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Background We recently conducted a de-escalation trial of low-dose tamoxifen 5 mg/day ("babytam", BT) or placebo given for 3 years in 500 women with noninvasive breast cancer. Women on babytam had a 52% reduction of recurrence (invasive breast cancer or DCIS) after 5 years. Since menopausal symptoms are major reasons for treatment withdrawal during tamoxifen preventive therapy, we compared and analyzed the patient-reported outcomes (PROs) with the physician-reported adverse events and studied their association with recurrence. Methods Menopausal symptoms recorded by physicians using the Common Terminology Criteria (CTCAEs) were compared with a patient self-reported validated questionnaire reviewed by a research nurse at baseline and every 6 months up to 36 months. Hot flashes (HF), the main outcome measure, were detected through a self-report 7-day diary for frequency and intensity. Treatment adherence and efficacy were assessed by the Kaplan-Meier curves and the Cox model. Results The number of HF events at 12, 24, and 36 months for PROs versus CTCAEs was 246 versus 12, 238 versus 8, and 210 versus 4, respectively. The majority of events were grade 1. There was no difference in PROs between babytam and placebo except for HF daily frequency, which increased by 1.5 events (95% CI, 1.1-1.8) on placebo to 2.1 on babytam (95% CI, 1.7-2.5, p = 0.05). The presence of HF at baseline was a favorable prognostic factor for recurrence and a predictive factor for response to babytam. Adherence was similar between babytam and placebo. Conclusions The use of PROs is effective for identifying frequent mild grade menopausal symptoms which are underestimated by physicians but important prognostic and predictive factors. Research nurse can use these results as a tool to reassure patients about symptoms, improve adherence to treatment, and limit dropouts.

Purpose Initial findings in patients with cancer suggest a lower seroconversion to SARS-COV-2 vaccination possibly related to myelo-immunosuppressive therapies. We conducted a prospective study to assess factors predicting poor seroconversion and adverse events following immunization (AEFI) to the BNT162b2 vaccine in patients on active treatment. Patients and methods Cancer patients candidate to two doses of BNT162b2 SARS-COV-2 vaccination were enrolled. Patients on active surveillance served as controls. The primary endpoint was poor seroconversion (anti S1/S2 IgG

Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.

Background: mRNA-based vaccines have shown 95% protection from SARS-COV-2 disease in healthy populations. Initial findings in cancer patients suggest a lower seroconversion and greater toxicity possibly related to myelo-immunosuppressive therapies. Methods: We conducted a prospective study to assess factors predicting poor seroconversion and adverse events following immunization (AEFI) to the BNT162b2 vaccine in cancer patients on active treatment. The primary endpoint was poor seroconversion (IgG 6 months on active surveillance served as controls. Multivariable logistic model and mixed effect models for repeated measures investigated independent factors associated with poor seroconversion and AEFI, adjusting for confounders. Findings: Between March 15 and July 21, 2021, 320 subjects were recruited and 291 were assessable for IgG response. The lack of seroconversion at 42 days was 1.6% (95% CI, 0.4-8.7) on active surveillance, 13.9% (8.2-21.6) on chemotherapy, 11.4% (5.1-21.3) on hormone therapy, 21.7% (7.5-43.7) on biological therapy and 4.8% (0.12-23.8) on immunotherapy. Compared to controls, risk of no IgG response was greater for chemotherapy (P=0.023), biological therapy (0.009) and hormonotherapy (P=0.052). Older age and advanced stage also predicted poor seroconversion. Overall, 43 patients (14.8%) complained of AEFI, mostly of mild grade. Risk of AEFI was greater in females (P=0.001) and younger patients (P=0.009). There was a trend to a D-dimer increase in IgG responders (p=0.01). Interpretation: Except for immunotherapy, chemotherapy, biological therapy and hormone therapy as well as increasing age and advanced stage predict poor seroconversion after two doses of BNT162b2 in up to 20% of patients, indicating the need for a booster dose and long-term serological testing in vaccine non-responders. AEFI occur much more frequently in women and younger subjects who may benefit from preventive medications. Trial Registration: ClinicalTrials.gov Identifier: NCT04932863 Funding: Ospedali Galliera, Associazione WeCare, Lions-Club Genova Sant’Agata. Italian Health Ministry, Ricerca Corrente and 5×1,000 (IEO). Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Lazzaro Spallanzani National Institute for Infectious Diseases, Rome, Italy, and the local Ethical Committee.

