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1046 Background: Trastuzumab Deruxtecan (TDXd), a novel antibody-drug conjugate (ADC) that combines trastuzumab with a topoisomerase I inhibitor, has recently demonstrated high efficacy in HER2-overexpressing breast cancer after trastuzumab failure. Resistance to TDM1 have recently suggested to be dynamically associated with distinct circulating ctDNA species ( Allegretti et al, Mol Cancer 2021). A prospective study aiming to evaluate the feasibility of Liquid Biobsy (LB) in monitoring ctDNA in pts receiving TDXd in the national Expanded Access Program was conducted. Methods: In this prospective study, LB for ctDNA analysis (evaluating ‘ per pt’ ctDNA species and Variant Allelic Frequencies, VAF) was performed using 52-gene targeted NGS panel, in patients who progressed after two or more prior anti-HER2-based regimens and candidates to TDXd (3-weekly 5.4 mg/kg). This preliminary analysis reports data referring to Time-0 (T0) and T6 (cycle 6) assays. Results: From April 2021, LBs were collected for 14 pts and to date 8 are evaluable for LB. Median pts’ age was 59 yrs (range 38-72) and median number of previous anti-HER2 lines was 6 (2-11); 4 pts had Pertuzumab/Trastuzumab plus taxane as first-line and all pts received TDM-1. Median cycles of TDXd administered was 7.5 (1-10). At T0, 5/8 pts had at least one detectable ctDNA specie, and the remaining 3 developed at least one ctDNA at T6. ctDNA species and VAFs ranged from 1 to 5, and A0.1% to 68.94%, respectively. Decreases and increases were observed simultaneously in the same pt. The former varied from marginal to drastic, whereas the latter were invariably below 0.5% in VAFs. ctDNA monitoring was possible in 8/8 pts and at T6 ctDNA progression was detectable in 5/8 pts. Two pts displayed multiple HER2 copy number variations. Conclusions: The early results of this study suggest that considerable ctDNA burden, marked clonal complexity, and variable clonal response to TDXd can be found in pretreated HER2 positive patients, who progressed after antiHER2 therapies. Although the very small sample, this complex tumor evolution is surprising in light of the bystander payload effect of TDXd.

Purpose CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. Patients and Methods Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m2 per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m2 per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). Results The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, −1.6%; 95% CI, −2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. Conclusion CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.

e12507 Background: T-DM1 is widely used in HER2 positive metastatic breast cancer (MBC) patients (pts), often for many cycles until progression. However, little is known about its long term toxicity. The aim of this study was to evaluate the safety profile of T-DM1 when delivered for ≥12 cycles. Methods: HER2 positive MBC pts who had received ≥12 cycles of T-DM1 across 18 Italian cancer centers were enrolled from January 2017 to September 2018. The 12 cycles cut-off was chosen based on the EMILIA trial median PFS (9.6 months), to identify a patient population treated with T-DM1 for longer time. Tumor and clinical characteristics were collected. Standard haematological tests, blood chemistries and side effects (nausea, vomiting, diarrhea, stomatitis, asthenia) were recorded cycle by cycle, according CTCAE criteria version 4. Haematological and laboratory toxicities were available for 86 patients, while other toxicities for all 115 patients. Results: Overall, 115 pts were enrolled. Median age was 54.5 (range 29.6–81.9); median time from diagnosis of metastatic disease to first T-DM1 cycle was 32.5 months. T-DM1 was administered as 2nd line and 3rd line of treatment in 45.2% and 27.8% of pts, respectively. Median number of cycles was 18 (range 12-59). Complete response, partial response and stable disease rates were 11.4%, 43% and 45.6%, respectively. Treatment related side effects are shown in table 1. Interestingly, no increased liver toxicity was observed in pts with liver metastases. Analysis of mean CTCAE grade by cycle showed that no relevant incremental toxicity was observed during long term T-DM1 therapy. Conclusions: T-DM1 is safe and well tolerated in these long responding pts. We found no relevant cumulative toxicity. Patients should be treated with T-DM1 as long as their tumor responds, as no safety issues are related to its long term use. [Table: see text]

