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Immunotherapy; PARP inhibitors; Pembrolizumab Immunoteràpia; Inhibidors de PARP; Pembrolizumab Inmunoterapia; Inhibidores de PARP; Pembrolizumab Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic review and multiple Bayesian network meta-analyses according to treatment line to establish an optimal therapeutic sequencing strategy for this lethal disease. We included 125 first-line trials (37,812 patients) and 33 s/further-lines trials (11,321 patients). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rates (ORR), overall survival (OS) and safety, for first and further lines, separately. We also estimated separate treatment rankings for the first and subsequent lines according to each endpoint, based on (surface under the cumulative ranking curve) SUCRA values. No first-line treatment was associated with superior PFS and OS than paclitaxel ± bevacizumab. Platinum-based polychemotherapies were generally superior in terms of ORR, at the cost of higher toxicity.. PARP-inhibitors in germline-BRCA1/2-mutant patients, and immunotherapy + chemotherapy in PD-L1-positive mTNBC, performed similar to paclitaxel ± bevacizumab. In PD-L1-positive mTNBC, pembrolizumab + chemotherapy was better than atezolizumab + nab-paclitaxel in terms of OS according to SUCRA values. In second/further-lines, sacituzumab govitecan outperformed all other treatments on all endpoints, followed by PARP-inhibitors in germline-BRCA1/2-mutant tumors. Trastuzumab deruxtecan in HER2-low mTNBC performed similarly and was the best advanced-line treatment in terms of PFS and OS after sacituzumab govitecan, according to SUCRA values. Moreover, comparisons with sacituzumab govitecan, talazoparib and olaparib were not statistically significant. The most effective alternatives or candidates for subsequent lines were represented by nab-paclitaxel (in ORR), capecitabine (in PFS) and eribulin (in PFS and OS).

Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non‐pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450–480 mg/m2. Following three pivotal first‐line phase III trials in HER2‐negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2‐negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms., SCOPUS: re.j, info:eu-repo/semantics/published

Background: TNBC shows a very bad prognosis: median time to relapse is 18 months and median overall survival (OS) is less than 24 months. Methods: AMBRA is a longitudinal cohort study, describing the choice of 1st- and subsequent treatments in HER2-ve MBC pts in the years 2012-2015. The present analysis is focused on TNBC pts (127 out of 879 evaluable; 14.4%) and CHT strategies, overall and according to adj treatment. Kaplan Meyer probability of survival from primary (DFS), 1st(PFS1) and 2nd(PFS2) progression and Time from last CHT and death were calculated for the whole population and according the main adj regimens. Results: Median age at primary diagnosis was 53 years. The most used regimens in the adj setting were anthra/taxane(tax) 50.7%, anthra 22.1% or others (CMF included) 20.6%. Median time to events was: DFS 23.2, PFS1 6.5 and PFS2 4.3 months, respectively. CHT choices in the metastatic setting according to adj treatment were: Adj Anthra-basedAdj Taxane-basedAdj other1st-lineTax* 57.6% - VRL/CAPE 18.2% - Plat 15.2% Other 3% - None 6.1%Tax* 46.2% - VRL/CAPE 24.6% Plat 24.6% - Other 4.6%Tax*52% - VRL/CAPE 16% - Anthra 16% - Anthra/Tax 8%2nd-lineTax**18.2% - Anthra 13.6% - VRL/CAPE 22.7% - Plat 27.3% - Erib 9.1% - Other 9.1%Tax**22% - VRL/CAPE 22% Plat 22% - Erib 14.6% - Other 17.1%VRL/CAPE 38.5% - Anthra 23.1% - Tax**23.1% - Plat 15.4%3rd lineVRL/CAPE 37.5% - Erib 25% - Anthra 18.8% - Tax***12.5% - Plat 6.3%Erib 26.9% - VRL/CAPE 23.1% - Plat 15.4% - Anthra 11.5% - Tax***11.5% - Other 11.5%VRL/CAPE 42.9% - Erib 28.6% - Plat 14.3% - Other 14.3%*docetaxel 8.4%, nab-paclitaxel 7%, paclitaxel 59%**docetaxel 7%, nab-paclitaxel 71.4%, paclitaxel 21%***docetaxel 20%, nab-paclitaxel 80%At a median follow up of 3.3 years 50% of pts are still alive. OS rates at 5 and 8 years from primary are 50% and 40%. OS rates from 1st progression are 50% and 20% at 22 and 40 months. Median OS (months) according to 1st line regimen was similar (ns) across the regimens (paclitaxel+bevacizumab: 17.8; Platinum-based: 14.1; CAPE/VRL: 16.3). Median time from last CHT and death was 1.5 months (29.6%< 1 month; 14% < 2 weeks) Conclusion: Our results show that taxanes play a crucial role in MBC even if used in 50% of Adj. CAPE/VRL, Platinum regimens and Eribuline are also widely used. Time from last CHT administration and Death is very short in 30% of cases Citation Format: Giorgio Mustacchi, Alessandra Beano, Alessandra Fabi, Lorenzo Livi, Antonio Bernardo, Ferdinando Riccardi, Paolo Marchetti, Ornella Garrone, Lucrezia Diodati, Laura Biganzoli, Monica Giordano, Anna Turletti, Livio Blasi, Andrea Milani, Clara Natoli, Marta Riemma, Alessia D'Alonzo, Grazia Arpino, Paolo Pronzato, Marina E Cazzaniga, on behalf of GIM-13 AMBRA Study Group. Triple negative (TNBC) metastatic breast cancer (MBC) patients (pts): Is chemotherapy (CHT) choice influenced by adjuvant (adj) treatments? Results from the GIM-13 AMBRA study [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 P2-15-14.

An added value of peer reviewing is gaining better knowledge on how health systems are organized and working worldwide, particularly in the so-called middle-low/middle-upper income countries.A rece...

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new virus that has never been identified in humans before. COVID-19 caused at the time of writing of this article, 2.5 million cases of infections in 193 countries with 165,000 deaths, including two-third in Europe. In this context, Oncology Departments of the affected countries had to adapt quickly their health system care and establish new organizations and priorities. Thus, numerous recommendations and therapeutic options have been reported to optimize therapy delivery to patients with chronic disease and cancer. Obviously, while these cancer care recommendations are immediately applicable in Europe, they may not be applicable in certain emerging and low- and middle-income countries (LMICs). In this review, we aimed to summarize these international guidelines in accordance with cancer types, making a synthesis for daily practice to protect patients, staff and tailor anti-cancer therapy delivery taking into account patients/tumour criteria and tools availability. Thus, we will discuss their applicability in the LMICs with different organizations, limited means and different constraints., Highlights • The first recommendations concerned mainly staff and patients with cancer protection. • More than half of the worldwide cancers are diagnosed in low- and middle-income countries (LMICs). • Organization in accordance with available means: main key for anti-cancer strategy in LMICs. • European recommendations applicability for coronavirus disease 2019 (COVID-19) pandemic is questioned in LMICs. • Amplification of pandemic effects on both COVID and cancer is to be feared in LMICs.

This abstract was not presented at the conference. Citation Format: Cazzaniga ME, Blasi L, Pronzato P, Giordano M, Garrone O, Donadio M, Del Mastro L, Livi L, Natoli C, Michelotti A, Turletti A, Riccardi F, De Laurentiis M, Marchetti P, Montemurro F, Romagnoli E, De Placido S, Biganzoli L, Bologna A, Bria E, Mustacchi G. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-04.

