3, 6 and 12 months. The efficacy was primary analyzed through progression free survival (PFS). ResultsBetween Dec 2015 and Nov 2017, a total of 58 women (median age 65 yrs) from 7 oncology centers were included after a mean of 34m ± 36.9 (SD) of being diagnosed with stage IV disease; most (62.1%) had ≥3 organs involved and 84.5% had ≥2 prior metastatic treatment lines. The mean follow-up duration was 185.5 ± 100.0 days. The mean UAR for exemestane, everolimus and the combination were 92.9 %, 84.8 % and 81.7 % respectively. For everolimus and the combination therapy these rates differ significantly from the mean AAR, with p < 0.05 (see table 1). For the AAR of the combination therapy, 13.8 % of the patients showed optimal adherence (100 %). Six patients (10.3%) interrupted their treatment with exemestane with a mean time of treatment pause of 34.3 ± 19.1 days. The treatment with everolimus was interrupted by 36 (62.1%), with a mean interruption time of 24.3 ± 16.5 days, which corresponds with a mean of 19.6 % ± 17.6% of the total follow-up duration. Some patients interrupted their treatment multiple times. The most common side effect was mucositis (n=26 at 1 month, of whom 8 patients grade 3 and 15 patients grade 2)). Six (10.4 %) of the 58 patients stopped treatment with everolimus and exemestane due to side effects. The median PFS was 170 days. With regard to quality of life, patients scored lowest on emotional and functional well-being. However, there were no significant differences measured for the mean FACT-G score between Day0, M1 and M3 (P = 0.273). Also, patients scored overall low on the ‘CTSQ’. Conclusion Despite close monitoring and preventive measures to overcome side effects, adherence to everolimus and exemestane was rather low. Many patients needed to interrupt the treatment due to side effects; treatment is perceived as intensive. Nevertheless, median PFS is 170 days, even when used late in the therapeutic journey of breast cancer patients. Table 1. UAR and AAR for Exemestane, Everolimus and the combinationExemestaneEverolimusCombination therapyUAR (%)mean ± SD92.97 ± 13.1784.86 ± 19.4081.74 ± 20.98AAR (%)mean ± SD93.07 ± 13.1491.81 ± 15.0487.55 ± 18.17Significance differenceP-value0.277< 0.001< 0.001 Citation Format: Veerle Foulon, Carrie Visser, Sandra De Coster, Lise-Marie Kinnaer, Ellen Reynders, Anne Deblander, Patrick Berteloot, Kevin Punie, Hans Wildiers, Véronique Cocquyt, Hannelore Denys, Ahmad Awada, Eric Strobbe, Andrea Gombos, Isabelle Spoormans, Ximena Elzo-Kraemer, Christof Vulsteke, Marleen Borms, Philip Debruyne, Wim Wynendaele, Patrick Neven. Adherence to and patient satisfaction with the combination therapy of exemestane and everolimus in postmenopausal women with HR+ HER2- advanced breast cancer: Results from the IPSOC-mamma study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-06.