The challenge of effective management of ductal carcinoma in situ (DCIS) and other pre-malignant disorders of the breast is to select patients who will not progress to invasive carcinoma from those at the highest risk who require radiotherapy and/or endocrine therapy to minimize the risk of a subsequent invasive recurrence. Although IBIS-II and NSABP-B35 DCIS phase III trials proved that tamoxifen 20 mg/day and anastrozole reduce the risk of ipsilateral and contralateral events, the toxicities of both drugs have hampered the drug uptake by high-risk women. We recently reported results of a 3-year placebo-controlled trial of low-dose (5 mg/d) tamoxifen in 500 women with intraepithelial neoplasia (70% DCIS). At a median follow-up of 5 years, women randomly assigned to low-dose tamoxifen had half the number of subsequent diagnoses of DCIS or invasive cancer compared with those randomly assigned to placebo but no increase in thromboembolic events or endometrial cancers. The 5-year number needed to treat was 22 (95% CI, 20-27). Our attention is now focused on prognostic and predictive markers to identify patients who can derive the greatest benefits from low dose tamoxifen, such as for instance the expression of 23 genes involved in cell cycle progression (CCP). In conclusion, we endorse an active treatment of DCIS as the standard of care.

Author(s): Guerrieri-Gonzaga, Aliana; Serrano, Davide; Thomas, Parjhitham; Crew, Katherine D; Kumar, Nagi B; Gandini, Sara; Vornik, Lana A; Lee, Jack; Cagnacci, Sara; Vicini, Elisa; Accornero, Chiara A; D'Amico, Mauro; Guasone, Flavio; Spinaci, Stefano; Webber, Tania B; Brown, Powel H; Szabo, Eva; Heckman-Stoddard, Brandy; Bonanni, Bernardo | Abstract: IntroductionAromatase inhibitors are effective in lowering breast cancer incidence among postmenopausal women, but adverse events represent a barrier to their acceptability and adherence as a preventive treatment. This study aims to assess whether lowering exemestane schedule may retain biological activity while improving tolerability in breast cancer patients.Methods/designWe are conducting a, pre-surgical, non-inferiority phase IIb study in postmenopausal women with newly diagnosed estrogen receptor-positive breast cancer. Participants are randomized to receive either exemestane 25nmg/day or 25nmg/three times-week or once a week for 4 to 6nweeks prior to surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery comparing the three arms. Sample size of 180 women was calculated assuming a 6% non-inferiority of the percent change of estradiol in the lower dose arms compared with the 80% decrease predicted in the full dose arm, with 80% power and using a one-sided 5% significance level and a two-sample t-test. Main secondary outcomes are: safety; change in Ki-67 in cancer and adjacent pre-cancer tissue, circulating sex hormones, adipokines, lipid profile, insulin and glucose changes, in correlation with drug and metabolites concentrations.Results and discussionThe present paper is focused on methodology and operational aspects of the study. A total of 180 participants have ben enrolled. The trial is still blinded, and the analyses are ongoing. Despite the short term duration, results may have relevant implications for clinical management of women at increased risk of developing a ER positive breast cancer.