BACKGROUND Pts with ABC have a diverse clinical course and OS rates vary significantly among pts. New strategies had potentially changed the natural history of these pts, however data from clinical studies are still lacking and Real-World Studies (RWS) are crucial in clinical outcome evaluation. PATIENTS AND METHODS AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve ABC pts receiving at least one CHT (SABCS 2016, P5-15-07 & P5-14-09) in the years 2012-2015. The present analysis is focused on the description of Progression-Free Survival (PFS) and OS according to the biologic subtype in the deceased population. So far, 791/1500 pts have been registered into the study and 255 (32.2%) are evaluable. Time to event analysis between subtypes was evaluated by Cox-Mantel Hazard Ratio and Logrank Test. DFS by Wilcoxon Rank-Sum Test RESULTS Pts distribution according to molecular subtype was: Luminal A (86, 33.7%), Luminal B (107 (42.1%), TNBC (62, 24.3%). Median ages at diagnosis were 55.8, 52.9 and 55.1 years for the 3 subgroups, respectively. Mean DFS was significantly different according to the molecular subtypes: 87.28, 61.37 and 23.9 months. The difference between Luminal B and TNBC is statistically significant as well. Mean PFS of 1st-line therapy was 17.9 11.7 and 7.8 months respectively. Mean OS from 1stprogression was 32.9 24.2 and 15.8 months respectively. CONCLUSIONS Our data confirm in a RWS the different biological behaviour between Lum A and B. Metastatic life span is quite good for Luminals and disappointing for TNBC. Median time from last CHT and Death is quite short and similar. Luminal ALuminal BTNBCMean DFS (months)87.28 [95%CI: 72.9-101.7]61.37 [95%CI: 52.3-70.4] p=0003623.9 months [95%CI: 18.5-29.3] p=0.000000Mean PFS (months)17.9 [95%CI: 12.5-23.5]11.7 [95%CI:9.8-13.7]7.8 months [95%CI: 5.9-9.6]Mean OS from 1st progression (months)32.9 [95%CI:25.4-40.4]24.2 [95%CI: 21.3-26.9]15.8 [95%CI: 13.0-18.6]Median time from last CHT and Death (months)2.231.951.53Lum A/Lum B HR (p value)Lum A/TNBC HR (p value)Lum B/TNBC HR (p value)PFS 1st-Line0.73 (0.02)0.49 (0.0000)0.63 (0.003)OS from diagnosis (years)0.59 (0.0003)0.25 (0.0000)0.34 (0.0000)OS from 1st-PD0.72 (0.02)0.47 (0.0000)0.50 (0.0002) Citation Format: Marina Elena Cazzaniga, Sabino De Placido, Alessia D'Alonzo, Michela Piezzo, Clara Natoli, Andrea Milani, Alessandra Bologna, Massimiliano Alu, Anna Turletti, Palma Pugliese, Laura Biganzoli, Claudia De Angelis, Ornella Garrone, Paolo Marchetti, Ferdinando Riccardi, Antonio Bernardo, Lorenzo Livi, Alessandra Fabi, Cristiana Taverniti, Emanuela Romagnoli, Paolo Pronzato, Giorgio Mustacchi, on behalf of GIM-13 AMBRA Study Group. Progression-free survival (PFS) and overall survival (OS) in HER2-ve advanced breast cancer (ABC) patients (pts) according to the molecular subtype in the era of modern agents. Results from the GIM-13 AMBRA study [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 P5-07-10.

BACKGROUND The open-label randomized phase III IMELDA trial demonstrated that adding CAP to maintenance BEV until disease progression after initial BEV + docetaxel (DOC) provides statistically significant and clinically meaningful improvements in both progression-free survival (PFS [primary endpoint]; hazard ratio [HR] 0.38, 95% CI 0.27–0.55; log-rank p METHODS In IMELDA, patients (pts) with HER2-negative measurable mBC and no prior chemotherapy for mBC received 3-6 cycles of BEV + DOC. Pts with a response or stable disease were randomized to BEV alone or BEV + CAP (BEV 15 mg/kg d1 q3w; CAP 1000 mg/m2 bid d1-14 q3w) until disease progression, unacceptable toxicity, or consent withdrawal. OS from randomization was a secondary endpoint. In post-IMELDA, data until study closure were collected retrospectively from available records of pts randomized in IMELDA. Ethics, consent, and feasibility reasons prevented some sites participating in post-IMELDA. RESULTS Post-IMELDA data were available from 118 (64%) of the 185 randomized pts. Of these, all but 8 had received further systemic anticancer therapy and 92 of 118 (78%) had received chemotherapy. Post-progression treatment exposure and efficacy are shown below. In Cox regression models stratified by further anticancer therapy after stopping study therapy, HRs were 0.30 (95% CI 0.19–0.48) for PFS and 0.50 (95% CI 0.30–0.82) for OS. Sensitivity analyses using two extremes of imputation (assuming all pts with missing follow-up data did vs did not receive further anticancer therapy) supported OS findings. ParameterBEV (n=59)BEV + CAP (n=59)Any further systemic anticancer therapy, n (%)56 (95)54 (92)Chemotherapy 49 (83)43 (73) CAP34 (58)7 (12) Non-CAP-containing43 (73)41 (69)Targeted therapy/immunotherapy 12 (20)3 (5) BEV8 (14)1 (2)Endocrine therapy 24 (41)31 (53)Other 11 (19)10 (17)Median PFS, months (95% CI)4.3 (2.7–7.4)15.0 (9.9–19.3)Subgroup with further anticancer therapy 4.3 (3.5–7.4)14.1 (9.9–19.3)Median OS, months (95% CI)22.3 (12.1–29.8)36.5 (27.6–NE)Subgroup with further anticancer therapy 22.9 (16.5–31.7)36.5 (24.0–NE)NE=not estimable CONCLUSIONS Post-IMELDA is limited by retrospective collection of data from only two-thirds of randomized pts and only until the date of study closure (thus potentially underestimating crossover to CAP). Nevertheless, these analyses suggest that the OS benefit from adding CAP to maintenance BEV in the IMELDA trial was robust despite extensive post-progression therapy in both treatment arms and crossover to CAP in more than half of pts randomized to maintenance BEV alone. Ongoing and future mBC trials should include prospective collection of information on subsequent therapy. Citation Format: Mustacchi G, Bines J, Alba E, Cortes P, Doval D, de Ducla S, Button P, Gligorov J. Impact of post-progression therapy on overall survival (OS) in the IMELDA randomized phase III trial evaluating the addition of capecitabine (CAP) to maintenance bevacizumab (BEV) for HER2-negative metastatic breast cancer (mBC) [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 P5-15-06.