Background: Young women present more often with aggressive breast cancer phenotypes and have worse prognosis. It remains controversial whether age is an independent prognostic factor in early stage breast cancer. Arbitrarily chosen age cut-off values have been proposed in different studies. Furthermore, few studies have examined the impact of breast cancer subtypes on the prognostic value of age. This abstract represents an update of a prior analysis (San Antonio Breast Cancer Symposium, December 4-8 2012, P06-07-29). Methods: We included all primary operable female breast cancer patients from our prospectively managed database in UZ Leuven, Belgium. We assessed the effect of age on locoregional free interval (LRRFI), distant metastasis interval (DMFI) and breast cancer specific survival (BCSS). In univariate analysis, using Cox regression models, we determined the best categorization of age at diagnosis into two or three age groups by considering all possible combinations of cut-off values. Best categorization was obtained with three age groups. We further determined, using multivariate analysis (correcting for phenotype, tumor size, nodal status, adjuvant chemo -, hormone – and radiotherapy, type of surgery and procedure of axillary staging), whether age at diagnosis remains an independent predictor of outcome (LRRFI, DMFI and BCSS). We further explored whether age at diagnosis is an independent predictor of event risk (LRRFI, DMFI and BCSS) in different breast cancer subtypes. Luminal A-like (grade I or II, ER and/or PR positive, HER 2 positive), Luminal B-like (idem but grade III), Luminal HER 2 like (ER and/or PR positive, HER 2 positive), HER 2 like (ER/PR negative, HER 2 positive), triple negative (ER/PR negative, HER 2 negative). Results: We included 4180 patients with a mean/median age of 58/57 year and with a median follow up of 8.9 year. Multivariate analysis confirmed age as an independent prognostic variable for LRRFI, DMFI and BCSS. Results multivariable analysis with age in 3 groups (HR (95% CI) P-VALUE) LRRFIDMFIBCSSYoungest versus middle1.61 (1.18-2.18) 0.00251.54 (1.23-1.93) 0.00021.72 (1.26-2.36) 0.0007Youngest versus oldest3.45 (1.85-6.45) 0.00011.25 (0.89-1.77) 0.19821.31 (0.85-2.02) 0.2220Middle versus oldest2.15 (1.22-3.79) 0.00820.81 (0.61-1.09) 0,17060.76 (0.55-1.06) 0.1014 We found optimal cut-off values for LRRFI at 44y and 72y, for DMFI at 47y and 71y and for BCSS at 41y and 70y. In an exploratory analysis, with age as continuous variable, by subtype we found a significant independent association between age and LRRFI (P=0.0169), DMFI (P=0.0344) in luminal A-like, LRRFI (P=0.0022) in luminal B-like and DMFI (P=0.0010) and BCSS (P=0.0053) in triple negative breast cancer. No significant associations were found in luminal HER2 and HER2 like breast cancers. Conclusion: This study has shown that young age is an independent prognostic factor for LRRFI, DMFI and BCSS after correction for the most important clinical prognostic factors. The prognostic effect is most important in luminal A and triple negative subtypes. Additional analyses for subtypes with age as a categorical variable will be performed and optimal cut off values will be defined. Citation Format: Poppe A, Brouckaert O, Laenen A, Soubry A, Remmerie C, Floris G, Leunen K, Berteloot P, Amant F, Vergote I, Nevelsteen I, Smeets A, Christiaens M-R, Weltens C, Peeters S, Van Limbergen E, Wildiers H, Neven P. Independent prognostic value of age depends on breast cancer subtype. [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 P6-09-11.

OBJECTIVE: The levonorgestrel-intrauterine device (LNG-IUD) is a widely used contraceptive method. It is not clear if LNG-IUD users are more likely to develop breast cancer. Breast cancer growth through the estrogen and/or the human epidermal growth factor receptor 2 (HER2) pathway could be influenced by a continuous low systemic dose of levonorgestrel. In this study, we compare breast cancer characteristics and the receptor expression of estrogen (ER), progesterone (PR) and HER2 in women with and without a LNG- IUD at the time of diagnosis. METHODS: In this retrospective, observational study, we included 2599 consecutive breast cancer patients who were younger than 55 years at diagnosis and treated between 2000 and 2014 in the University Hospitals Leuven for a primary invasive, non-metastatic tumor. The non LNG-IUD group was matched by age and parity at diagnosis. ER, PR and HER2 status were reported according to ASCO/CAP guidelines. The Chi-square test was used to compare receptor status between groups. All tests were two-sided, and a 5% significance level was assumed. An additional analysis was performed to detect the occurrence of HER 2 expression with or without intake of oral contraception by diagnosis in the control group. RESULTS: 366 LNG-IUD users and 2233 women without a LNG-IUD were included. Compared to the control group, the LNG-IUD users had a lower Nottingham prognostic index (4.2 vs 4.4; p=0.048), more PR expression (79.2% vs 73.4%; p=0.021) but less HER2 expression (11.6% vs 17.2%; p=0.009). A significant higher rate of ER+PR+HER2- was observed in the LNG-IUD group (63.26 % vs 73.46%; p CONCLUSION: We found in a breast cancer population, matched for age and parity, significant differences in the PR and HER2 expression according to use of LNG-IUD at time of diagnosis. ER positive, PR positive and HER2 negative breast cancers are more frequently seen in LNG-IUD users. There is a trend of less HER 2 positivity in LNG-IUD users and it is more common seen in oral contraception users. Citation Format: Borowski E, Poppe A, Laenen A, Remmerie C, Van Asten K, Nevelsteen I, Smeets A, Weltens C, Peeters S, Leunen K, Berteloot P, Amant F, Vergote I, Van Limbergen E, Christiaens M-R, Wildiers H, Floris G, Poppe W, Neven P. Breast cancer characteristics and the levonorgestrel intrauterine device. A monocentric retrospective 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 P6-09-12.

