María José Escudero

18F-fluoromisonidazole PET and Activity of Neoadjuvant Nintedanib in Early HER2-Negative Breast Cancer: A Window-of-Opportunity Randomized Trial

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.

Critically short telomeres and toxicity of chemotherapy in early breast cancer

Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres (< 3 kilobases, CSTs), but not average telomere length by itself, accounts for limited tissue renewal and turnover capacity. The impact of this parameter (which can be modified with different therapies) in chemotherapy-derived toxicity has not been studied. Blood from 115 treatment-naive patients from a clinical trial in early HER2-negative breast cancer that received weekly paclitaxel (80 mg/m2 for 12 weeks) either alone or in combination with nintedanib and from 85 healthy controls was prospectively obtained and individual CSTs and average telomere lenght were determined by HT Q-FISH (high-throughput quantitative FISH). Toxicity was graded according to NCI common toxicity criteria for adverse events (NCI CTCAE V.4.0). The variable under study was “number of toxic episodes” during the 12 weeks of therapy. The percentage of CSTs ranged from 6.5%–49.4% and was directly associated with the number of toxic events (R2 = 0.333; P < 0.001). According to a linear regression model, each 18% increase in the percentage of CSTs was associated to one additional toxic episode during the paclitaxel cycles; this effect was independent of the age or treatment arm. Patients in the upper quartile (> 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.

Frequency of breast cancer with hereditary risk features in Spain: Analysis from GEICAM “El Álamo III” retrospective study

Purpose To determine the frequency of breast cancer (BC) patients with hereditary risk features in a wide retrospective cohort of patients in Spain. Methods a retrospective analysis was conducted from 10,638 BC patients diagnosed between 1998 and 2001 in the GEICAM registry “El Álamo III”, dividing them into four groups according to modified ESMO and SEOM hereditary cancer risk criteria: Sporadic breast cancer group (R0); Individual risk group (IR); Familial risk group (FR); Individual and familial risk group (IFR) with both individual and familial risk criteria. Results 7,641 patients were evaluable. Of them, 2,252 patients (29.5%) had at least one hereditary risk criteria, being subclassified in: FR 1.105 (14.5%), IR 970 (12.7%), IFR 177 (2.3%). There was a higher frequency of newly diagnosed metastatic patients in the IR group (5.1% vs 3.2%, p = 0.02). In contrast, in RO were lower proportion of big tumors (> T2) (43.8% vs 47.4%, p = 0.023), nodal involvement (43.4% vs 48.1%, p = 0.004) and lower histological grades (20.9% G3 for the R0 vs 29.8%) when compared to patients with any risk criteria. Conclusions Almost three out of ten BC patients have at least one hereditary risk cancer feature that would warrant further genetic counseling. Patients with hereditary cancer risk seems to be diagnosed with worse prognosis factors.

Abstract P2-13-17: Impact on survival of primary tumor resection in women with de novo metastatic breast cancer. The GEICAM Alamo I-III breast cancer registry (1990-2001)

Introduction: Retrospective data from institutional series and population-based databases have suggested a potential benefit of the primary tumor (PT) surgery in de novo metastatic breast cancer (MBC) patients (pts). Recently reported prospective data from 2 randomized trials and a multicenter registry questioned the real role of the local approach in the modern individualized systemic treatment era. Methods: The ALAMO (A) is a retrospective analysis of pts diagnosed with BC between 1990 and 2001 across 56 GEICAM hospitals in Spain. Patterns of BC presentation (tumor and host characteristics), treatment and survival were recorded in 3 cohorts, AI (1990-93, 4529 pts, closed by 2000), AII (1994-97, 10453 pts, closed by 2003) and AIII (1998-2001, 10675 pts, closed by 2007). MBC pts at first diagnosis excluding those without complete information about their PT surgery were included. Descriptive, Kaplan-Meier and Cox regression analyses were carried out. Results: 5.5% (N=1415) of the ALAMO database pts were initially diagnosed with MBC, 1331 fulfilled the present analysis criteria (327 from AI, 619 from AII and 385 from AIII). Median age was 63.1 years (range: 21.6-96.0), 51.8% had single-organ metastasis, and their distribution according to the predominant site of disease was skin/soft tissue (16.2%), bone (33.7%), and visceral (48.4%). Surgery of the PT was done in 44.5% (N=592) of pts (512 with radical procedures, 46 with palliative procedures and 34 unknown); besides, 427 pts underwent axillary dissection. Initial local treatment was the choice for 380 pts (358 surgery and 22 radiotherapy), 722 received initial systemic therapy (480 chemotherapy, 214 endocrine treatment and 28 both), 29 received best supportive care and for 200 pts the treatment sequence could not be established. Pts in the surgery (S) group were younger (19.5% vs 11.8% were Citation Format: Sara Lopez-Tarruella, Maria Jose Escudero, Miguel Martin, Carlos Jara, Angel Guerrero, Ana Lluch, Ana Santaballa, Purificacion Martinez del Prado, Juan Lao, Emilio Alba, Antonio Fernandez, Raquel Andres, Antonio Llombart, Norberto Batista, Ignacio Porras, Jose Manuel Lopez-Vega, Encarna Adrover, Lourdes Calvo, Marina Pollan, Eva Carrasco. Impact on survival of primary tumor resection in women with de novo metastatic breast cancer. The GEICAM Alamo I-III breast cancer registry (1990-2001) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-17.