Frequency of CHT regimens according to biological subtypes and Setting of treatmentLuminal TumoursSettingRegimenAdj (%)1st-line (%)2nd-line (%)3rd-line (%)anthra-based (w/o Taxanes)44.27.15.19.9Anthra-Taxanes30.52.60.50CMF-like17.50.61.02.1Taxane mono/combo*6.319.314.521.5Pacliataxel + Bevacizumab020.24.33.7Platinum-based03.61.70.8Capecitabine +/- Vinorelbine019.122.217.4Eribuline002.312.4 TNBCSettingRegimenAdj (%)1st-line (%)2nd-line (%)3rd-line (%)Anthra-based (w/o Taxanes)25.73.15.116.2Anthra-Taxanes36.11.100CMF-like8.22.15.10Taxane mono/combo*6.318.417.810.8Paclitaxel + Bevacizumab024.71.70Platinum-based020.622.42.7Capecitabine +/- Vinorelbine025.720.610.8Eribuline003.429.7**Irrespectively of biological subtype, nab-paclitaxel was used in 3.6%, 15.3% and 16.4% of cases in 1st, 2nd and 3rd line, respectively BACKGROUND Breast Cancer prognosis improved in the last years due both to early diagnosis and Adj treatments. The choice of CHT regimens should consider previous Adj treatments, pattern of relapse and biological subtype. There are few information on the treatment of MBC in the clinical practice outside controlled trials, last study has been published 15 yrs ago in Italy. PATIENTS AND METHODS The GIM13-AMBRA Study is a multicenter longitudinal cohort study, describing the choice of first and subsequent lines of treatment for MBC in HER2-ve pts. We are collecting data of 30 consecutive pts from 42 Italian Centres who developed the first relapse in the years 2012-2015 and were treated with CHT, (+/- previous endocrine treatments (HT)) for MBC. One of the secondary aims is to evaluate the Time to Treatment Change (TTC) (time between treatment start and its change for any reason) as surrogate endpoint for Time To Progression outside clinical trials. The present report is focused on the choice of treatments in any line and TTC, according to biological subtypes. . RESULTS For the present analysis, 683 pts are evaluable. Pts with Luminal A and B tumours received CHT and HT in 65.3% (Adjuvant), 21.7% (1st line), 7.1% (2nd line) and 7% (3rd line) of the cases. The most used regimens according to tumour subtype and line of treatment are shown in Table 1. Median TTC from 1st to 2nd line was 8.1 and 17.9 months in TNBC and Luminal tumours, respectively, whereas TTC from 2nd to 3rd line was 3.1 and 12.9 months, respectively. CONCLUSION Preliminary results of the AMBRA-GIM13 Italian observational study confirm that in most cases treatment for MBC is strongly related to the type of the Adj regimen, being the use of anthracyclines marginal in MBC, whereas taxanes are widely used in any line. In 1st line the most used regimens are Taxane and Bevacizumab or Capecitabine/Vinorelbine combinations. The last one remains the most used CHT in 2nd and 3rd lines. No difference have been observed according to biological subtype, except for Platinum-based regimens in TNBC. HT alone remains the preferred choice in 1st and 2nd line in Luminal cases. TTC seems to be a reliable surrogate for PFS in the “real world” practice . CHT still plays a crucial role in the treatment of MBC HER2-ve pts. Citation Format: Mustacchi G, Cazzaniga ME, Biganzoli L, De Laurentiis M, Del Mastro L, De Placido S, Donadio M, Garrone O, Giordano M, Latini L, Livi L, Marchetti P, Michelotti A, Montemurro F, Natoli C, Pronzato P, Riccardi F, Turletti A. First and further line choices of treatment for HER2-VE metastatic breast cancer (MBC) according to adjuvant treatment and biological subtype. Preliminary results of the observational “GIM-13 – AMBRA” Italian study [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 P5-15-07.

BACKGROUND The addition of CAP to maintenance BEV demonstrated statistically significant and clinically relevant improvements in progression-free survival (PFS [primary endpoint]; HR 0.38 [95% CI 0.27–0.55]; log-rank p METHODS Pts with HER2-negative measurable mBC, ECOG PS RESULTS Adherence with questionnaire completion was 65–85% for all assessment timepoints during the first year of maintenance therapy. MMRM analysis of the global health status/QoL subscale showed no difference between the treatment arms in change from randomization (least squares mean estimate 0.40 [95% CI –6.07 to 6.87]). Similar results were observed for other subscales, including the diarrhea symptom subscale. No. of pts (%)BEV (N=94)BEV–CAP (N=91)Week 9aN=51N=59Improved15 (29.4)17 (28.8)Stable26 (51.0)34 (57.6)Week 18aN=29N=57Improved11 (37.9)12 (21.1)Stable12 (41.4)30 (52.6)Week 27aN=23N=43Improved7 (30.4)16 (37.2)Stable12 (52.2)20 (46.5)Week 36aN=15N=35Improved4 (26.7)14 (40.0)Stable9 (60.0)17 (48.6)aNo. of patients with completed questionnaires at both randomization and the respective week. Only weeks with ≥10 pts in both arms shown. CONCLUSIONS The IMELDA sample size was smaller than planned but protocol adherence with PRO completion was relatively high. Prespecified change from randomization and exploratory post hoc MMRM analyses of PROs suggest that the clinically meaningful PFS and OS benefit from adding CAP to BEV is achieved while maintaining QoL, with no difference between BEV and BEV–CAP treatments. Responder analyses over time showed improved or stable global health status/QoL scores in the majority of pts at each timepoint in both treatment arms. Citation Format: Dinesh Doval, Saverio Cinieri, Hakan Bozcuk, Jean-Yves Pierga, Kadri Altundag, Xiaojia Wang, Sudeep Gupta, Guillermo Lopez Vivanco, Vineet Gupta, Ewa Chmielowska, Jose Bines, Philippe Montcuquet, Alfred Namour, Emilio Alba, Giorgio Mustacchi, Paulo Cortes, Sabine de Ducla, Ulrich Freudensprung, Lesley Fallowfield, Joseph Gligorov. Exploratory post hoc analyses of patient-reported outcomes (PROs) in the IMELDA randomized phase III trial: Maintenance bevacizumab (BEV) ± capecitabine (CAP) after initial first-line BEV plus docetaxel (DOC) for HER2-negative metastatic breast can [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 P2-12-16.

ABSTRACT Aim: This observational study investigates the use of adjuvant trastuzumab (AT) in HER2-positive breast cancer patients in a real-life setting, focusing on relapse and discontinuation rates. Patients & methods: Data on a group of HER2-positive patients collected from 13 oncology centers of northeast Italy were analyzed. Results: In total, 1245 patients were analyzed. 13.1% of patients were excluded from AT because of comorbidities, age, tumor stage, refusal or other reasons; 8.2% of patients who received AT interrupted the therapy, mainly for toxicity. Overall the relapse rate was 10.9% in the AT-treated population versus 22.6% in nontreated patients (follow-up: 37.4 and 62.1 months, respectively). Disease-free survival (DFS) was lower in AT-relapsed patients than in not-relapsed. Statistical analysis showed a correlation between DFS and estrogen receptor status in AT-treated patients. Conclusion: Relapse rates are lower in clinical setting compared to clinical trials. Overall, AT is effective in HER2-positive early-stage breast cancer patients.

BACKGROUND The open-label randomized phase III IMELDA trial demonstrated that adding CAP to maintenance BEV until disease progression (PD) after initial BEV–docetaxel (DOC) provides statistically significant and clinically meaningful improvements in both progression-free survival (PFS [primary endpoint]; hazard ratio [HR] 0.38 [95% CI 0.27–0.55]; log-rank p METHODS Patients (pts) with HER2-negative measurable mBC, ECOG PS RESULTS Between Jun 2009 and Mar 2011, 284 pts were enrolled and treated. Of these, 99 were not eligible for randomization (most commonly due to PD [41%] or AEs/toxicity [31%]) and 185 (65%) were randomized. At the time of the primary PFS analysis, representing study closure, median follow-up (from randomization) was 31.6 months. Median OS from randomization was 23.7 months in the BEV arm and 39.0 months in the BEV–CAP arm (events in 36% of pts). The HR for OS in the two randomized arms showed consistency between subgroups, favoring the BEV–CAP arm in all subgroups analyzed. SubgroupNo. of events/No. of pts (%)Unstratified HR (95% CI)1-y OS rate (%) BEVBEV–CAP BEVBEV–CAPAll53/94 (56)33/91 (36)0.43 (0.26-0.69)a72901.5×ULNb3/5 (60)3/6 (50)1.01 (0.20-5.00)6044aStratified analysis. bStratification factor. CONCLUSIONS. Combining maintenance BEV with CAP until PD after initial BEV–DOC for mBC provides a statistically significant and clinically meaningful improvement in OS (secondary endpoint), seen consistently irrespective of baseline characteristics. Citation Format: Joseph Gligorov, Jose Bines, Emilio Alba, Giorgio Mustacchi, Saverio Cinieri, Vineet Gupta, Jean-Yves Pierga, Hakan Bozcuk, Rabab Gaafar, Sudeep Gupta, Guillermo Lopez Vivanco, Xiaojia Wang, Romulo Costa, Kadri Altundag, Ewa Chmielowska, Sabine de Ducla, Ulrich Freudensprung, Paulo Cortes, Dinesh Doval. Overall survival (OS) in the IMELDA randomized phase III trial of maintenance bevacizumab (BEV) with or without capecitabine (CAP) for HER2-negative metastatic breast cancer (mBC) [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 P2-17-01.

