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Background The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is 60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis. We have previoulsy shown that the functional HRD biomarker RAD51, tested in FFPE tumor samples using an optimized immunofluorescence-based assay, is associated with platinum response in early TNBC and PARPi response in preclinical BC models. We hypothesize that the RAD51 test would help to expand the clinical benefit of PARPi by predicting response to olaparib in MBC with germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation and beyond. Study design RADIOLA is an open-label, single-arm, multicentre phase II study evaluating treatment with olaparib in male or female ≥18 years patients with HER2-negative MBC with ≤ two prior chemotherapy lines in two cohorts: cohort 1 (N=41) with known germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation; cohort 2 (N=25) with functional HRD, namely RAD51-low score (≤10%), in wild-type/unknown mutation status at study entry. All patients will receive olaparib 300mg po BID until progression or unacceptable toxicity. Primary objective will assess, in terms of overall response rate (ORR), the capacity of the RAD51 score to predict olaparib efficacy in cohort 1. Secondary objectives include PFS, clinical benefit rate, duration of response, safety in both cohorts and ORR in cohort 2. Recruitment Recruitment (11 sites) started in March 2022. As of July 2022, 7 patients have been enrolled in Spain. Funding This study is financially supported by AstraZeneca. Citation Format: Judith Balmaña, Tomás Pascual, Alba Llop-Guevara, Pablo Tolosa, Isabel Blancas, Maria-Eva Perez-Lopez, Barbara Adamo, Iris Teruel, Jose Ponce, Marta Gonzalez, Gemma Viñas, Laura Lema, Francisco Javier Salvador, Mª Teresa Martinez, Alejandra Espinosa, Aleix Prat, Violeta Serra. SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL [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 OT3-11-02.

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

(A) 231 and 231DXR and (B) HCC and HCCDXR cells were treated with increasing concentrations of doxorubicin (50 - 350 nM) for 48h. Experiments were performed three times in triplicate. Results shown are mean {plus minus} SEM. *(p < 0.05), **(p < 0.01) and ***(p < 0.001) indicate levels of statistically significance.

cells (A) 231 and 231DXR and (B) HCC and HCCDXR cells were treated with increasing concentrations of cetuximab (0,5 - 4 µM), C75 (20 - 60 µM) or EGCG ( 25 - 150 µM) for 4 days. Results are expressed as mean {plus minus} SEM. Experiments were performed at least three times in triplicate. *(p < 0.05), **(p < 0.01) and ***(p < 0.001) indicate levels of statistically significance.

(A) 231 and 231DXR and (B) HCC and HCCDXR cells were treated with doxorubicin (50-100-150nM) and C75 (20µM for HCC, HCCDXR; 40µM for 231, 231DXR) or the combination for 48h. (C) 231 and 231DXR and (D) HCC and HCCDXR cells were treated with doxorubicin (50-100-150nM), EGCG (100µM for 231, 231DXR; 120µM for HCC, HCCDXR) or the combination of both for 48h. Results shown are mean {plus minus} SEM. *(p < 0.05), **(p < 0.01) and ***(p < 0.001) indicate levels of statistically significance.

CONSORT DIAGRAM

Purpose: Triple-negative breast cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of fatty acid synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC.Experimental Design: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG, or the combination in TNBC orthoxenograft models.Results: TNBC cell lines showed overexpression of FASN enzyme and its inhibition correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity.Conclusions: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC. Clin Cancer Res; 22(18); 4687–97. ©2016 AACR.

Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-of-opportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial.Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/changes.Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB = 3 (P = 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P = 0.09). In Arm B, 18F-FMISO-PET lacked predictive/prognostic value.Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib. Clin Cancer Res; 23(6); 1432–41. ©2016 AACR.

(A) Mice bearing 231 and (B) 231DXR xenografts were treated with saline (Control), EGCG (30mg/Kg, 3 days a week), cetuximab (0.5mg/mice 1 day a week) or the combination (EGCG plus cetuximab) for 12 days. (C) Mice bearing HCC and (D) HCCDXR xenografts were treated with saline (Control), EGCG (30mg/Kg, 3 days a week), cetuximab (100uL/mice 1 day a week) or the combination (EGCG plus cetuximab) for 10 days. Total volume is shown as (Final Volume - Initial Volume). Dots are mean of each experimental group and bars, SEM. *(p < 0.05), **(p < 0.01) and ***(p < 0.001) indicate levels of statistically significance.