1553 Background: Low dose tamoxifen (T, 5 mg/d) given for 3 years halved recurrence in 500 women with non-invasive disease (DeCensi et al. JCO 2019). Retrospective studies with 20 mg/d have shown an association between low levels of endoxifen (9-16 nM) or Z-4OHtam (3.26 nM) and recurrence, but recent prospective studies have not confirmed these findings. We measured CYP2D6 genotype and 8 metabolite levels to determine their associations with adverse events, tumor biomarkers (IGF-I, SHBG, C-reactive protein, CRP) and breast cancer recurrence. Methods: CYP2D6 genotyping was performed in the T arm (n = 183) as previously described (Johansson H et al. BCRT 2016). T and metabolites were measured at 1 (n = 169) and 3 y (n = 152) as previously described (Helland T et al. BCR 2017). We tested linear relationships between metabolite levels and biomarkers, adjusting for age, BMI, treatment compliance and baseline biomarker levels. Cumulative incidence of recurrence according to endoxifen levels was calculated by the Cox model. Results: Endoxifen concentrations were associated to CYP2D6 metabolizer status (p < 0.001). Median (IQR) endoxifen levels were 8.4 (5.2-11.3) and 8.8 (5.8-11.5) at 1 and 3 y, with only 42% and 47% of subjects reaching 9 nM. Median endoxifen levels were related to pill count (5.5, 7.1 and 9.0 nM/L for medication possession rate < 83.3%, 83.4-99.9%, 100%, respectively). There was no difference in metabolite levels and menopausal symptoms. There was an inverse relationship between endoxifen and endometrial thickness at 3 y (p = 0.04), and between endoxifen or tamoxifen levels and IGF-I levels at 3 y (p = 0.001). T levels were positively associated with SHBG levels in postmenopausal women (p-interaction = 0.04). Endoxifen, T and 4OHtam decreased CRP, with a greater effect in premenopausal women (p-interaction = 0.02). An increase in CRP after 3 years was associated with a HR of 4.37 (95% CI, 1.14-16.73, P = 0.03) of recurrence compared to women with no increase of CRP. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3-11.4) in patients who recurred vs 7.5 (5.1-10.2) in those who did not recur (p = 0.6), although this comparison was underpowered. Conclusions: T levels themselves may contribute to clinical activity by decreasing IGF-I and increasing SHBG. Elevated CRP is a predictive factor for recurrence which is down-regulated by T and metabolites. Endoxifen is below 9 nM in the majority of subjects treated with 5 mg/day, although this threshold was obtained in studies up to 20 years. Clinical trial information: NCT01357772.

Metastatic breast cancer is a heterogeneous disease and hence it is desirable to have a variety of treatment options to meet different treatment aims in individual patients. Anthracyclines are extremely effective single agents in the treatment of metastatic breast cancer, and combination therapy with anthracycline-containing regimens significantly improves response rates and progression-free survival, compared with non-anthracycline regimens. The addition of taxanes further increases the efficacy of anthracyclines as first-line therapy. Combination therapy with trastuzumab, taxanes and anthracyclines has been shown to produce significant improvements in survival, compared with taxanes and anthracyclines alone; however, trastuzumab is associated with significant cardiotoxicity, and augments the cardiotoxicity associated with anthracycline-based regimens. New anthracycline formulations such as non-pegylated liposomal doxorubicin (NPLD) have an important role in the treatment of metastatic breast cancer. NPLD is as effective as conventional doxorubicin formulations, and can be combined with trastuzumab with acceptable toxicity. However, a number of questions remain as to how anthracycline therapy can be optimised. Ultimately, the choice of regimen will require a balance between efficacy and the impact of treatment on the patient's quality of life.

Purpose: (Neo)adjuvant treatment with chemotherapy plus trastuzumab reduces recurrence and death risk in HER2-positive (HER2+) breast cancer. Randomized trials assessed HER2 dual block by adding lapatinib to trastuzumab and chemotherapy in the neoadjuvant setting using pathologic complete response (pCR) as the outcome measure. We conducted a meta-analysis of randomized trials testing neoadjuvant dual block with lapatinib and trastuzumab versus trastuzumab alone in HER2+ breast cancer. Experimental Design: Trials were identified by Medline (PubMed), ISI Web of Science (Science Citation Index Expanded), Embase, Cochrane library, and reference lists of published studies, review articles, editorials, and by hand-searched reports from major cancer meeting reports. Results: Six randomized trials including 1,155 patients were identified, of whom 483 (41.8%) were hormone receptor–negative, 672 (58.2%) hormone receptor–positive, 534 (46.2%) received taxanes alone, and 621 (53.8%) anthracyclines plus taxanes or the docetaxel–carboplatin regimen. Overall, the dual block was associated with a significant 13% absolute improvement in pCR rate compared with single-agent trastuzumab (summary risk difference, SRD 0.13; 95% CI, 0.08–0.19). The activity was greater in hormone receptor–negative patients who received chemotherapy with taxanes alone (SRD 0.25; 95% CI, 0.13–0.37), compared to hormone receptor–positive or hormone receptor–negative disease treated with anthracyclines plus taxanes or the docetaxel–carboplatin regimen (SRD 0.09; 95% CI, 0.02–0.15; Pinteraction = 0.05). Conclusions: On the basis of ΔpCR data, the dual block with trastuzumab and lapatinib plus chemotherapy is a very active treatment only in HER2+ and hormone receptor–negative breast cancer treated with taxane monochemotherapy. Clin Cancer Res; 22(18); 4594–603. ©2016 AACR.