Background: In the Phase III ‘GRETA’ trial 474 women aged ≥70 years with early breast cancer were randomly assigned to surgery plus tamoxifen for 5 years or tamoxifen alone for 5 years. This is a long-term update. Patients & methods: Focusing on patients still alive in 2003, outcome end points has been recalculated. Results: Median distant metastases disease-free survival is longer with tamoxifen alone for 5 years; (48.8 vs 37.9 months; p = 0.009). No difference was found in distant metastases rate, disease-free survival, breast cancer and overall survival. Conclusion: Primary endocrine treatment until the the best response, followed by minimal surgery and prosecution endocrine treatment for 5–10 years is a suitable option for elderly breast cancer patients. Delayed surgery does not prejudice overall survival.

Background Tumor phenotype may change during breast cancer (BC) progression and discordance between primary and metastases ranges between 16% and 21% for Hormone Receptor (HR) expression in some series. The impact of this change on patient (pts) management and outcome is not yet clear, even though preliminary data indicate that the molecular characterization of recurrent breast cancer may induce clinicians to modify the treatment choice in ∼14% of the cases and that a change in the receptor status is associated with poorer survival. This analysis evaluates the prognostic impact of receptor discordance between paired primaries and recurrences. Methods We used data of 879 pts of the longitudinal cohort AMBRA study, identifying 3 different groups: Group A: HR+ BC remaining HR+ at relapse; Group BHR+ BC becoming TNBC; Group C:TNBC remaining TNBC. Change in HR status was evaluated on the biopsy done at the moment of relapse. Time to event was evaluated by Cox-Mantel Hazard Ratio and Logrank Test; Mean/median by Wilcoxon Rank-Sum Test. Results Pts who underwent biopsy at the time of relapse were 545/879 (62%), of those 462 (84.4%) were classified as Luminal tumors and 83 (15.2%) TNBC on primary. Change in tumor phenotype occurred in 31 (6.7%) of Luminal BC and 16 (19.3%) TNBC, probably due to a higher genomic instability (p = 0.021). Median DFS between Luminal BC was not different: HR+aHR+: 74.56 months (95%CI 66.8-82.1) vs HR+aTNBC: 89.73 months (95%CI:44.73-103.46). Table summarizes main data in time to event in the 3 identified groups. *PFS at 1strelapse; **PFS at 2nd relapse; ***Time to Treatment Change at 1strelapse; °OS at 1strelapse; §OS from 1stPD. Table . 325P HR+/HR + (range) Group A HR+/TNBC (range) Group B p value Group A vs C TNBC/TNBC (range) Group C PFS1* (months) 13.65 (0,77-162,03) 9.45 (3,97-52,73) 0.36 8.13 (6.3-10.9) PFS2** (months) 6.83 (0,00-57,13) 6.12 (2,67-26,30) 0.84 4.20 (0,33-22,17) TTC1*** (months) 12.43 (0,13-163,10) 8.88 (0,00-48,40) 0.50 7.88 (0,23-27,80) TTC2**** (months) 7.45 (0,00-55,97) 6.73 (3,77-26,80) na na OS1° (months) 23.1 (20-26) 15 (8.7-26.3) 0.031 3.60 (0,60-25,38) OS (years) 8.52 (0,26-115,92) 7.86 (0,19-30,67) 0.43 3.58 (2.91-2.39) OS from PD1§ (months) 25.8 (0,00-207,53) 17.23 (2,67-104,30) 0.82 17.90 (2,37-53,57) Conclusions Change in tumor phenotype has a significant impact on OS; BC pts who become TNBC at relapse should be treated in the same way as TNBC pts at diagnosis. Anyway, OS of Luminal BC who change phenotype seems to be better than TNBC. Legal entity responsible for the study GIM - Gruppo Italiano Mammella. Funding Celgene. Disclosure All authors have declared no conflicts of interest.

Clinical trials have shown the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancers, but routine clinical use awaits evaluation of compliance, safety, and effectiveness. Adjuvant trastuzumab-based therapy in routine clinical use was evaluated in the retrospective study GHEA, recording 1,002 patients treated according to the HERA protocol between March 2005 and December 2009 in 42 Italian oncology departments; 874 (87.23 %) patients completed 1-year trastuzumab treatment. In 128 patients (12.77 %), trastuzumab was withdrawn due to cardiac or non-cardiac toxicity (28 and 29 patients, respectively), disease progression (5 patients) or the clinician’s decision (66 patients). In addition, 156 patients experienced minor non-cardiac toxicities; 10 and 44 patients showed CHF and decreased LVEF, respectively, at the end of treatment. Compliance and safety of adjuvant trastuzumab-based therapy in Italian hospitals were high and close to those reported in the HERA trial. With a median follow-up of 32 months, 107 breast cancer relapses were recorded (overall frequency, 10.67 %), and lymph node involvement, estrogen receptor negativity, lymphoid infiltration, and vascular invasion were identified as independent prognostic factors for tumor recurrence, indicating that relapses were associated with advanced tumor stage. Analysis of site and frequency of distant metastases showed that bone metastases were significantly more frequent during or immediately after trastuzumab (18 months from the start of treatment) (35.89 vs. 14.28 %, p = 0.0240); no significant differences were observed in recurrences in the other recorded body sites, raising the possibility that the protection exerted by trastuzumab is lower in bone metastases.

In our first lesson together we used to ask to our students "what is the price of a life?". The answer was always "there is no price of a life". Although nice, it’s not true; unfortunately, the only costless man is a dead one. In the last few years there has been a heated debate about cost and benefit in oncology, focused in particular on breast cancer screening and the availability and affordability of new drugs. In our opinion, an affordable, ethically and politically correctbudget for healthcare is government issued as part of a social healthcare system. In this context, all governments should declare how much is affordable in relationship with the economic situation of the country and decide what drugs and treatments can be provided for free (as part of a life-long system of national taxation) and which cannot

Background: In the early 2000s, we identified treatment patterns of early breast cancer (EBC) in Italy (NORA study). To ascertain whether attitudes have changed, we conducted a similar study in 2008. Patients and methods: In this retrospective study (NEMESI), we recorded the clinical, tumour and treatment characteristics of 1.894 EBC patients in 63 Italian oncological centres in 2008, and compared the results with those of NORA, on 3.515 patients in 70 same/similar Italian institutions, in 2000–2003. Tumor stage, surgery and endocrine-responsiveness are not comparable because of different recruitment protocols, patients charactheristics and adjuvant treatment strategies are perfectly comparable as a reliable picture of adjuvant strategies in Italy. Results: There was no difference in age class distribution, menopausal status, ECOG performance status, tumor grade, ki67 and estrogen receptors content. HER2 status was simila but determined in 98% of cases in NEMESI vs 46.2% in NORA. The overall use of endocrine treatment (HT) increased from 80.3% in NORA to 83.5% in NEMESI (p = 0.005); the overall use of chemotherapy (CHT) decreased from 68.4% to 57.8% (p = 0.00001). HT alone increased from 31.6% to 42.2% (P = 0.00001) and CHT alone decreased from 18.8% to 16.2% (p = 0.017). The use of both treatments decreased from 49.2% to 41.6% (p = 0.00001). Trastuzumab was never given in NORA and in 15% of cases in NEMESI (85% of all HER2 positive cases). The choice for HT was tamoxifen for 5 years in 32.5% of cases in NEMESI and 86.6% in NORA (p = 0.000001), and aromatase inhibitors for 5 years in 55.2% vs 13.3% of cases, respectively (P = 0.000001). The “switch” from tamoxifen 2–3 years to aromatase inhibitors 2–3 years was planned in 10.1% of cases in NEMESI and actually done in 12.9% of cases in NORA (p = 0.001). The overall use of LHRH analogues was significantly higher in NEMESI vs NORA (26.7% vs 3.0%, p = 0.00001). CMF-like regimens decreased from 37.0% in NORA to 9.1% (p = 0.000001). Anthracycline-containing regimens decreased from 52.1% in NORA to 48.8% in NEMESI; p = 0.0001) in favour of of regimens containing anthracyclines and taxanes, either in combination or sequential (0.9% in NORA vs 38.4% in NEMESIS, p = 0.000001). The use of taxanes alone regimens remained low (3.5% vs 3.7%, ns). The overall use of anthracyclines and taxanes increased from 53.0% to 87.5% and from 4.3% to 42.1%, respectively (both p =0.00001). Conclusions: EBC treatment has changed significantly in 6 years. Adjuvant strategies are significantly different, with a great increase of aromatase inhibitors and LHRH analogues associated with tamoxifen; anthra-taxane combinations have also significantly increased. Financial Support by Sanofi Aventis Italy Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-04.