Figure S1 legend

Hypoxic volumes

(A) 231 and 231DXR and (B) HCC and HCCDXR. mRNA levels were obtained by Real-Time PCR and normalized against the β-actin gene. Results shown are mean {plus minus} SEM from 3 independent experiments.

TNBC Patients demographics and clinical characteristics (n=26).

(A) 231 and 231DXR cells were treated with increasing concentrations of EGCG ( 100 - 200 µM) or C75 (30 - 90 µM) for 48h. (B) HCC and HCCDXR cells were treated with increasing concentrations of EGCG ( 100 - 250 µM) or C75 (20 - 60 µM) for 48h. Results are expressed as mean {plus minus} SEM. Experiments were performed at least three times in triplicate.

Breast cancer (BC) is globally the most frequent cancer in women. Adherence to endocrine therapy (ET) in hormone-receptor-positive BC patients is active and voluntary for the first five years after diagnosis. This study examines the impact of adherence to ET on 10-year excess mortality (EM) in patients diagnosed with Stages I to III BC (N = 2297). Since sample size is an issue for estimating age-and stage-specific survival indicators, we developed a method, ComSynSurData, for generating a large synthetic dataset (SynD) through probabilistic graphical modeling of the original cohort. We derived population-based survival indicators using a Bayesian relative survival model fitted to the SynD. Our modeling showed that hormone-receptor-positive BC patients diagnosed beyond 49 years of age at Stage I or beyond 59 years at Stage II do not have 10-year EM if they follow the prescribed ET regimen. This result calls for developing interventions to promote adherence to ET in patients with hormone receptor-positive BC and in turn improving cancer survival. The presented methodology here demonstrates the potential use of probabilistic graphical modeling for generating reliable synthetic datasets for validating population-based survival indicators when sample size is an issue This work was supported by Instituto de Salud Carlos III PI18/01836 funded by FEDER funds/European Regional Development Fund (ERDF)-a way to Build Europe-//FONDOS FEDER “una manera de hacer Europa”

Mortality from cardiovascular disease (CVD), second tumours, and other causes is of clinical interest in the long-term follow-up of breast cancer (BC) patients. Using a cohort of BC patients (N = 6758) from the cancer registries of Girona and Tarragona (north-eastern Spain), we studied the 10-year probabilities of death due to BC, other cancers, and CVD according to stage at diagnosis and hormone receptor (HR) status. Among the non-BC causes of death (N = 720), CVD (N = 218) surpassed other cancers (N = 196). The BC cohort presented a significantly higher risk of death due to endometrial and ovarian cancers than the general population. In Stage I, HR− patients showed a 1.72-fold higher probability of all-cause death and a 6.11-fold higher probability of breast cancer death than HR+ patients. In Stages II–III, the probability of CVD death (range 3.11% to 3.86%) surpassed that of other cancers (range 0.54% to 3.11%). In Stage IV patients, the probability of death from any cancer drove the mortality risk. Promoting screening and preventive measures in BC patients are warranted, since long-term control should encompass early detection of second neoplasms, ruling out the possibility of late recurrence. In patients diagnosed in Stages II–III at an older age, surveillance for preventing late cardiotoxicity is crucial.