Abstract PD5-8: Phase I clinical trial of neoadjuvant BIBF1120 plus weekly paclitaxel (P) in early HER-2 negative breast cancer. CNIO-BR-01-2010/GEICAM 2010-10 study

Background: BIBF1120 has shown promising preclinical efficacy in breast cancer, and weekly paclitaxel (P) is a standard of care in BC. We designed a phase I/II trial of BIBF 1120 plus weekly P in early breast cancer, and report here the phase I part of the trial. The recommended dose has been determined and, additionally, efficacy has been assessed. Methods: Eligible patients had pathologically confirmed HER2 negative stage II or IIIA untreated breast cancer. BIBF1120 and P were administered at the following dose levels (DL): DL1: BIBF1120 150 mg bid p.o. days 1-21 plus P 80 mg/ m2 iv on days 1, 8 and 15 q21 days; DL2: BIBF1120 200 mg bid p.o. days 1-21 plus P same dose as level 1, q21 days. On the P-infusion day, the morning BIBF1120 dose was skipped to avoid potential PK interactions. A 3+3 escalation scheme with common dose-limiting toxicity (DLT) definitions was adopted. Four three-week cycles of BIBF1120 plus P followed by 4 AC cycles were administered. Surgery was planned 4-5 weeks after the last AC dose. We report the phase I part results of the phase I/II trial. Results: 9 patients have been evaluated for toxicity (6 patients in DL1 and 3 in DL2). Median age was 47.6 years (38.1-66.7) and 8 patients (89%) were premenopausal; median tumour size was 3.0 cm (2.7-6.5), 6 patients (66.7%) had stage II disease and 3 patients (33.3%) stage III. Seven cases (78%) were hormone-receptor (HR) positive and 2 (22%) negative. Two patients had DLT at DL2: ALT grade 3 (one patient); and ALT grade 4, AST grade 3 and GGT grade 3 (one patient). One case was reduced to DL1 and one withdrew consent after 7 days of treatment. Main related toxicities during treatment: DL1 GGT grade 2 (16.7%), hypertension grade 2 (50%), DL2 ALT grade 3 (33.3%), AST grade 3 (33.3%), bilirubin grade 2 (33.3%), GGT grade 2/3 (100%). Toxicities observed at DL2 were reversible by withholding BIBF1120 administration. Eight patients were evaluable for efficacy after surgery and have been assessed for pathological response: 2/2 (100%) HR(-) and 2/6 (33%) HR(+) patients, for a total of 4/8 (50%) patients, pCR defined as Miller&Payne score scale of 5. Three of these received DL1 and 1 DL2. A total of 6 patients (75%) underwent conservative surgery. Conclusions: Concomitant administration in early stage HER-2 negative breast cancer of BIBF1120 plus P at DL1 was manageable and had mild toxicity, showing remarkable efficacy specially in triple-negative breast cancer. BIBF1120 150 mg bid plus weekly P 80mg/m2 is the recommended dose for the ongoing phase II part of study CNIO-BR-01-2012/GEICAM 2010-10 with an enrolment target of 130 patients, of which 81 have been already recruited. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-8.

Combination or sequential single agent for the treatment of metastatic breast cancer (MBC) patients (pts). Impact of further chemotherapy (CT) in overall survival (OS) in the Alamo registry.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #2121 Introduction: Combinations can improve OS in MBC; however sequential single agent is sometimes preferred. In a recent report, pts receiving paclitaxel monotherapy in first line had a significantly worse OS if they were not receiving post study CT (PSC); no difference was seen in pts receiving paclitaxel+gemcitabine (Llombart, EBCC 2008). In this trial only 58% of pts received PSC. Purpose: To assess, outside the context of a clinical trial, the amount of MBC pts receiving CT beyond first line, as well as the impact of combination use and further CT lines in their OS. Methods: Alamo 1-2 is a breast cancer patient registry run by the GEICAM. 15482 pts diagnosed from 1990-1997 in 54 sites were included in the database. 4668 pts were stage IV; 778 (16.7%) metastatic at diagnosis and 3890 (83.3%) have had a recurrence. Results: 3045 (65%) pts received CT in first line, 83% were combinations (with anthracyclines 42%, CMF 16%, taxane+anthracyclines 9.4% or +other agents 8%) and 16% were monotherapy. Among other variables studied, only previous treatment (in early stage) was influencing the choice of a combination (pts without previous CT received more combinations than pts receiving CMF, than pts receiving anthracyclines). Median survival for pts receiving single agent was significantly shorter compared to pts receiving combination, 16.2 and 21.85 months (m) respectively, HR=1.37 (IC 95%: 1.21-1.55; p 65, negative hormonal receptor status, hepatic disease, Grade 3 and ≥ 3 disease sites. Half of the pts never received further CT after first line treatment. Only age and number of disease sites were influencing this decision in the Cox multivariate model. Median survival was 24.9 m in pts receiving further CT and 14.5 m in the ones not receiving it. In pts not receiving further CT, median OS was significantly shorter if they were treated with single agent in first line in comparison to those receiving previous combination: HR= 1.59 (IC 95%: 1.33-1.89; p< 0,00001). This difference was not significant in pts receiving further CT: HR= 1.15 (IC 95%: 0.97-1.37; p=0.101). Conclusion: Our data show that only half of the MBC pts receive further CT after first line; they have longer survival. We found significant evidence that further CT is impacting the OS in pts treated with single agent in first line, but not in those receiving previous combination. Those facts should be taken into consideration when selecting single agent or a combination in first line. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2121.