Objective: To assess the burden of renal cell carcinoma (RCC) in epidemiologic and economic terms. Methods: Retrospective, naturalistic longitudinal study on the occurrence, outcomes and cost of RCC using an administrative database. We selected residents of Friuli-Venezia-Giulia (FVG), a North-eastern Region of Italy, who had a RCC first hospital admission during the period 2000-2004, and we followed them up until: 30th June 2005, death or transfers. Direct medical costs were quantified in the perspective of FVG Regional Health Service. Results: We enrolled 1358 patients (63% male), the 18.8% presenting a metastatic-stage, leading to a crude incidence of 23/100.000 person-years. During the follow-up, 76% of the metastatic patients and 21% of the non-metastatic patients died. Total health care costs per-patient over the maximum of follow-up were 16,090€ for the localised stage group and 17,656€ in the metastatic-stage group. Discussion: RCC imposes a significant epidemiologic and economic burden to the healthcare-system and the society. © 2008 Elsevier Ltd. All rights reserved.

Background: This pilot study was conducted to evaluate the feasibility, activity, and safety of an induction dose of epoetin α in cancer patients with moderate or severe anemia who were receiving chemotherapy. Patients and methods: Thirty patients with solid tumors and hemoglobin (Hb) levels

Gene expression profiling tests are used in an attempt to determine the right treatment for the right person with early-stage breast cancer that may have spread to nearby lymph nodes but not to distant parts of the body. These new diagnostic approaches are designed to spare people who do not need additional treatment (adjuvant therapy) the side effects of unnecessary treatment, and allow people who may benefit from adjuvant therapy to receive it. In the present review we discuss in detail the major diagnostic tests available such as MammaPrint dx, Oncotype dx, PAM50, Mammostrat, IHC4, MapQuant DX, Theros-Breast Cancer Gene Expression Ratio Assay, and their potential clinical applications.

Background To evaluate the efficacy of tamoxifen as primary treatment in women aged over 70 years with operable breast cancer versus surgery followed by adjuvant tamoxifen. Patients and methods Patients randomly received tamoxifen alone (160 mg day 1, then 20 mg/day) for 5 years or surgery followed by tamoxifen (20 mg/day) for 5 years. Overall survival was the main study end point; secondary objectives included breast cancer survival and local control of the disease. Results Between 1987 and 1992, 239 patients were assigned to surgery plus tamoxifen and 235 to tamoxifen alone. Treatment arms were comparable for tumor size, clinical nodal status and performance status. At a median follow-up of 80 months 274 patients had died. No difference between groups had emerged in overall and breast cancer survival. There were 27 local progressions in the surgery plus tamoxifen group and 106 in the tamoxifen-alone group (P = 0.0001). In the surgery plus tamoxifen group, no difference in overall survival had emerged according to the extension of operation. Conclusions The long-term results of the study confirm the 3-year interim analysis already reported. Surgery (radical or minimal) followed by adjuvant tamoxifen does not modify overall and breast cancer survival as compared with tamoxifen alone in early breast cancer of older women. Because of the high rate of local progressions with tamoxifen alone, minimal surgery followed by tamoxifen appears to be the appropriate treatment in such patients. More extensive surgery is not useful. Tamoxifen alone is an adequate alternative treatment in very old or frail patients.

Breast cancer (BC) is the most frequent tumor worldwide. Triple-negative BCs are characterized by the negative estrogen and progesterone receptors and negative HER2, and represent 15% of all BCs. In this review, data on the use of taxanes in triple-negative BCs are analyzed, concluding they are effective in any clinical setting (neoadjuvant, adjuvant, and metastatic). Further, the role of nab-paclitaxel (formulation of albumin-bound paclitaxel) in these tumors is also evaluated. The available data show the clinical potential of nab-paclitaxel based combinations in terms of long-duration response, increased survival, and better quality of life of patients with triple-negative metastatic BC. The ongoing trials will give further information on the better management of this type of tumor.

Background To evaluate the efficacy and safety of the combination of cisplatin and vinorelbine in metastatic breast cancer. Patients and methods Cisplatin (80 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1 and 8) were administrated every 3 weeks to 52 patients (mean age 57 years; range 35–75 years) with metastatic breast cancer. Thirty-two patients were previously untreated for metastatic disease. Treatment was repeated for a maximum of six cycles. Results Objective responses were obtained in 27 patients (52.9%; complete response 9.8%). The response rate was similar in pretreated and untreated patients (50% and 54.7%, respectively; P = 0.7). ECOG performance status was good (grade 0 or 1) in 55.7% of patients at baseline assessment and in 90.3% at the end of treatment (P = 0.0001). Median time to progression was 8.5 months (8.5 months in first-line and 8.7 months in second-line patients). Median survival was 16.6 months (21.2 months in first-line and 16.1 months in second-line patients). Grade 3/4 toxicity included neutropenia (44% in first-line, 60% in second-line patients), nausea (17.3%), anemia (17%), asthenia (3.8%) and thrombocytopenia (1.9%). There were no cases of febrile neutropenia or treatment-related deaths. Alopecia did not develop in any of the patients. Conclusions Cisplatin plus vinorelbine is active and tolerable in metastatic breast cancer, in untreated and pretreated patients.

Adjuvant trastuzumab (AT) dramatically improved HER2-positive breast cancer prognosis. Relapsed disease after AT has different patterns and information is available from observational studies. In this Review Chemotherapy regimens combined to anti-HER2 blockade are discussed, focusing in particular the role of anthracyclines, taxanes and capecitabine. The use of trastuzumab beyond progression and the role of other anti-HER2 agents like lapatinib, pertuzumab and T-DM1 are explored, as also dual blockade and in trastuzumab resistant Patients. Metastatic "de novo" HER2 Luminal (co-expression of HER2 and hormone receptors) Patients are eligible for anastrozole and trastuzumab but if pretreated with trastuzumab they are also eligible for lapatinib and letrozole. In any case endocrine treatment plays a complementary role to chemotherapy which remains pivotal. The last topic explored is treatment options for patients with brain metastases where both trastuzumab given concurrent with radiotherapy or lapatinib and capecitabine appear as potentially active.

Previous results from our preclinical studies have shown that lonidamine (LND) can positively modulate the antiproliferative activity of doxorubicin (DOX) on breast cancer cell lines. To evaluate the effect of LND in a clinical setting, a multicenter randomized trial was carried out on patients with advanced breast cancer. From September 1991 to July 1993, 181 patients were enrolled in the trial and received an initial treatment of DOX at 75 mg/m2 for 3 cycles. The 137 patients who reached complete remission, partial remission, or stable disease were randomized to receive either DOX alone (75 mg/m2 day 1) (arm A) or DOX plus LND (600 mg orally/day) (arm B). The patients enrolled in the two arms were fairly homogeneous in terms of major clinical characteristics. Toxicity was similar in both arms except for myalgia: WHO gradeor=2 was observed in 57% of arm B patients. Overall response rate to DOX + LND was 50% and to DOX alone 38% in evaluable patients, and 48% vs 37% in all registered patients, as determined by an intention-to-treat analysis. The differences did not reach statistical significance. Conversely, in agreement with previous findings, we observed a significant difference in response rate in the subgroup of patients with liver metastases, regardless of the extent of hepatic involvement (DOX + LND 68% vs DOX 33%, p=0.03). This observation makes LND an important tool in association with anthracyclines in the treatment of this subgroup of patients.