Introduction Benefit from adjuvant chemotherapy (CT) is doubtful in a high percentage of patients with early breast cancer. The 21-gene recurrence-score (RS) assay (Oncotype DX, Genomic Health) is one gene-expression assay that provide prognostic and predictive information in hormone-receptor (RH) positive breast cancer. The results of the TAILORx study have confirmed that the majority of patients with tumors RH + and HER2 negative can avoid CT without increasing their risk of relapse. From 2012 to 2015 we used Mammaprint (MMP), in our institution and 60% of cases could avoided CT (communicated in SABCS 2015). Since 2017 we use RS for this purpose. Primary Objective To analyze the impact of using RS to change the indication of adjuvant CT. Secondary Objectives To analyze the association between different clinical pathological factors and the RS value, and calculate the difference between the cost of all RS test and the cost in direct expense of the treatment with CT of all patients who could avoid it thanks to the RS Material and methods We analyzed all RS test performed in the three ICO centers during 2017. We sent 112 tumor samples; in 2 samples adequated RNA for RS was not obtained. We compared the adjuvant treatment initially planned according to institutional treatment protocol with the treatment given after RS. We compared the direct economic costs of CT with the costs of the diagnostic test, and performed a logistic regression analysis of some pathological factors and RS value. Results The RS could be determined in 110 of 112 cases, in which there was indication of adjuvant CT. Only 14 patients received CT (12,72%) with the RS value, so CT was avoided in 96 patients (87,28%). The clinical-pathological characteristics of the series are summarized in the table 1. Of the risk factors analyzed, only grade 3 (p 0.001) and PR 25. No association was found between age, nodal status, tumor diameter, Ki67, Infiltrating Ductal Carcinoma vs neither Infiltrating Lobular Carcinoma nor Lympho-Vascular invasion. The cost of the genetic studies was 180000€ (1636€ each). The cost of each CT schedule (EC x 4 followed by paclitaxel x 12) was 7214€ and the total cost of 96 cases 692590€. Direct costs savings estimated from the reduction in CT treatment were 512590€ Conclusion: Our series shows that RS avoided unnecessary CT in 87% of cases and was more cost-effective than a previous series with MMP. G3 and RP 25. Table 1.Patients characteristics and clinical-pathological details from the analyzed tumorsPatient characteristicsAge, mean (range)53,76 (19 – 75)≥50y72 (65.5%) Citation Format: Ferrer M, Dorcas J, Quiroga V, Margelí M, del Barco S, Stradella A, Petit A, Falo C, Viñas G, Romeo M, Villanueva R, Cirauqui B, Vázquez S, Fernández A, Recalde S, Vethencourt A, Soler T, Pérez-Martín X, Gil-Gil M. Impact of oncotype dx genetic signature used in early breast cancer. Clinical and economic analisys of a 110 patient cohort treated in the Catalan Oncologic Institute (ICO), Spain [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 P5-15-09.

The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3–80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7–74.5]; OR 1.34 [95% CI: 0.46–3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 μmol/L, 95% CI: 3.6–8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

Question Which is the optimal endocrine partner (fulvestrant vs letrozole) for cyclin-dependent kinase 4 and 6 inhibitor palbociclib in previously untreated, endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer? Findings In this randomized, open-label, phase 2 trial, 486 patients were assigned in equal numbers to receive palbociclib plus fulvestrant or letrozole. Median investigator-assessed progression-free survival was 27.9 months for fulvestrant-palbociclib vs 32.8 months for letrozole-palbociclib, a difference that was not statistically significant. Meaning Fulvestrant-palbociclib demonstrated no improvement in progression-free survival over letrozole-palbociclib, confirming letrozole as the preferred palbociclib partner in this patient population. This randomized clinical trial investigates fulvestrant-palbociclib vs letrozole-palbociclib as initial therapy for endocrine-sensitive, hormone receptor-positive, ERBB2-negative breast cancer. IMPORTANCE The cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population. OBJECTIVE To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario. DESIGN, SETTING, AND PARTICIPANTS In this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020. INTERVENTIONS Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no). MAIN OUTCOMES AND MEASURES The primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported. CONCLUSIONS AND RELEVANCE Although fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer.