504 Background: The effect of extended adjuvant endocrine therapy (ET) with aromatase inhibitors (AI) after sequential ET with tamoxifen (Tam) followed by AI for 5 years is still controversial. We conduct a clinical trial to assess different durations of ET of letrozole after tam. Methods: The GIM4 LEAD (Gruppo Italiano Mammella 4- Letrozole adjuvant therapy duration study, ClinicalTrials.gov:NCT01064635 ) was a prospective, randomized, Italian multicentric trial. Post-menopausal patients (pts) with hormone receptor positive early breast cancer free of recurrence after 2-3 years of adjuvant tam, were randomized in a 1:1 ratio to receive 3-2 years (short arm, S) or 5 years (long arm, L) of letrozole. The primary study end point was disease-free survival (DFS). Results: Between August 2005 and May 2010, 2056 pts were randomly assigned to receive 3-2 years (n=1030) or 5 years (n=1026) of letrozole. Main patients characteristics in the S and L arms were, respectively: median age 60 vs 61 years, node negative 56 vs 56%, (neo)adjuvant chemotherapy 53.4 vs 54.1%. The median follow-up was 10 years (IQR range: 8.6-11.4). The 8-year DFS was 80% (95% CI:77.3-82.7) and 85% (95% CI:82.9-87.6) in the S and L arm, respectively (hazard ratio, HR 0.82; 95% CI:0.68-0.98; p=0.031). This effect did not change in a multivariate Cox model that included nodal status, grading and age. No evidence of interaction between random assignment and nodal status, age and grading was observed. Among 1960 pts evaluable for toxicity, osteoporosis was diagnosed in 47 (4.8%) in S arm and 81 (8.3%) pts in L arm (chi-square=9.88; p=0.002). Bone fractures occurred in 5 (0.5%) and 9 (0.9%) pts in S and L arm, respectively ( p=0.29, Fisher exact test). Conclusions: After 2-3 years of adjuvant tam, extended treatment with 5 years of letrozole resulted in significant improvement in DFS compared to the standard duration of 2-3 years of letrozole. Clinical trial information: NCT01064635.

e12528 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. 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 first-line therapy was 17.9 11.7 and 7.8 months respectively. Mean OS from first progression was 32.9 24.2 and 15.8 months respectively. Statistical details. Conclusions: Our data confirm in a RWS the different biological behaviour between Lum A and B. Metastatic life span is quite good for Luminal and disappointing for TNBC. Median time from last CHT and Death is quite short and similar.[Table: see text]

3116 Background: MBC is an incurable disease and therefore treatment focuses mainly on prolonging pts survival and improving quality of life. Eribulin (E) is a microtubule inhibitor that increased overall survival in pretreated pts. E peripheral N is reported in 13.9-35% of cases. PAINTER main objective was to survey tolerability of E in real life in MBC, while secondary endpoints were to investigate the relationships between specific genetic polymorphisms and incidence and severity of peripheral N. Methods: This is a multicenter, interventional, single-arm, phase IV study, that enrolled pts who received E after taxanes and antracyclines (dose 1.4 mg/m2 day 1, 8 every 21 days). PAINTER study follow-up is still ongoing. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit. Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with avaliable clinical data and who completed E treatment. N was evaluated by medical examination. The associations between peripheral N (any grade) and the selected polymorphisms were evaluated with Fisher exact test. Results: From May 2014 to June 2018, 180 pts were enrolled in the PAINTER study from 20 Italian hospitals and 135 were analysed for the present report. Pts and tumor characteristics were as follow: median age 62 years (31-85), ductal carcinoma 78.5%, visceral disease 70.4%, luminal type 62.6%, Her2 positive 20.3%, triple negative 17.1%, previous median treatment lines for MBC 5 (0-18), previous N reported in 17.8% of pts (sensory 87.5%, motor 12.5%). N (all grades) were reported in 33.4% of patients (G3-G4: 3%). Among the selected SNPs, one allelic variant (rs2233335 G/G versus G/T or T/T) in NDRG1 gene had a statistically significant association with N (p 0.0010). Conclusions: The data reported demonstrate for the first time that the allelic variant rs2233335 (G/T and T/T) in NDRG1 gene correlates with E induced N. These data, if corroborated, will allow a tailored treatment with E. Clinical trial information: NCT02864030. [Table: see text]