Background Longer duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting. Methods We did this open-label randomised phase 3 trial at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. We enrolled patients with HER2-negative measurable metastatic breast cancer; each received three to six cycles of first-line bevacizumab (15 mg/kg) and docetaxel (75–100 mg/m2) every 3 weeks. Progression-free patients were randomly assigned with an interactive voice-response system by block (size four) randomisation (1:1) to receive either bevacizumab and capecitabine or bevacizumab only (bevacizumab 15 mg/kg on day 1; capecitabine 1000 mg/m2 twice per day on days 1–14, every 3 weeks) until progression, stratified by oestrogen receptor status (positive vs negative), visceral metastases (present vs absent), response status (stable disease vs response vs non-measurable), and lactate dehydrogenase concentration (≤1·5 vs >1·5 × upper limit of normal). Neither patients nor investigators were masked to allocation. The primary endpoint was progression-free survival (from randomisation) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00929240. Findings Between July 16, 2009, and March 7, 2011 (when enrolment was prematurely terminated), 284 patients received initial bevacizumab and docetaxel; 185 (65%) were randomly assigned (91 to bevacizumab and capecitabine versus 94 to bevacizumab only). Progression-free survival was significantly longer in the bevacizumab and capecitabine group than in the bevacizumab only group (median 11·9 months [95% CI 9·8–15·4] vs 4·3 months [3·9–6·8]; stratified hazard ratio 0·38 [95% CI 0·27–0·55]; two-sided log-rank p

Molecular tests predicting the outcome of breast cancer patients based on gene expression levels can be used to assist in making treatment decisions after consideration of conventional markers. In this study we identified a subset of 20 mRNA differentially regulated in breast cancer analyzing several publicly available array gene expression data using R/Bioconductor package. Using RTqPCR we evaluate 261 consecutive invasive breast cancer cases not selected for age, adjuvant treatment, nodal and estrogen receptor status from paraffin embedded sections. The biological samples dataset was split into a training (137 cases) and a validation set (124 cases). The gene signature was developed on the training set and a multivariate stepwise Cox analysis selected five genes independently associated with DFS: FGF18 (HR = 1.13, p = 0.05), BCL2 (HR = 0.57, p = 0.001), PRC1 (HR = 1.51, p = 0.001), MMP9 (HR = 1.11, p = 0.08), SERF1a (HR = 0.83, p = 0.007). These five genes were combined into a linear score (signature) weighted according to the coefficients of the Cox model, as: 0.125FGF18 − 0.560BCL2 + 0.409PRC1 + 0.104MMP9 − 0.188SERF1A (HR = 2.7, 95% CI = 1.9–4.0, p < 0.001). The signature was then evaluated on the validation set assessing the discrimination ability by a Kaplan Meier analysis, using the same cut offs classifying patients at low, intermediate or high risk of disease relapse as defined on the training set (p < 0.001). Our signature, after a further clinical validation, could be proposed as prognostic signature for disease free survival in breast cancer patients where the indication for adjuvant chemotherapy added to endocrine treatment is uncertain.

Background International treatment guidelines recommend administration of adjuvant chemotherapy in early breast cancer based on clinical, prognostic and predictive parameters. Methods An observational study (NEMESI) was conducted in 63 Italian oncology centres in patients with early breast cancer. Age, performance status, concomitant disease, menopausal status, histology, tumor dimension (pT), axillary lymph node status (pN), grading (G), estrogen and progesterone receptor (ER and PgR), proliferative index (ki67 or MIB-1), human epidermal growth factor receptor 2 (HER2) and type of adjuvant treatment were recorded. The primary objective of the study was to define parameters influencing the decision to prescribe adjuvant chemotherapy and the type of chemotherapy. Results Data for 1894 patients were available. 69.0% postmenopausal, 67.0% pT1, 22.3% pTmic/pT1a/pT1b, 61.0% pN0, 48.7% luminal A, 18.1% luminal B, 16.1% HER2 positive, 8.7% triple negative, 8.4% unknown. 57.8% received adjuvant chemotherapy: 38.1% of luminal A, 67.3% luminal B, 88.2% HER2-positive, 97.6% triple negative. Regimens administered: 9.1% CMF-like, 48.8% anthracyclines, 38.4% anthracyclines plus taxanes, 3.7% taxanes alone. Increasing pT/pN and, marginally, HER2-positive were associated with the prescription of anthracyclines plus taxanes. Suboptimal schedules (CMF-like or AC/EC or FEC-75) were prescribed in 37.3% receiving chemotherapy, even in HER2-positive and triple negative disease (36.5% and 34.0%, respectively). Conclusions This study showed an overprescription of adjuvant chemotherapy for early breast cancer, particularly referred to luminal A. pT, pN and, marginally, HER2 were the principal determinants for the choice of chemotherapy type. Suboptimal chemotherapy regimens were adopted in at least one third of HER2-positve and triple negative.

Background. Difficulties in coping with cancer, and the accompanying anxious and depressive symptoms, have been shown to affect the mood and the quality of life in breast cancer patients. 5-Hydroxytryptamine Transporter Gene-linked Polymorphic Region (5-HTTLPR) functional polymorphism of serotonin transporter has been shown to influence the adaptation to stressful life events. The aim of this prospective study was therefore to examine the association of 5-HTTLPR with the mental adaptation to cancer diagnosis and treatment. Patients and methods. Forty eight consecutive patients with early mammary carcinoma were evaluated at enrolment and at follow up after one and three months. The patients were characterized psychometrically using the Hospital Anxiety and Depression Scale (HADS) and the Mini-Mental Adjustment to Cancer Scale (Mini-MAC); 5-HTTLPR allelic variants were determined using PCR-based techniques. Results. In women with early breast cancer, the mental adaptation to the disease was associated with high scores of avoidance and anxious preoccupation of Mini-MAC, which decreased with time at follow up. Anxious preoccupation decreased with time less in patients with the S/S and S/L genetic variant of 5-HTTLPR as compared with the L/L carriers (p=0.023), indicating gene - environment interactions. Conclusions. These results indicate that the characterization of 5-HTTLPR allows the identification of breast cancer patients in greater risk of mental suffering, for which specific intervention may be focused; in case of drug therapy, they provide indications for the choice of most appropriate agent in a pharmacogenetic perspective.

Background. The present paper described the biological characteristics and clinical behavior of young women in the cohort NORA study Patients and Methods. From 2000–2002, patients ( 𝑁 > 3 5 0 0 ) were enrolled at 77 Italian hospitals. Women aged ≤ 5 0 years ( 𝑁 = 1 0 1 3 ) were stratified into age groups ( ≤ 3 5 , 36–40, 41–45, and 46–50 years). The relationship between age and patient characteristics, cancer presentation, and treatment was analyzed. Results. Younger women more frequently had tumors with ER/PgR-negative( 𝜒 2 = 7 . 0 7 ; 𝑃 = . 0 0 8 ), HER2 amplification ( 𝜒 2 = 5 . 7 6 ; 𝑃 = . 0 1 ), and high ( ≥ 1 0 % ) Ki67 labelling index ( 𝜒 2 = 9 . 5 3 ; 𝑃 = . 0 0 2 ). Positive nodal status, large tumors, and elevated Ki67 all associated with the choice for chemotherapy followed by endocrine therapy in hormone receptor-positive patients ( 𝑃 < . 0 0 0 1 ). At univariate analysis, ER-ve status, chemotherapy and age resulted as the only statistically significant variables ( H R = 2 . 0 2 , 𝑃 = . 0 0 4 , and > 4 0 versus ≤ 4 0 , 𝑃 < . 0 0 0 1 , resp.). At multivariate analysis, after adjustment for significant clinical and pathological factors, age remains a significant prognostic variable ( H R = 0 . 9 3 , 𝑃 = . 0 0 2 1 ). Conclusion. This cohort study suggests that age per sè is an important prognostic factor. The restricted role of early diagnosis and the aggressive behavior of cancer in this population make necessary the application of targeted medical strategies crucial.