// Ariadna Giro-Perafita 1, * , Ariadna Sarrats 1, * , Ferran Perez-Bueno 1, 2 , Gloria Oliveras 1, 3 , Maria Buxo 4 , Joan Brunet 1, 3 , Gemma Vinas 1, 3 and Teresa Puig Miquel 1 1 New Terapeutics Targets Laboratory (TargetsLab), Department of Medical Sciences, University of Girona, Girona, Spain 2 Pathology Department, Dr. Josep Trueta Hospital and Catalan Institute of Health (ICS), Girona, Spain 3 Medical Oncology Department, Catalan Institute of Oncology (ICO), Girona, Spain 4 Girona Biomedical Research Institute (IDIBGI), Girona, Spain * These authors have contributed equally to this work Correspondence to: Teresa Puig Miquel, email: teresa.puig@udg.edu Gemma Vinas, email: G.vinyes@iconcologia.net Keywords: EGFR, breast cancer molecular subtypes Received: January 25, 2017 Accepted: May 05, 2017 Published: August 10, 2017 ABSTRACT Triple-Negative Breast Cancer (TNBC) has poor prognosis and no approved targeted therapy. We previously showed that the enzyme fatty acid synthase (FASN) was largely expressed in a small TNBC patients’ cohort and its inhibition synergized with cetuximab in TNBC preclinical mouse models. Here, we evaluated FASN and EGFR expression in a cohort of TNBC patients and we study their prognostic role and their association with clinico-histopathological features, intrinsic TNBC subtypes and survival. FASN, EGFR, CK5/6 and vimentin expression were retrospective evaluated by Immunohistochemistry in 100 primary TNBC tumors. FASN expression was classified into high and low FASN groups. EGFR, CK5/6 and vimentin expression were used in TNBC intrinsic subtypes classification. FASN was expressed in most of the TNBC patients but did not correlate with overall survival or disease-free survival in this cohort. High FASN group was significantly associated with positive node status. FASN expression was significantly higher in Basal-Like patients than in Mesenchymal-Like ones. EGFR expression was positive in 50% of the tumors, and those patients showed poorer DFS. Altogether, our findings provide a rationale for further investigation the prognostic role of FASN and EGFR expression in a larger cohort of TNBC patients.

Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-of-opportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial. Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/changes. Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB = 3 (P = 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P = 0.09). In Arm B, 18F-FMISO-PET lacked predictive/prognostic value. Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib. Clin Cancer Res; 23(6); 1432–41. ©2016 AACR.

Background Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8mg/kg loading dose, then 6mg/kg every 3weeks (q3w)] and pertuzumab (840mg loading dose, then 420mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54years; 29% had received prior trastuzumab. Median treatment duration was 16months for pertuzumab and trastuzumab and 4months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Conclusions Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. ClinicalTrials.gov NCT01572038.

Homocisteïna; Càncer de mama; Dieta cetogènica Homocisteína; Cáncer de mama; Dieta cetogénica Homocysteine; Breast cancer; Ketogenic diet Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the “drug plus diet” approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body β-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response. This work was supported by grants from the Ministerio de Sanidad, Servicios Sociales e Igualdad (EC10-125, Ayudas para el Fomento de la Investigación Clínica Independiente to Begoña Martin-Castillo). Work in the Menendez laboratory is supported by the Ministerio de Ciencia e Innovación (Grant SAF2016-80639-P, Plan Nacional de l+D+I, founded by the European Regional Development Fund [EU FEDER], Spain) and by an unrestricted research grant from the Fundació Oncolliga Girona (Lliga catalana d’ajuda al malalt de càncer, Girona).