Purpose Unresponsiveness to erythropoiesis-stimulating agents, occurring in 30% to 50% of patients, is a major limitation to the treatment of chemotherapy-related anemia. We have prospectively evaluated whether intravenous iron can increase the proportion of patients with chemotherapy-related anemia who respond to darbepoetin. Patients and Methods Between December 2004 and February 2006, 149 patients with lung, gynecologic, breast, and colorectal cancers and ≥ 12 weeks of planned chemotherapy were enrolled from 33 institutions. Patients were required to have hemoglobin ≤ 11 g/L and no absolute or functional iron deficiency. All patients received darbepoetin 150 μg subcutaneously once weekly for 12 weeks and were randomly assigned to sodium ferric gluconate 125 mg intravenously (IV) weekly for the first 6 weeks (n = 73) or no iron (n = 76). Primary end point of the study was the percentage of patients achieving hematopoietic response (hemoglobin ≥ 12 g/dL or ≥ 2 g/dL increase). Results Hematopoietic response by intention-to-treat analysis was 76.7% (95%CI, 65.4% to 85.8%) in the darbepoetin/iron group and 61.8% (95%CI, 50.0% to 72.7%) in the darbepoetin group (P = .0495). Among patients fulfilling eligibility criteria and having received at least four darbepoetin administrations, hematopoietic responses in the darbepoetin/iron group (n = 53) and in the darbepoetin-only group (n = 50) were 92.5% (95% CI, 81.8% to 97.9%) and 70% (95% CI, 55.4% to 82.1%), respectively (P = .0033). Increase of hemoglobin during treatment period showed a time profile favoring darbepoetin/iron with statistically significant effect from week 5 on. The safety profile was comparable in the two arms. Conclusion In patients with chemotherapy-related anemia and no iron deficiency, IV iron supplementation significantly reduces treatment failures to darbepoetin without additional toxicity.

e12019Background: T-DM1 showed remarkable activity in metastatic (m) HER-2 positive breast cancer (BC) and it recently was approved for clinical use in patients (pts) who previously failed trastuzumab and taxanes. The impact of drug prescription in real life compared with the findings reported in clinical trials exerting a strict accrual criteria has been rarely assessed. We investigated use and effectiveness of T-DM1 in daily practice. Methods: We included all pts with HER2-positive mBC, diagnosed in 12 Italian oncology hospitals between 2013 and 2015. Our aim was to assess the actual use of T-DM1 in HER2 positive mBC pts and its efficacy in clinical practice. Results: The data of 119 pts were retrospectively collected. The median age was 49 years (28-78), visceral metastases were present in 91 pts (77%) and brain metastases in 44 (37%). It is noteworthy that 29 pts (24%) received T-DM1 as second-line, 42 (35%) as third-line, and 43 (36%) as fourth- or further-line option. Moreover, 4 pts had TDM-1 as fi...

549 Background: Bevacizumab (B) combined with paclitaxel (P) is a treatment option in MBC patients (pts). This multicenter observational study was performed in order to evaluate activity of both B-...

2047 Background: The treatment of recurrent glioblastoma (GBM) remains an open issue, and the role of bevacizumab (BEV) has been widely debated since a few studies compared this agent with the stan...

2091 Background: Brain tumors have been widely evaluated with 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine (18F-FDOPA) PET examination, that demonstrated higher sensitivity and specificity for glioma...

2085 Background: Glioblastoma (GBM) is one of the most vascularized human tumors and GBM cells produce proangiogenic factors, including vascular endothelial growth factor (VEGF). Bevacizumab (BV), ...