5-HTTLPR genetic polymorphism of serotonin transporter (SERT) and stressful life events facilitate depression. The aim of this investigation was therefore to determine the correlations between SERT polymorphism and mental adjustment to cancer.Breast cancer patients early after surgery, and subjects with various advanced tumours were recruited, evaluated using the Mini Mental Adjustment to Cancer Scale and Hospital Anxiety and Depression Scale (HADS), and genotyped.In early breast cancer patients (n=53), hopelessness-helplessness (HH) and anxious preoccupation (AP) significantly correlated with depression and anxiety; avoidance (AV) correlated with anxiety. Advanced cancer patients (n=73) displayed similar correlations, and a negative correlation of HADS depression with fighting spirit (FS) and AV. The stratification for 5-HTTLPR showed that early breast cancer carriers of the L/L variant displayed a significant correlation between HH and depression.Among early breast cancer patients, a specific set, characterized by their 5-HTTLPR variant, display differential correlations between HH and depression, with possible implications for treatment options.

Background: The steroidal aromatase inhibitor exemestane has demonstrated efficacy for the treatment of breast cancer in the metastatic and adjuvant settings. Smaller trials have also reported efficacy in the neo-adjuvant setting. Patients and methods: This phase II, open-label, multicentre study examined the efficacy and safety of neo- adjuvant exemestane in women aged >70 years with operable, receptor-rich breast cancer. Consecutive eligible patients received exemestane 25 mg/day for 6 months before planned surgery. The primary end point was clinical response. Results: Overall, 117 patients were recruited (median age 80 years). The objective response rate in 112 assessable patients (85 with clinical and mammographic evaluation; 27 with clinical evaluation only) was 69.6% (two complete responses; 76 partial responses). In patients who responded, median tumour size reduced from 4.81 to 2.12 cm. Seventy-seven patients (68.7%) continued to surgery. Of the 40 patients eligible for breast-conserving surgery, 34 (85%) deemed unfit for this procedure at baseline. Exemestane-related adverse events were unremarkable except for grade 3 allergic skin reactions in two patients (1.8%). Conclusion: Neo-adjuvant exemestane given for 6 months appears to be effective for receptor-rich breast cancer in older patients. There may now be sufficient evidence to support the use of neo-adjuvant in this patient population. Key words: aromatase inhibitor, breast cancer, endocrine therapy, exemestane, neo-adjuvant

Background: The incidence of breast cancer increases with age, and the disease affects many older women; however, attitudes about prevention and treatment of breast cancer vary based on the patient's age. Older women have less access to clinical trials and fewer opportunities for treatment with innovative therapies. The National Oncological Research observatory on Adjuvant therapy in breast cancer (NORA) study was a cohort study designed to obtain information about adjuvant strategies for treatment of breast cancer after surgery, patterns of recurrence, and possible correlations between cancer-related events and biological factors. Patients and methods: This report describes patient characteristics, disease status, and local and systemic adjuvant treatments in a population of breast cancer patients aged ≥65 years. The NORA study consecutively enrolled >3500 patients from 2000 through 2002 at 77 Italian hospitals; of these, 1085 were aged ≥65 years. Data on patient characteristics, cancer presentation, and treatments were analyzed to identify possible relationships between these factors and age. Results: The findings indicate that age is significantly related to later diagnosis and different patterns of treatment. Choice of adjuvant systemic treatment was primarily related to hormone receptor status and tumor stage but was strongly influenced by the patient's age; there was a proportional relationship between endocrine treatment and increasing age. Cyclophosphamide, methotrexate, and 5-fluorouracil as well as anthracyclines were widely used, but the use of taxanes was limited to a very small percentage of patients. Conclusions: The findings of the NORA study may help to change attitudes that currently exclude a significant proportion of breast cancer patients from secondary prevention policies, more active treatment strategies, and clinical research trials based on age.

BACKGROUND The superiority of new generation aromatase inhibitors over tamoxifen in the adjuvant treatment of early breast carcinoma has emerged from several randomized trials. However, until now not all previous studies have shown a mortality benefit. METHODS A pooled analysis of 2 prospective multicentric trials, sharing the same study design and nearly identical inclusion criteria, was performed. In both trials, women treated previously with tamoxifen for 2 or 3 years were randomly assigned to either continuing tamoxifen for an additional 2 or 3 years or to having their treatment switched to aminoglutethimide or anastrozole for a comparable time period. Mortality was analyzed according to allocated treatment and other patient and tumor variables. RESULTS In all, 828 postmenopausal women, mostly with estrogen receptor (ER)-positive and node-positive tumors who had been monitored for a median time of 78 months (range, 6–141 months) were analyzed. Of these women, 415 were randomly selected to continue tamoxifen and 413 switched to aminoglutethimide or anastrozole. All-cause mortality and breast cancer-specific mortality were significantly improved by the switch: all-cause mortality: hazard ratio (HR) = 0.61 (0.42–0.88) P = .007; breast cancer-specific mortality: HR = 0.61 (0.39–0.94) P = .025. No increase was recorded in breast cancer-unrelated mortality in women after switching. Multivariate analysis showed that patient age, tumor size, allocated treatment, and nodal status, in that order, were independent mortality predictors. CONCLUSIONS Switching to an aromatase inhibitor after 2 or 3 years of tamoxifen therapy significantly improves survival compared with continuing 2 or 3 years of additional tamoxifen treatment. Cancer 2007. © 2007 American Cancer Society.

Breast cancer (BC) is the most frequent tumor worldwide. Triple-negative BCs are characterized by the negative estrogen and progesterone receptors and negative HER2, and represent 15% of all BCs. In this review, data on the use of taxanes in triple-negative BCs are analyzed, concluding they are effective in any clinical setting (neoadjuvant, adjuvant, and metastatic). Further, the role of nab-paclitaxel (formulation of albumin-bound paclitaxel) in these tumors is also evaluated. The available data show the clinical potential of nab-paclitaxel based combinations in terms of long-duration response, increased survival, and better quality of life of patients with triple-negative metastatic BC. The ongoing trials will give further information on the better management of this type of tumor.