Background Benefit derived from adjuvant chemotherapy (CT) is doubtful in a high percentage of patients (pt) with hormone-receptor–positive HER2 negative early breast cancer. The 21-gene recurrence-score (RS) assay Oncotype DX, provide prognostic and predictive information. Results of the TAYLORx study have confirmed that most of patients with negative node status and RS > 25 can avoid CT without increasing their risk of relapse. However, pt 20 showed benefit with CT. Methods Aim: To analyse the impact of age using RS test to change the indication of adjuvant CT and the relationship between different clinical pathological factors and the RS value. We analysed 240 cases out of 251 RS test performed in the 3 ICO Centers during 2017-2018. We compared the adjuvant treatment initially planned according to institutional protocol with the treatment given after RS in the total cohort and in pt Results CT was indicated in all pt before knowing the RS results. Only 46 pt (19%) received CT after RS results. 14 out of 88 pt 25 ( 25 in a multivariate analysis. Table . 209P Age median (range) 53 (19-76) Tumor size median 15 mm Histological grade G1 23% G2 69.7% G3 4.4% Progesterone receptor ≤20% 21% >20% 78% Ki67 median (p25-75) 20 (13,28) ≤14 27% 14-25 41% >25% 31% Nodal status pN0 57% pN1mic 15% pN1a 27% Conclusions 82% of pt of our series could avoid CT, however this proportion change after TAYLORx results in younger patients. Today 75% of these pt would had avoided CT. Ki67 > 25% and Progesterone Receptor ≤20% were the only pathological factors associated with an increased risk of RS > 25. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background: The minor allele (C) of the single-nucleotide polymorphism (SNP) rs11212617, located near the ataxia telangiectasia mutated (ATM) gene, has been associated with an increased likelihood of treatment success with metformin in type 2 diabetes. We herein investigated whether the same SNP would predict clinical response to neoadjuvant metformin in women with early breast cancer (BC). Methods: DNA was collected from 79 patients included in the intention-to-treat population of the METTEN study, a phase 2 clinical trial of HER2-positive BC patients randomized to receive either metformin combined with anthracycline/taxane-based chemotherapy and trastuzumab or equivalent regimen without metformin, before surgery. SNP rs11212617 genotyping was assessed using allelic discrimination by quantitative polymerase chain reaction. Results: Logistic regression analyses revealed a significant relationship between the rs11212617 genotype and the ability of treatment arms to achieve a pathological complete response (pCR) in patients (odds ratio [OR]genotype×arm = 10.33, 95% confidence interval [CI]: 1.29–82.89, p = 0.028). In the metformin-containing arm, patients bearing the rs11212617 C allele had a significantly higher probability of pCR (ORA/C,C/C = 7.94, 95%CI: 1.60–39.42, p = 0.011). Conversely, no association was found between rs11212617 and clinical response in the reference arm (ORA/C,C/C = 0.77, 95%CI: 0.20–2.92, p = 0.700). After controlling for tumor size and hormone receptor status, the rs11212617 C allele remained a significant predictor of pCR solely in the metformin-containing arm. Conclusions: If reproducible, the rs11212617 C allele might warrant consideration as a predictive clinical biomarker to inform the personalized use of metformin in BC patients. Trial Registration: EU Clinical Trials Register, EudraCT number 2011-000490-30. Registered 28 February 2011, https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000490-30/ES.

Metformina; Ki67; Càncer de mama Metformina; Ki67; Cáncer de mama Metformin; Ki67; Breast cancer The proliferative capacity of residual breast cancer (BC) disease indicates the existence of partial treatment resistance and higher probability of tumor recurrence. We explored the therapeutic potential of adding neoadjuvant metformin as an innovative strategy to decrease the proliferative potential of residual BC cells in patients failing to achieve pathological complete response (pCR) after pre-operative therapy. We performed a prospective analysis involving the intention-to-treat population of the (Metformin and Trastuzumab in Neoadjuvancy) METTEN study, a randomized multicenter phase II trial of women with primary, non-metastatic (human epidermal growth factor receptor 2) HER2-positive BC evaluating the efficacy, tolerability, and safety of oral metformin (850 mg twice-daily) for 24 weeks combined with anthracycline/taxane-based chemotherapy and trastuzumab (arm A) or equivalent regimen without metformin (arm B), before surgery. We centrally evaluated the proliferation marker Ki67 on sequential core biopsies using visual assessment (VA) and an (Food and Drug Administration) FDA-cleared automated digital image analysis (ADIA) algorithm. ADIA-based pre-operative values of high Ki67 (≥20%), but not those from VA, significantly predicted the occurrence of pCR in both arms irrespective of the hormone receptor status (p = 0.024 and 0.120, respectively). Changes in Ki67 in residual tumors of non-pCR patients were significantly higher in the metformin-containing arm (p = 0.025), with half of all patients exhibiting high Ki67 at baseline moving into the low-Ki67 (

Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44+CD24-/low CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44+CD24-/low CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44+CD24-/low CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44+CD24-/low mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of "Trojan horse" approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC subtypes might inform on their CSC-determined sensitivity to trastuzumab, thus providing a better delineation of the predictive value of cHER2+ in BC by incorporating CSCs-driven intra-tumor heterogeneity into clinical decisions.