9614 Background: A combination of AP + a 5-HT3 receptor antagonist + D and AP alone is recommended, respectively, for the prophylaxis of acute and delayed emesis induced by A+C CT in breast cancer pts. In the registrative study the role of AP in delayed emesis was not defined because prophylaxis of acute emesis was different between the two arms, and the superiority of AP on delayed emesis could be the consequence of a dependent effect on the different results achieved in acute phase. Aim of this study was to compare the efficacy of AP versus D in preventing delayed emesis in pts receiving the same prophylaxis of acute emesis. Methods: A randomized double-blind study comparing AP versus D was completed in naive breast cancer pts treated with A+C. Before CT, all pts were treated with intravenous palonosetron 0.25 mg and D 8 mg, and oral AP 125 mg. On days 2 and 3 pts randomly received D 4 mg bid or AP 80 mg qd. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) from days 2 - 5 after CT. Results: From September 2009 to July 2012, 580 pts were enrolled; 551 were fully evaluated, 273 in arm D and 278 in arm AP. Day 1 complete response rates were similar: 239/273 (87.6%) in D arm and 236/278 (84.9%) in AP arm. From day 2-5, complete response was the same with both antiemetic prophylaxes (79.5%), and all secondary endpoints (complete protection, total control, no vomiting, no nausea, score of FLIE) assumed similar values. During the delayed phase, incidence of insomnia (2.9% vs. 0.4%) and heartburn (8.1% vs. 3.6%) was significantly superior in D arm. Conclusions: In breast cancer pts submitted to A+C CT and receiving the same antiemetic prophylaxis for acute emesis, D and AP present similar efficacy and toxicity. Clinical trial information: NCT 00869973.

e19052 Background: Specific EGFR tyrosine kinase inhibitors (TKIs) are recommended as first-line therapy in patients with non-small cell lung cancer (NSCLC) that have active EGFR mutations. Although cytology and tumor biopsy are a very common approaches to evaluate patient eligibility to TKIs, the limited number of tumor cells present in these samples may often constitute a bias for molecular analysis. In this context, the use of sensitive methods to detect EGFR mutations may be of pivotal clinical importance. The aim of this study was two-fold: 1) to determine the accuracy and sensitivity in detecting EGFR mutations between liquid-based cytology (LBC) and bioptic specimens, 2) to compare the performance of direct DNA sequencing and real-time PCR (qPCR) in two different series of cytologic and histologic primary and metastatic NSCLC. Methods: DNA wasextracted from 537 specimens of NSCLC patients including 422 biopsies and 115 ThinPrep (TP) collected samples respectively. EGFR mutations were analyzed by direct sequencing (exons 19 and 21) in 284 biopsies and 68 TP samples and by qPCR (exons 18, 19, 20, 21) in 138 biopsies and 47 LBC samples. Results: The overall specimen insufficiency rate between LBC and biopsies was significantly higher by direct sequencing compared to qPCR (biopsies: 11.6% vs 7.2%) and (LBC: 14.7% vs 2.3%). In the series of 309 valuable cases analyzed by direct sequencing (251 bioptic and 58 LBC), we found 34 (11%) EGFR mutations (11.2% biopsies and 10.3% LBC ). Of interest, a higher percentage of EGFR mutant cases (18.1%) was observed in the 170 valuable cases analyzed by qPCR (11.1% biopsies and 21.4% LBC). Conclusions: Our data indicate that TP collected specimens seem to be more reliable than formalin fixed biopsies for molecular analysis, probably due to the better quality of the extracted DNA. Furthermore, qPCR enabled detection of EGFR mutations in samples with low tumor content for which conventional Sanger sequencing was not informative.