Background Evidence suggests that premenopausal obesity decreases and postmenopausal obesity increases breast cancer risk. While it has been hypothesized that carcinogenesis may be accelerated by a disrupted metabolic homeostasis in obese women, it is unclear why this dual relationship is observed. We here study whether body mass index (BMI) affects (a) age at breast cancer diagnosis and (b) the probability of being diagnosed with a specific breast cancer phenotype, taking menopausal status into account. Patients and methods All patients with non-metastatic operable breast cancer from UZ Leuven diagnosed between January 1, 2000 and December 31, 2013 were included (n=7020). Luminal A like (= grade 1 or 2, ER and/or PR positive, HER2 negative), Luminal B like (= grade 3 ER and/or PR positive, HER2 negative), Luminal HER2 like (ER and/or PR positive, HER2 positive), HER2 like (ER and PR negative, HER2 positive) and triple negative breast cancer (TNBC = ER and PR and HER2 negative). For statistical analysis, linear models and logistic regression were used to study respectively the association between BMI and age at diagnosis and BMI and breast cancer phenotype by menopausal status. Results There was a quadratic relationship between BMI and age at breast cancer diagnosis studying the overall population (p We observed a linear relationship between BMI and the probability of being diagnosed with Luminal B like, Luminal HER2 like and HER2 like breast cancer (table 1). This linear relationship interacts with menopausal status for Luminal B like and HER2 like breast cancers (table 1). Table 1: Probability of being diagnosed with a certain breast cancer phenotype by BMI (linear model) and the impact of menopausal status.Effect of BMI on the probabilityLinear modelof being diagnosed withp-valueeffectLuminal A like0.4430n/aLuminal B like0.0276BMI +5kg/m2 OR 1.07 (95% CI 1.01-1.14)Luminal HER2 like0.0367BMI +5kg/m2 OR 0.91 (95% CI 0.83-1.00)HER2 like0.0219BMI +5kg/m2 OR 0.88 (95% CI 0.78-0.98)TNBC0.5454n/aInteraction with menopausal statusp-valueeffectLuminal A0,2204n/aLuminal B0,0487Premenopausal OR 0,996 (CI 0,974-1,019), p=0,7449; Postmenopausal OR 1,023 (CI 1,008-1,038), p=0.0023Luminal HER20,2571n/aHER2 like0,0031Premenopausal OR 1,020 (CI 0,983-1,059), p=0,2923; Postmenopausal OR 0,947 (CI 0,919-0,976), p=0.0004TNBC0,1638n/a Conclusion We could not confirm the hypothesis that increasing BMI decreases (increases) age at diagnosis in postmenopausal (premenopausal) women. Obesity does affect the probability of being diagnosed with certain breast cancer phenotypes, but for certain breast cancer phenotypes an interaction with menopause was observed. We presume a potential biological link through BMI between Luminal B and HER2 like breast cancer that needs further exploration. Citation Format: Brouckaert O, Poppe A, Laenen A, Floris G, Leunen K, Berteloot P, Amant F, Vergote I, Smeets A, Weltens C, Peeters S, Van Limbergen E, Wildiers H, Christiaens M-R, Neven P. The impact of body mass index on age at breast cancer diagnosis and breast cancer phenotype. [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 P6-10-06.