BACKGROUND: In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival-a secondary endpoint-and report treatment efficacy in RAS and BRAF molecular subgroups. METHODS: TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m2 intravenous infusion of irinotecan for 60 min followed by a 200 mg/m2 intravenous infusion of leucovorin for 120 min, a 400 mg/m2 intravenous bolus of fluorouracil, and a 2400 mg/m2 continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m2 intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m2 intravenous infusion of oxaliplatin given concurrently with 200 mg/m2 leucovorin for 120 min, followed by a 3200 mg/m2 continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014. The trial is registered with ClinicalTrials.gov, number NCT00719797. FINDINGS: Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7-55·6), median overall survival was 29·8 months (95% CI 26·0-34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5-29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65-0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7-42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4-28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11-1·99) and 13·4 months (8·2-24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75-4·46; likelihood-ratio test p

Background The addition of bevacizumab to standard chemotherapy prolongs progression free survival in the first line treatment of epithelial ovarian cancer (EOC), but its cost/effectiveness is debated. We assessed the safety and activity of a lower dose of bevacizumab in pretreated advanced stage EOC. Methods We treated 15 patients, mostly with platinum resistant EOC, who had received a median of four prior cytotoxic regimens, with bevacizumab 5–7.5 mg/kg q21 days in combination with either carboplatin (n = 8), oral cyclofosfamide (n = 5) or weekly paclitaxel (n = 2). Bevacizumab was administered until disease progression. Tumor response was assessed by CA125 and fusion 18 F-FDG PET/contrast enhanced CT. Results The median number of bevacizumab cycles was 21 (range 3–59). The median baseline CA125 was 272 U/ml and decreased to 15.2 U/ml at nadir. Tumor response was 4 complete response (CR) (26.7%) and 7 partial response (PR) (46.7%) by chemotherapy (CT), with an overall response rate of 73.4% (95% CI, 51.0 – 95.8) according to Response Evaluation Criteria In Solid Tumors (RECIST), and 6 CR (40%) and 4 PR (26.7%) by PET, for an overall metabolic response rate of 67% (95%CI, 42.8 – 90.6) according to PET Response Criteria in Solid Tumors (PERCIST). Median progression free survival (PFS) was 21 months and median overall survival (OS) was 24 months. Grade 3 adverse events related to bevacizumab were hypertension (n = 2), proteinuria (n = 1) and epistaxis (n = 5). Treatment was delayed in five patients for nasal bleeding or uncontrolled hypertension. Conclusions Low-dose bevacizumab and chemotherapy was well tolerated and active in a heavily pretreated population of advanced EOC. Further studies should assess the activity of low dose bevacizumab in EOC.

The treatment of metastatic breast cancer is mainly palliative, but optimal management might result in survival improvement as well. For this reason, many trials have attempted to optimize the therapeutic approach in this disease setting. Among the possible options, chemotherapy represents the backbone of the treatment and survival improvements that have been shown by the use of modern chemotherapeutic agents. Whereas the type of chemotherapy is generally dictated by patient characteristics and those of their disease, substantial controversy still remains on how long chemotherapy should be administered after disease control is achieved. In this review, we have analysed all available evidence on the duration of first-line chemotherapy in advanced breast cancer.

3532 Background: Adverse drug reactions (ADRs) caused by fluoropyrimidines depend, at least in part, from DPD deficiency resulting from the loss-of-function mutations c.1905+1G > A and c.2846A > T....