// Miguel Quintela-Fandino 1 , Nora Soberon 2 , Ana Lluch 3 , Luis Manso 4 , Isabel Calvo 5 , Javier Cortes 6, 7 , Fernando Moreno-Anton 8 , Miguel Gil-Gil 9 , Noelia Martinez-Janez 7 , Antonio Gonzalez-Martin 10 , Encarna Adrover 11 , Raquel de Andres 12 , Gemma Vinas 13 , Antonio Llombart-Cussac 14 , Emilio Alba 15 , Silvana Mouron 1 , Juan Guerra 16 , Begona Bermejo 3 , Esther Zamora 6 , Jose Angel Garcia-Saenz 8 , Sonia Pernas Simon 9 , Eva Carrasco 17 , Maria Jose Escudero 17 , Ruth Campo 17 , Ramon Colomer 18 , Maria A. Blasco 2 1 Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain 2 Telomeres and Telomerase Group, Molecular Oncology Programme, CNIO-Spanish National Cancer Research Center, Madrid, Spain 3 Medical Oncology Department, Hospital Clinico Universitario, Valencia, Spain 4 Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain 5 Medical Oncology Department, Hospital de Monteprincipe, Madrid, Spain 6 Medical Oncology Department, Hospital Vall d´Hebron, Barcelona, Spain 7 Medical Oncology Department, Hospital Ramon y Cajal, Madrid, Spain 8 Medical Oncology Department, Hospital Clinico San Carlos, Madrid, Spain 9 Medical Oncology Department, Institut Catala d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain 10 Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain 11 Medical Oncology Department, Hospital General de Albacete, Albacete, Spain 12 Medical Oncology Department, Hospital Lozano Blesa, Zaragoza, Spain 13 Medical Oncology Department, Institut Catala d'Oncologia-Hospital Dr. Josep Trueta, Girona, Spain 14 Medical Oncology Department, Hospital Arnau de Vilanova, Valencia, Spain 15 Medical Oncology Department, Hospital Clinico Universitario Virgen de la Victoria, Malaga, Spain 16 Medical Oncology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain 17 GEICAM, Madrid, Spain 18 Medical Oncology Department, Hospital Universitario La Princesa, Madrid, Spain Correspondence to: Miguel Quintela-Fandino, email: mquintela@cnio.es Maria A. Blasco, email: mblasco@cnio.es Keywords: telomere length, critically short telomeres, breast cancer, weekly paclitaxel, toxicity Received: October 25, 2016 Accepted: January 27, 2017 Published: February 21, 2017 ABSTRACT Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres ( 21.9% CSTs) had 2-fold higher number of neuropathy ( P = 0.04) or fatigue ( P = 0.019) episodes and >3-fold higher number of myalgia episodes ( P = 0.005). The average telomere length was unrelated to the incidence of side effects. The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.

Oxidative stress is a biochemical condition of imbalance between free radicals and antioxidant defence mechanisms. Cancer is an inducing oxidative stress disease. Metabolic changes in neoplastic cells, tumor infiltration by inflammatory cells, malnutrition and specific cancer treatment contribute to high levels of oxidative stress in cancer patients. The toxic effects of oxidative stress on normal cells could be counteracted by use of antioxidants, even though they may abrogate the harmful effects of oxidative stress on tumor cells and prevent apoptosis. Thus, currently, there is not enough scientific evidence to support the use of antioxidants in patients with cancer.

OBJECTIVE Overexpression of fatty acid synthase (FASN), the enzyme involved in the de novo synthesis of fatty acids, has been reported in several human carcinomas, including breast cancer, and has been related to poor prognosis. Our aim was to analyze the association of FASN tumor tissue expression with clinicopathological and anthropometrical features in early-stage breast cancer patients. METHODS We prospectively studied 53 women with early-stage breast cancer who were treated with surgical operation and postoperative chemotherapy. RESULTS Menopause status and age were strongly associated with higher levels of FASN tumor expression (P < 0.005 and P = 0.038, respectively). Body mass index and pathological stage were also related to FASN tumor expression. CONCLUSIONS Our findings suggest that FASN could be a potential therapeutic target in postmenopausal breast cancer patients. However, further studies are needed.

Oxidative stress is a biochemical condition of imbalance between free radicals and antioxidant defence mechanisms. Cancer is an inducing oxidative stress disease. Metabolic changes in neoplastic cells, tumor infiltration by inflammatory cells, malnutrition and specific cancer treatment contribute to high levels of oxidative stress in cancer patients. The toxic effects of oxidative stress on normal cells could be counteracted by use of antioxidants, even though they may abrogate the harmful effects of oxidative stress on tumor cells and prevent apoptosis. Thus, currently, there is not enough scientific evidence to support the use of antioxidants in patients with cancer.