Background: Tamoxifen is commonly used for the treatment of all stages of estrogen receptor (ER) positive breast cancer (BC), the largest group of BC. In postmenopausal women, known endometrial side-effects are cystic appearance, hyperplasia, polyps and endometrial cancer. Tamoxifen is converted through several CYP450 enzymes into the active metabolite endoxifen. Patients with particular single nucleotide polymorphisms (SNPs) in those CYP450 enzymes (e.g. CYP2D6) have lower endoxifen concentrations and therefore could experience less benefit from tamoxifen. However, the clinical significance stays controversial in the literature as results remain contradictory. Our primary hypothesis is that women with lower endoxifen levels do not have the typical tamoxifen-induced increase in endometrial thickness. The aim of this study is to test the association between endoxifen concentration and the increase in double endometrial thickness (DET). Patients and methods: CYPTAM-BRUT 3 is a prospective, multicentric study including postmenopausal women with an ER positive BC receiving tamoxifen in the adjuvant setting. Primary objective is the association between serum endoxifen levels and change in DET between baseline and follow-up after 3 - 6 months. Secondary objectives are investigating the relation between serum endoxifen levels and other endometrial changes (i.e. the presence of cysts/polyps), menopausal symptoms assessed with a questionnaire and serum levels of follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG). Other objectives are the association between the 'CYP2D6 tamoxifen activity score', based on SNPs and co-medication, and DET, other endometrial changes, FSH and SHBG. The CYPTAM-BRUT 3 study is a sub-study of the CYPTAM study in Leiden, The Netherlands, with survival as primary outcome. Results: 144 women were included in 19 hospitals. There was no significant association found between endoxifen and change in DET (p=0.888), as for the association between endoxifen and the development of cysts or polyps (p=0.208). For the questionnaire items no correlation was found (p≥0.051). Changes of FSH and SHBG were in the range of what would be expected during tamoxifen treatment in the general population and there was no association with endoxifen (p=0.726 and p=0.181). In addition, no association was found between the CYP2D6 TAS score and DET (p=0.613), other endometrial changes (p=0.196), FSH (p=0.976) and SHBG (p=0.900). Conclusion: Our study is one of the first studies that prospectively investigated the relation between tamoxifen metabolization, in correlation with endometrial thickness and SNPs. We can conclude that the typical increase in endometrial thickness seen in a significant proportion of postmenopausal women under tamoxifen cannot be used to predict that those women have a high endoxifen concentration or that women without an increased endometrial thickness have a significantly lower endoxifen concentration. The same conclusions can be made for the other tamoxifen-induced changes as cysts and polyps, menopausal symptoms, FSH and SHBG. It may also apply to tamoxifen efficacy but further prospective studies looking at survival are needed to answer that question. Citation Format: Poppe A, Dieudonné A-S, Lintermans A, Laenen A, Blomme C, Lambrechts D, Wildiers H, Christiaens M-R, Timmerman D, Van Calster B, Vereecke C, Vandeputte G, Fontaine C, Decloedt J, Berteloot P, Depypere H, Joerger M, Dezentjé V, Neven P. CYPTAM-BRUT 3: Endometrial thickness cannot be used as a marker for tamoxifen metabolization in postmenopausal breast cancer patients. [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 P3-07-46.

e13031 Background: Some breast cancer subtype-specific demographics and histopathological characteristics can be associated with metastatic outcome. Semi-quantitative oestrogen receptor (sqER) is prognostic in ER-positive HER2-negative tumours. Here, we studied sqER for outcome in early diagnosed triple positive breast cancers (TPBC;ER+/PR+/HER2+). Methods: Retrospective monocentric study of all consecutive early diagnosed TPBC (July 2002 - Dec 2017). Immunohistochemistry (IHC) was used for ER, PR and HER2; IHC ≥1% ER/PR was pos; HER2 was FISH-confirmed. Low sqER was defined as Allred score < 7/8. Local therapy was surgery +/- radiotherapy; systemic treatment was (neo)-adjuvant chemotherapy and trastuzumab and endocrine treatment. The clinicopathological variables we studied apart from sqER were age, menopausal status, BMI, parity, tumor grade and clinical stage at diagnosis. Variables were analysed by a Fishers Exact or Mann-Whitney U test. All reported p-values are two-sided. Cox regression was used to investigate howqER is associated with distant metastasis. Results: We included 415 female patients. 18% had low sqER; these were younger and more likely premenopausal at diagnosis; p < 0.001. Other studied variables didn’t differ by sqER-expression. 7% developed metastasis after a mean follow up of 86 months. High sqER-TPBCs as compared to low sqER-TPBCs were less likely to metastasize (HR 0.42; 95 CI 0.19-0.91). Conclusions: Low sqER in TPBC, present in about a fifth of these tumours, is typically associated with younger age and premenopausal status at diagnosis. Low sqER TPBC are more likely to metastasize when compared to TPBC with high sqER levels. [Table: see text]