TO THE EDITOR: We have read with great interest the article by Dawood et al, and we think that the findings reported by the authors deserve some comments. Between June 2000 and January 2004, we consecutively enrolled 68 women with metastatic breast cancer: 33 patients received vinorelbine alone, while 35 patients were given trastuzumab plus vinorelbine according to human epidermal growth factor receptor-2 (HER2) expression determined by immunohistochemistry. This was formally a phase II study, which demonstrated that women with HER2-overexpressing metastatic breast cancer when treated with trastuzumab and vinorelbine had a better prognosis than those with HER2-negative disease treated with vinorelbine alone. In our study, the vast majority of patients received chemotherapy for metastatic disease. No one had previously received vinorelbine and only three women with HER2-positive disease had previously received trastuzumab for metastatic disease. Thus, by our findings, we provocatively suggested that the assumption that HER2positive tumors have a worse prognosis could be no longer valid when treated with trastuzumab. In fact, with the use of trastuzumab, women with HER2-positive disease appeared to do far better than did patients with HER2-negative tumors, exhibiting consistently higher rates of response, longer time to progression, and improved overall survival. Given that HER2-positive breast cancer is being treated as a distinct clinical entity, we cannot include women with HER2-positive breast cancer in trials recruiting patients regardless of HER2 status. Our study was criticized because it lacked a randomization plan. But, because in HER2-positive tumors chemotherapy alone as first-line treatment has been replaced with a combination of chemotherapy and trastuzumab, a trial without trastuzumab in HER2-positive patients with breast cancer would be ethically inappropriate. Thus, a prospective comparison between patients treated for HER2-positive disease and women treated for HER2-negative breast cancer can be formally performed only as a phase II study, in which consecutively enrolled patients with metastatic breast cancer are treated with chemotherapy with or without trastuzumab, according to HER2 status. Decades of randomized clinical trials on the first-line treatment of metastatic breast cancer have never been able to show so remarkable differences in time to progression and overall survival as the three fundamental randomized trials comparing chemotherapy with chemotherapy plus trastuzumab in women with HER2overexpressing metastatic breast cancer have been able to do. The merit of the study by Dawood et al is to have retrospectively compared the prognosis of three groups of patients: women with metastatic HER2-positive breast cancer with and without the addition of trastuzumab with women with HER2-negative disease. We agree with the authors that trastuzumab has not only beneficially changed the natural history of HER2-positive breast cancer, but it has also improved the prognostic outcomes of women with HER2overexpressing tumors beyond those of women with HER2negative disease.

9620 Background: We have recently shown non-inferiority in preventing acute and delayed nausea and vomiting associated with MEC between the PALO plus 1-day DEX and PALO plus 3-day DEX regimens. Planned analysis stratified by type of chemotherapy (anthracycline + cyclophosphamide [AC] group or patients receiving at least one moderately emetogenic agent according to modified Hesketh classification) has been performed. Methods: A total of 332 chemo-naïve patients with solid tumors were randomized to receive a single IV dose of PALO 0.25 mg plus DEX 8 mg IV on day 1 of chemotherapy (arm A; n=166) or the same regimen followed by DEX 8 mg orally on days 2 and 3 (arm B; n=166). Endpoints included complete response rates (CR: no emetic episodes [EE], no rescue antiemetics; primary endpoint) and proportion of patients with no EE throughout the 5 days after the first cycle of chemotherapy. Subgroups were analyzed by two-sided chi-square test. Results: Per-protocol population included 324 patients (65% women; median age 57.5 years); 35% received AC regimens, and 65% other MEC regimens. There were no significant differences between arms in CR rates according to the type of chemotherapy: 1) CR rates on AC regimens (arm A, 55.8% versus arm B, 60.7%; p=0.599); and 2) CR rates on other MEC regimens (arm A, 68.5% versus arm B, 72%; p=0.576). No significant differences between arms were also observed in the rates of patients with no EE: 1) emesis-free patients on AC regimens (arm A, 78.8% versus arm B, 73.8%; p=0.528); 2) emesis-free patients on other MEC regimens (arm A, 83.8% versus arm B, 90%; p=0.184); 3) nausea-free patients on AC regimens (arm A, 38.5% versus arm B, 44.3%; p=0.533); and 4) nausea-free patients on other MEC regimens (arm A, 58.6% versus arm B, 64%; p=0.418). Conclusions: The single-day regimen of PALO and DEX can provide effective protection against acute and delayed emesis from AC- and MEC-based regimens while avoiding to unnecessarily prolong treatment with DEX. No significant financial relationships to disclose.