This section focuses on different aspects of the individualization of hormone treatment in breast cancer. This includes tumor-related biological factors such as expression of hormone receptors, HER-2, and Ki-67; host-related factors such as CYP2D6 or body mass index, and risk and/or development of specific toxicities and treatment adherence. The best predictor of response to hormonal interventions is the expression of hormone receptors, in particular, estrogen receptors. Treatment adherence and compliance are key factors and strategies aiming to identify and intervene when patients are at risk of abandoning treatment. Currently, routine assessment of CYP2D6 is not recommended to guide tamoxifen treatment. Likewise, there are no criteria regarding bone mass density, lipid profile, or arthralgias to recommend one class of agent versus another. Aromatase inhibitors should not be administered to patients who are pre- or perimenopausal.

16006 Background: In non-urban areas, there is a controversy about whether medical cancer treatments should be administered exclusively in referral cancer centers (CC) or in community hospitals (CH) (Br J Cancer 2004; 90: 1688). Limitations such as geographical distance or absence of treatment guidelines may reduce the access to specialized cancer care or clinical trials. A network organization that involves at the same time a CC and the CH from the same geographical area may provide an adequate balance between proximity, equity and quality of cancer services. Methods: We designed a cancer network in 2003 in order to consolidate all Oncology resources in an area covering a population of 700,000. A CC is placed adjacent to a general hospital in a centrally located urban area of 250,000. The remaining area is served by 6 CH. Our cancer network is based on: 1) approximately half of the Medical Oncology Dpt staff members work part-time at a CH, participating in outpatient clinic, chemotherapy treatments administration, and multidisciplinary meetings; and 2) other cancer health professionals are organized in network groups like the pharmacy group and the chemotherapy nursing group. Specialized medical cancer care included concomitant radio-chemotherapy, complex outpatient or inpatient therapies, genetic counseling and therapy for some pre-defined malignancies such as germ cell and ovarian cancers. Results: From January to December 2004, 1862 new patients were visited, 1013 (54%) at the CC (Medical Oncology Dpt.), and 849 (46%) at the CH. One-hundred ninety-three cancer patients were referred from the CH to the CC. In total, 141 of the cancer patients seen at the CC were included in clinical trials. It is remarkable that clinical trial participation was much enhanced by referrals, since 101 (72%) of patients in clinical trials came from non-urban areas. Conclusions: The establishment of a cancer network facilitates access to specialized cancer care and clinical trials for patients living in non-urban areas, therefore contributing to therapeutic equity. No significant financial relationships to disclose.

Purpose: Triple-negative breast cancer (TNBC) lacks an approved targeted therapy. Despite initial good response to chemotherapy, 30% of the patients relapse within 5 years after treatment. EGFR overexpression is a common marker in TNBC, and its expression has been correlated with poor outcome. Inhibition of fatty acid synthase (FASN) activity leads to apoptosis of human carcinoma cells overexpressing FASN. We tested the hypothesis that blocking FASN in combination with anti-EGFR signaling agents would be an effective antitumor strategy in sensitive and chemoresistant TNBC. Experimental Design: Several TNBC cell lines and 29 primary tumors were included to determine whether FASN is a potential target in TNBC. Doxorubicin-resistant TNBC cell lines (231DXR and HCCDXR) have been developed and characterized in our laboratory. Cellular and molecular interactions of anti-FASN compounds (EGCG and C75) with cetuximab were analyzed. In vivo tumor growth inhibition was evaluated after cetuximab, EGCG, or the combination in TNBC orthoxenograft models. Results: TNBC cell lines showed overexpression of FASN enzyme and its inhibition correlated to FASN levels. FASN staining was observed in all of the 29 TNBC tumor samples. In vitro, EGCG and C75 plus cetuximab showed strong synergism in sensitive and chemoresistant cells. In vivo, the combination of EGCG with cetuximab displayed strong antitumor activity against the sensitive and chemoresistant TNBC orthoxenografts, without signs of toxicity. Conclusions: Our results show that the simultaneous blockade of FASN and EGFR is effective in preclinical models of sensitive and chemoresistant TNBC. Clin Cancer Res; 22(18); 4687–97. ©2016 AACR.