5507 Background: The CLIO trial (NCT02822157) evaluated olaparib single-agent therapy versus standard of care chemotherapy in platinum-resistant (recurrence within 6 months after last platin) ovarian cancer (PROC). Methods: Eligible patients with measurable disease and ≥1 prior line of chemotherapy were randomized 2:1 to Olaparib (OLA) monotherapy (300 mg tablets, BID) or physician’s choice chemotherapy (CT; PLD 40 mg/m2 q 4 wks; Topotecan 1.25 mg/m2 day 1—5 q 3 wks; Paclitaxel 80 mg/m2 day 1, 8,15 q 3 wks; Gemcitabine 1000 mg/m2 day 1, 8 and 15 q 4 wks). Primary endpoint was objective overall response (ORR) per RECIST v1.1. Germline BRCA status was available for all patients. Disease control rate (DCR) was defined as response for at least 12 wks. Results: 100 patients with PROC were randomized 2:1 to OLA (N = 67) or CT (N = 33). Median prior lines of treatment was 3 (range: 1—8). ORR (unconfirmed) was 18% (12/67) for OLA and 6% (2/33) for CT. ORR for OLA was 38% (5/13) in gBRCAm and 13% (7/54) in gBRCAwt patients. Of note, 2 patients with gBRIP1 mutation had no response under OLA. DCR was 35.8% (24/67) for OLA and 42% (14/33) for CT. DCR under OLA in gBRCAm was 62% (8/13) compared to 30% (16/54) in gBRCAwt disease. The median duration of response (DOR) and the median progression-free survival (PFS) was similar: 5.4 months vs 4.5 months (DOR) and 2.9 vs 3.4 months (PFS) for OLA and CT, respectively. Grade ≥3 treatment-related AEs occurred in 60% vs 52% for OLA and CT, respectively. Somatic HRR mutation analysis is ongoing and will be presented. Conclusions: Olaparib monotherapy showed a favorable response rate in PROC compared with chemotherapy also in gBRCAwt patients. Analysis of clinical endpoints in relation to HRR is ongoing and will be presented. Clinical trial information: NCT02822157.

e12042 Background: The prognostic value of androgen receptor (AR) expression in triple-negative breast cancer (TNBC) is debated and might be partially masked by the use of adjuvant chemotherapy, which might benefit AR-negative TNBC more than AR-positive cases. We compared the prognostic value of AR in a case control study of consecutive women with TNBC treated or not with adjuvant chemotherapy (ACT). Methods: We retrospectively studied AR expression by immunohistochemistry in all consecutive patients with a secondary metastatic TNBC treated in UZ-Leuven between 2000 and 2009. The control group were cases of TNBC never developing secondary metastatic disease during a long follow-up period matched 1:1 for age and tumor grade. Relations between demographics and clinical pathological features and AR protein expression were studied, including stromal tumor infiltrating lymphocytes (sTILs). Secondary metastatic disease connections with AR protein expression was assessed using the Akaike information criterion; time-to metastasis (TTM) was studied using a linear model with and without ACT correcting for lymph node involvement. We explored whether results differed by AR protein expression levels (0%, 1-34%, ≥34% of tumor cells) and body-mass index (BMI) comparing normal ( < 25kg/m2) with overweight/obese patients BMI. Results: We included 139 patients (69 metastatic and 70 non-metastatic; median age 51.0 years); median follow-up for both groups was 8 years. AR protein expression level ≥ 1% was observed in 25% (n = 34) and ACT was given in 73% (n = 101). AR-positive as compared to AR-negative TNBC patients were older (p = 0.04). Results based on multivariable models including lymph node status and ACT as confounders showed that AR-negative cases have a higher metastasis risk compared to AR-positive patients (3.015 odds ratio (95% CI 1.199-7.582), p = 0.02); this difference was more significant in ACT-naive patients (10.823 odds ratio (95% CI 1.897-61.740), p = 0.007). ACT-treated patients had the best outcome if AR was low (1≤ and < 34%) followed by those with a normal weight and an AR-negative high sTIL TNBC. Conclusions: The AR is prognostic in TNBC and this is clearer in non-ACT treated patients with a TNBC. Our results might suggest that if ACT is given, only the AR-positive TNBC with low AR-expression do well.