Aim: Achieving an initial relevant and rapid tumor shrinkage may be an important objective in mCRC pts. The triplet FOLFOXIRI is a highly active regimen. The aim of the present analysis is to explore the impact of FOLFOXIRI plus BV or anti-EGFRs in determining tumor response in RAS and BRAF wt pts treated in clinical trials by the GONO group. Methods: 37 and 64 RAS and BRAF wt pts treated with FOLFOXIRI plus panitumumab and FOLFOXIRI plus cetuximab in TRIP and MACBETH trial respectively and evaluable for response were included in the anti-EGFR group (N = 101); 62 RAS and BRAF wt pts treated with FOLFOXIRI plus BV in the TRIBE trial and evaluable for response were included in the BV group. Best response according to RECIST, early tumor shrinkage (ETS) and deepness of response (DoR) in the two groups were analysed. Pts achieving a >20% reduction in the sum of longest diameters of RECIST target lesions at week 8 compared to baseline were defined as early responders. Since pts in TRIBE and TRIP trials received up to 12 cycles of treatment, while pts in MACBETH trial received up to 8 cycles, DoR was defined as the relative change in the sum of longest diameters of RECIST target lesions at the nadir within the first 8 cycles of treatment, compared to baseline. Results: 83 pts (82%) in the anti-EGFR group and 44 pts (71%) in the BV group achieved a RECIST response (p = 0.120). Early response was reported in 70 out of 95 evaluable pts (74%) and in 36 out of 58 evaluable pts (62%) in the anti-EGFR and in the BV group, respectively (p = 0.150). The median ETS in the anti-EGFR group was significantly higher than in the BV group (40.8% vs 26.4%, p = 0.003). A significantly better DoR was achieved in the anti-EGFR group as compared to the BV group (median DoR: 48.6% vs 37.8%, p = 0.005). Conclusions: Both FOLFOXIRI plus BV and FOLFOXIRI plus an anti-EGFR allow to achieve impressive results in terms of RECIST response rate (71% and 82% respectively) in the first-line treatment of RAS and BRAF wt mCRC pts. According to the present exploratory analysis the use of anti-EGFRs may be associated with an higher extent of ETS and a better DoR. Disclosure: A. Falcone: Consultant, honoraria and research funding: Roche, Merck, Amgen Consultant and honoraria: Sanofi Aventis, Bayer, Celgene. All other authors have declared no conflicts of interest.

3519 Background: Phase III TRIBE trial demonstrated that first-line FOLFOXIRI plus bev improved PFS and RECIST response and, at adjusted analyses, OS as compared to FOLFIRI plus bev. The prognostic...

521 Background: The TRIBE trial demonstrated that first-line FOLFOXIRI plus bevacizumab (bev) improves PFS, response rate (RECIST), and OS in comparison to FOLFIRI plus bev (ASCO Annual Meeting 2013). Recent experiences evidenced that both ETS and DoR may implement the assessment of response and correlate with survival in metastatic colorectal cancer (mCRC). Methods: ETS was defined as the relative change in the sum of longest diameters of RECIST target lesions at week 8 compared to baseline. A 20% decrease was adopted as cut-off value to discriminate early responders and non-responders. DoR was defined as the relative change in the sum of longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline. The median value was used as cut-off. Results: Out of 508 randomized patients, 443 and 484 patients were evaluable for ETS and DoR, respectively. Early responders achieved longer PFS (median PFS: 12.7 vs 10.0 mos, HR: 0.66 [0.52-0.79], p

3577 Background: Sequential combinations of FU and IRI or OXA are currently used as 1st and 2nd line therapy for advanced CRC. Multiple trials are also investigating the concomitant use of the thre...

566 Background: Obesity is an acknowledged risk factor for the development of breast cancer and an adverse prognostic factor in those women who have already been diagnosed with breast cancer. Howev...

3770 Background: A combination of OXA and FU is frequently used as 1st or 2nd line therapy for advanced CRC. Anyway, the optimal schedule for this drugs has not been defined. Methods: To identify the MTD of weekly OXA (60–70-80–90 mg/m2 d1,8,15) in combination with a fixed dose of FU CI (200mg/m2/die d1–21), at least 3 pts were treated at each dose level. Once identified the OXA recommended dose level (RDL), Leucovorin (LV; 20 mg/m2 d1,8,15) was added to the combination. Results: Since April 2000, 39 pts with progressive advanced CRC previously treated with fluoropyrimidines and Irinotecan (IRI) were accrued (males/females: 29/10; median age 67; ECOG PS 0/1/2: 10/24/5). Considering the first 2 cycles of treatment (2 months) no grade III-IV toxicity was observed up to 90 mg/m2/week of OXA (dose level 4). 3/6 pts treated at dose level 4 required a major change in the treatment program due to a dose limiting toxicity (DLT; asthenia, weight loss and unbearable peripheral sensory neuropathy) and OXA 90 mg/m2 +...