Background: Until regulatory withdrawal of BEV–DOC in 2011, the combination was considered a valid first-line option for HER2-negative mBC based on results of a phase III trial [Miles, JCO 2010]. Progression-free survival (PFS) and response rate (RR) with first-line DOC (max 9 cycles) were significantly improved by adding BEV continued until disease progression (PD). The open-label randomised phase III IMELDA trial tested whether adding CAP to maintenance BEV continued until PD after initial BEV–DOC improves PFS. Methods: Patients (pts) with HER2-negative measurable mBC, ECOG PS Results: Between Jun 2009 and Mar 2011 (when enrolment was prematurely terminated) 284 pts were enrolled and treated; 185 (65%) were randomised. BEV (N = 94) BEV–CAP (N = 91) Median age, years (range) 54 (24–77) 49 (24–80) Triple-negative mBC, n (%) 21 (22) 25 (27) Visceral metastases, n (%)a 65 (69) 62 (68) ≥3 metastatic organs, n (%) 54 (57) 43 (47) Median duration of follow-up, months (range)b 30.4 (1.3–43.3) 31.6 (0.8–41.6) PFSb Events, n (%) 83 (88) 69 (76) HRc (95% CI) 0.38 (0.27–0.55) Log-rank p Median PFS, months 4.3 11.9 OSb Events, n (%) 53 (56) 33 (36) HRc (95% CI) 0.43 (0.26–0.69) Log-rank p Median OS, months 23.7 39.0 1-year OS rate, % (95% CI) 72 (61–80) 90 (82–95) Grade ≥3 AEsb, n (%) All 28 (30) 47 (52) Hand-foot syndrome 0 30 (33) Hypertension 3 (3) 8 (9) Proteinuria 4 (4) 4 (4) Gastroenteritis 3 (3) 0 aAt randomisation. bFrom randomisation. cStratified. Conclusions: Adding CAP to maintenance BEV provided statistically significant and clinically meaningful improvements in PFS (HR 0.38, p

The Adjuvant Chemo-hormone Therapy Breast Cancer Study Group (GROCTA) was formed exactly 15 years ago with its main purpose to promote co-operation among surgeons, clinical oncologists, clinical pathologists and basic researchers in the field of adjuvant therapy of breast cancer. This chapter will review the main findings from the trials that have been performed since then.

Summary Background: Aminoglutethimide was the first aromatase inhibitor to be used successfully in breast cancer patients. However, this drug also inhibits mineralcorticoid and glucocorticoid synthesis, making co-medication with corticosteroids necessary, and it is often poorly tolerated. The primary objective of this trial was to evaluate the clinical efficacy and tolerability of vorozole, a new non-steroidal oral aromatase inhibitor, in postmenopausal breast cancer patients. The secondary objective was to evaluate the pharmacodynamic activity of the drug. Subjects and methods: Thirty-four postmenopausal patients previously treated with tamoxifen in the adjuvant setting and/ or for advanced disease were treated with vorozole, 2.5 mg once daily. Patients were monitored with respect to treatment efficacy and safety. Hormonal evaluations were performed at baseline and during the course of treatment in order to evaluate the pharmacodynamic efficacy and safety of vorozole. Results: According to UICC criteria, there were seven responders, one complete and six partial, for an overall response rate of 21% (95% confidence interval (CI) 9%-38%). The median duration of response was 9.6 months (95% CI 4.60), the median time to progression for the entire group was 4.7 months (95% CI 2.9-6.6) and the median survival time was 29.7 months (95% CI 19.1-0). Tolerability was excellent to good in 97% of the patients. Oestradiol and oestrone levels were suppressed to the limit of detection of the assays used. No effect was observed on the other endocrine parameters. Conclusions: Our results suggest that vorozole is an effective and safe drug for the treatment of advanced postmenopausal breast cancer following tamoxifen failure.

Background Combining BEV with 1st-line chemotherapy (CT) significantly improved progression-free survival (PFS) and response rate (RR) vs CT alone in 3 randomised phase III trials (E2100, AVADO, RIBBON-1). In AVADO, DOC 100 mg/m2 was given for a median of 5.5 months (maximum 9 cycles), after which BEV 15 mg/kg was continued as a single agent. IMELDA was designed in the context of BEV–DOC approval to determine whether efficacy is improved by adding CAP to BEV maintenance therapy after discontinuing DOC. Methods Eligible pts had HER2-negative measurable mBC, ECOG PS 0/1, had received no prior CT for mBC and were eligible for taxane-based CT. After initial 1st-line therapy with 3–6 cycles of BEV–DOC, pts free of progressive disease (PD) were randomised to BEV alone or BEV–CAP (BEV 15 mg/kg q3w; CAP 1000 mg/m2 bid d1–14 q3w) until PD. The primary endpoint is PFS; secondary endpoints include safety, RR and overall survival. Results Between June 2009 and March 2011 (when enrolment to the study was terminated prematurely after withdrawal of BEV–DOC regulatory approval), 284 pts began BEV–DOC. Median age was 52 y (range 24–80), 17% were aged ≥65 y, 53% had ECOG PS 0 and 30% had triple-negative mBC. Maintenance therapy was administered in 183 pts (64%). Key safety results are below. Table: 356P Pts, n (%) Initial BEV–DOC phase (N = 284) Maintenance BEV ± CAP phase (N = 183) Discontinued therapy 99 (35) 134 (73) PD AE Other/unknown 41 (14) 31 (11) 27 (10) 101 (55) 15 (8) 18 (10) Grade ≥3 AEs, n (%) 138 (49) 63 (34) Neutropenia Febrile neutropenia Diarrhoea Mucosal inflammation Asthenia Hand-foot syndrome 44 (15) 30 (11) 3 (1) 9 (3) 6 (2) 6 (2) 2 (1) 0 2 (1) 2 (1) 1 (1) 25 (14) Grade ≥3 BEV AEs of special interest Hypertension Proteinuria Bleeding Arterial TE Venous TE Wound-healing complication GI perforation 5 (2) 1 ( 9 (5) 3 (2) 2 (1) 2 (1) 2 (1) 0 0 AE = adverse event; TE = thromboembolic event Conclusions Most grade ≥3 AEs during BEV–DOC were typical DOC-related AEs. Apart from hypertension and proteinuria, BEV AEs occurred predominantly in early cycles, suggesting that long-term BEV is well tolerated. Efficacy results are expected in 2013. Disclosure J. Gligorov: JG has sat on Advisory Boards and received speaker honoraria from Roche. J. Bines: JB has served on Advisory Boards for Roche. P.A. Cortes: PC has served on Advisory Boards for Roche, BMS and Sanofi-Aventis. U. Freudensprung: UF works as a Contractor for F Hoffmann-La Roche Ltd. G. Mustacchi: GM has acted as a Consultant for Roche, Agendia, Celgene, Novartis, Merck, Glaxo, Eisai. All other authors have declared no conflicts of interest.

Abstract #6036 Background Recent meta-analyses on the interaction between HER2 status and efficacy of adjuvant anthracyclines suggest that patients with HER2 negative tumors derive no added benefits from anthracycline administration. Since topoisomerase IIa is a known target of the anthracyclines, it's expression has been proposed as a more accurate and biologically related predictive factor of anthracycline responsiveness. Additional evidence suggests that TOP2A gene amplification occurs only in HER2 amplified tumors, whereas it is rare among HER2 negative patients. The aim of the present study was to address the regulation of TOP2A expression, at the level of mRNA, in HER2 negative disease. Methods We used two previously published Affymetrix gene expression datasets: GSE 1456 (159 patients) and GSE 2494 (249 patients). Microarray data preprocessing was carried out using Bioconductor software (gcrma procedure). Expression of HER2 and TOP2A were evaluated extracting the Affy probes “210930_s_at” and ”216836_s_at” (for HER2) and the Affy probe "201292_at” (for TOP2A); overexpressed samples were defined those with expression values over the 75th percentile of the whole sample of patients. The distribution of TOP2A mRNA overexpression according to molecular subtype was evaluated in the GSE 1456 dataset. Results: Overall, 348 out of 408 patients were HER2 negative. TOP2A mRNA overexpression was detected in 65 out of 348 HER2 negative tumors (18,7%). In the GSE 1456 dataset TOP2A mRNA overexpression was detected in 48% of basal like tumors, 42% of Luminal B and 21% of Luminal A. Among HER2 positive tumors, TOP2A mRNA overexpression was detected in 40%. mRNA TOP2A overexpression was present in 27% of the ERBB2 and in 80% of the Luminal B (HER2 positive) molecular subtype. Conclusions: TOP2A overexpression, at the level of mRNA, is present in the HER2 negative population and it is distributed in all molecular subtypes, especially among the Basal like and Luminal B subtypes. We are currently evaluating the interaction between TOP2A mRNA expression and efficacy of adjuvant anthracyclines in a retrospective analysis of data including 200 early breast cancer patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6036.