Background In patients with clinically lymph node negative (cN0) early breast cancer (EBC) treated with neoadjuvant chemotherapy (NACT), the sentinel lymph node biopsy (SLNB) can be performed before or after NACT. We report safety of axillary staging performing the SLNB prior to NACT in cN0 EBC and estimate NACT-induced downstaging to ypN0 in previously NACT-treated cN1 EBC, to make an assumption for avoiding axillary lymph node dissection (ALND) if SLNB was done after NACT. Patients and Methods Monocentric retrospective study of consecutive triple negative (TNBC) and HER-2 amplified BC patients treated with standard NACT. cN0 patients had SLNB before NACT followed by local therapy. Axillary lymph node dissection (ALND) post-NACT was performed in all cN1 and in cN0 cases with a positive or failed SLNB. Using descriptive statistics, we here report SLNB-detection and SLNB-positive rate, SLNB-operative complications, complete tumor regression in the breast (ypT0/is) and disease-free survival (DFS) for cN0 cases and NACT-induced downstaging to ypN0 in previously NACT-treated cN1 EBC. Results We included 245 NACT-treated patients; 119 cN0 and 126 cN1. SLNB-detection rate in cN0 cases was 99,2%; 25 or 21% had ≥ 1 involved SLN, 21.8% experienced SLNB related-complications (e.g. infection, seroma, hematoma) leading to NACT-delay in 3 and interruption in 1 patient. Median start of NACT after SLNB was 7 days (range 1-20 days). In patients with a positive SLNB, there were no additional involved nodes in the ALND. In 5 of these patients, therapy response in a lymph node was described. Complete tumor regression in the breast (ypT0/is) was 52% in SLNB-positive and 59,1% in SLNB-negative cN0 cases. NACT-induced ypN0 was 61% in cN1 cases. At 30 months of median follow-up (range 1-86 months), DFS was 93,2% (4.2% metastatic; no axillary relapse) in cN0 cases. Median DFS was better for patients with complete tumor regression in the breast as compared to those with partial response; 95.6% and 90% respectively. Conclusion In conclusion, performing SLNB before NACT in cN0 cases is a safe and accurate method. While some pN1(sn) could have avoid ALND by NACT-induced axillary down-staging, based on our assumption, long term follow-up is needed to conclude whether SLNB after NACT is safe. Keywords: Breast cancer, neoadjuvant chemotherapy, timing sentinel lymph node biopsy Citation Format: Delameilleure M, Smeets A, Nevelsteen I, Han S, Van Nieuwenhuysen E, Berteloot P, Hoste G, Salihi R, Van Ongeval C, Keupers M, Prevos R, Wildiers H, Punie K, Van Limbergen E, Weltens C, Janssen H, Floris G, Vergote I, Neven P. Monocentric experience with the sentinel lymph node biopsy prior to neoadjuvant chemotherapy in clinically lymph node negative early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-32.

Objective. Based on its expression profile, folate receptor alpha (FRA) is an attractive candidate for targeted diagnostics and therapeutics. However, applicability of these agents in residual or recurrent disease could be influenced by chemotherapy. We evaluated whether chemotherapy modified FRA expression in non-mucinous epithelial ovarian (EOC) and endometrial carcinoma (EC). Methods. FRA staining was evaluated by immunohistochemistry, using MAb 26B3, in 81 patients (41 EOCs and 40 ECs) and 17 control tissues (5 benign ovarian cysts, 5 normal ovarian, and 7 normal endometrial tissues). Chemotherapy effect was evaluated in 42 patients (30 paired samples at primary and interval debulking surgery and 12 from primary and recurrent disease). FRA expression was assessed using a semi-quantitative staining algorithm, the M-score (range 0-50). Results. Median difference in M-score between tumor and control samples was 27.5 for EOC (95% CI 10.0 to 45.0) and 6.7 for EC (95% CI 6.7 to 21.7). Paired samples from both primary and interval debulking surgery did not differ in ERA expression in EOC (median difference of M-score between paired samples of 0.0 [95% CI - 2.6 to 2.6]). Recurrent EOC tumors reflected ERA status at diagnosis (median difference of M-score between paired samples of 33 [95% CI - 7.0 to 13.6]). Conclusions. This study shows no significant difference in FRA expression after chemotherapy, strengthening the rationale for FRA targeted diagnostics and therapeutics in FRA expressing tumors, whether newly diagnosed or at recurrence. (C) 2013 Elsevier Inc. All rights reserved

Objective. To evaluate the "Leuven" weekly paclitaxel/carboplatinum (TC) regimen in recurrent ovarian cancer in a retrospective study. Methods. Eighteen courses of paclitaxel (60 mg/m(2)) and carboplatinum (AUC 2.7) were administered weekly. Platinum-resistance was defined as progression during or within 6 months after platinum-based chemotherapy. Results. Sixty-three patients were included with a median number of prior treatment regimens of 4 (range 0-10). Forty-three patients were platinum resistant and 20 were platinum sensitive (14 intermediate sensitive and 5 sensitive). One patient in the platinum resistant group and 2 patients in the platinum sensitive group achieved complete remission, 15 patients in the platinum resistant and 5 patients in the platinum sensitive group achieved partial remission according to RECIST. In the entire patient population evaluable for response (n=62), the median progression free survival (PFS) was 6.7 months; the median overall survival (OS) was 9.7 months. Median PFS was 6 months for the platinum resistant and 8 months for the platinum sensitive group. The median OS was 9 months in the platinum resistant and 11 months in the platinum sensitive group. Toxicity was mostly bone marrow related with neutropenia grade 3/4 in 67% and neutropenic fever in 6% of patients. Dose reduction was necessary in 24% of patients. Nausea, vomiting and fatigue were the most frequent non-hematological side effects. Conclusion. Weekly paclitaxel and carboplatin is an effective regimen for patients with recurrence of ovarian cancer with a response rate of 37% in platinum resistant disease and a manageable toxicity profile. (C) 2012 Elsevier Inc. All rights reserved

BACKGROUND: The five prognostic surrogate phenotypes, defined by the 2011 St Gallen consensus, predict metastatic relapse following early breast cancer treatment (Brouckaert et al Ann Oncol 2012). It is unknown to what extent these surrogate phenotypes defined on the primary tumor predict metastatic survival (MS) in a cohort of consecutive women with metachronous metastases. PATIENTS & METHODS: All 4318 patients with primary operable breast cancer, diagnosed between 01–01-2000 and 31–12-2009 and treated in our center were prospectively entered in our institutional database. We included 345 patients with a (distant) metastatic relapse during their follow-up. We observed metastatic survival as the time between the diagnosis of the relapse and death. Tumor subtype was defined according to the 2011 St Gallen recommendations in 5 groups: luminal A (ER+/HER2−, grade 1–2), luminal B1 (ER+/HER2−, grade 3), luminal B2 or luminal-HER2 (ER+/HER2+), HER2-like (ER−/HER2−) and triple-negative. We focused on the value of the primary tumor subtype as a major prognostic determinant, but also assessed age at diagnosis, tumor size, lymph node involvement, tumor subtype, PR-status, primary detection (screening vs. palpation), histology, adjuvant therapy, distant-metastasis free interval (DMFI), first-line metastatic hormonal therapy, recurrence sites (isolate or multiple) and metastasis detection (clinical vs. biochemical). RESULTS: In our cohort, we recorded a median metastatic survival (MS) of 22.3 months (95% CI: 19.7–25.6) and a 5-year survival probability of 15%. Significant differences in median MS were noted when considering the primary tumor subtype (cf. table). We observed an independent prognostic effect for multiple recurrence sites (HR = 1.78, 95% CI 1.37–2.32), first-line metastatic hormonal therapy (HR = 0.30, 95% CI 0.18–0.49), DMFI (HR = 0.92 CI 0.85–0.98) and, finally, primary tumor subtype. CONCLUSION: Our results showed that primary tumor subtype, DMFI, solitary recurrence and first-line metastatic hormonal therapy act as independent prognostic factors in metastatic breast cancer. In order to overcome the biological complexity of metastatic breast cancer, we must appreciate the primary tumor subtype in our therapeutic approach. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-12.

Background Many easily measurable and readily available factors are now established as being prognostic in primary operable breast cancer. We here applied the 2011 St Gallen surrogate definition for breast cancer subclassification using tumor grade instead of Ki67. Patients and methods Four thousand three hundred and eighteen consecutive patients who had surgery for primary operable breast cancer (1 January 2000 and 31 December 2009) in UZ Leuven excluding primary metastastic male breast cancers and those receiving neoadjuvant therapy. Five different surrogate phenotypes were created using the combined expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 together with tumor grade. Disease-free interval (DFI), distant metastastis-free interval (DMFI), locoregional relapse-free interval (LRRFI), breast cancer-specific survival (BCSS) and overall survival (OS) were calculated. Results Surrogate phenotypes present with significant differences in DFI, DMFI, LRRFI, BCSS and OS. ‘Luminal A’ tumors presented with the best outcome parameters but the effect weakened at longer follow-up. Conclusions The four surrogate markers, agreed upon by the 2011 St Gallen consensus, defined five prognostic surrogate phenotypes in a large series of consecutively treated breast cancer patients. Their prognostic value changed with longer follow-up. The added value of gene expression profile over classical pathological assessment remains to be defined.

Background We studied the stellate ganglion block (SGB) recently suggested for the treatment of severe vasomotor symptoms and sleep disturbances in breast cancer survivors. Following an initial pilot study, which focused on the acceptability and safety of SGB for this important problem, we evaluated its short- and long-term efficacy. Materials and methods Postmenopausal breast cancer survivors with severe vasomotor symptoms resistant to standard nonhormonal pharmacological intervention were eligible. Diaries were used to measure daily hot flash scores (frequency and intensity) and sleep quality (Pittsburgh Sleep Quality Index) during scheduled visits at baseline, 1, 4, 12 and 24 weeks following the SGB. Efficacy data were analyzed using longitudinal regression models. Results Thirty-four patients participated and none refused the SGB procedure. Most patients received more than one SGB. The pilot study found SGB to be safe. In the main study, hot flash scores were reduced from baseline by 64% [95% confidence interval (CI) -74% to -49%] and 47% (95% CI -62% to -27%) at weeks 1 and 24, respectively. The odds ratio of better sleep quality relative to baseline was 3.4 at week 1 (95% CI 1.6–7.2) and 4.3 at week 24 (95% CI 1.9–9.8). Conclusion In the short term, SGB appears to be an effective treatment with acceptable morbidity for some breast cancer survivors with therapy-resistant vasomotor symptoms and/or sleep disturbances. Although sleep quality was maintained out to 24 weeks the efficacy of SGB for hot flashes was reduced over time. A randomized controlled trial is needed to confirm these findings.

Background and aims: To evaluate paclitaxel/carboplatin in a dose dense (TCdd) and weekly (TCw) regimen in recurrent or primary metastatic cervical cancer. Methods: Six courses of paclitaxel (90 mg/m(2)) and carboplatin (area under the curve (AUC) 4) were administered on d1, d8 q3 wks in TCdd. Eighteen courses of paclitaxel (60 mg/m(2)) and carboplatin (AUC 2.7) were administered weekly in TCw. Response rates were determined using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria. Toxicity was evaluated according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Criteria. Results: Sixty-six patients were included (44 TCdd and 22 TCw). TCdd and TCw were administered as first-line chemotherapy in 48% and 41%, second-line in 43% and 18%, and third/fourth-line in 9% and 41%, respectively. Response (confirmed or unconfirmed) was observed in 58% and 36% for TCdd and TCw, respectively. As first-line, the response rates for TCdd and TCw were the same (55%). As second or more line, the response rates for TCdd and TCw were 61% and 29%, respectively. In patients, receiving TCdd as first-line systemic treatment, median overall survival (OS) and progression-free survival (PFS) was 10 and 5 months. As first-line, the median OS for TCw also was 10 months (median PFS not reached). There was no statistical difference in PFS or OS between patients treated with TCw or TCdd. Grade 3-4 toxicity was mostly bone-marrow related and was more common with TCdd. Febrile neutropenia was observed in 0% and 12% of the patients treated with TCw and TCdd, respectively. Conclusions: Combination of paclitaxel and carboplatin in a dose dense regimen or weekly regimen resulted in favourable response rate and toxicity profile compared with cisplatin-based combination regimens. TCdd appears to be more toxic than TCw, but resulted in higher response rates than TCw in patients with recurrent metastatic cervical cancer who received prior chemotherapy. (C) 2012 Elsevier Ltd. All rights reserved