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519 Background: Successful therapeutic cancer prevention requires definition of the minimal effective dose of the proposed agent. Aromatase inhibitors substantially decreased breast cancer incidence in high risk postmenopausal women in phase III trials but their clinical use in prevention and adherence in adjuvant setting is limited by adverse events. We conducted a randomized presurgical phase IIb trial to evaluate two alternative doses of exemestane. Methods: We conducted a multi-center, pre-surgical, double-blind, 3-arm, non-inferiority phase IIb study in postmenopausal women with histologically confirmed estrogen receptor (ER)-positive breast cancer. Patients were randomized to receive either exemestane 25 mg/day (QD), or 25 mg/three times/week (TIW), or 25 mg once a week (QW) for 4-6 weeks before surgery. Blood and tissue biomarkers were collected at baseline and final visit. The primary aim was a non-inferiority percent change of circulating estradiol relative to the standard dose. Secondary endpoints were the change in Ki-67 and PgR expression in cancer tissue, blood sex hormones, lipid profile, toxicity and menopausal symptoms. For the power calculation we assumed a non-inferiority difference of 6% in the percentage change of estradiol among arms, using a one-sided, two-sample t-test. Assuming a 10% drop-out rate, a total sample size of 180 participants (60 per arm) had 80% power to detect a 6% margin of equivalence. The significance level for the main endpoint was 0.025 to account for multiple comparisons and 0.05 for secondary endpoints. Results: A total of 230 women were screened, 180 agreed to participate and 173 were evaluable for response. The median percent change of estradiol was -98%, -98%, and -70% for exemestane QD (n = 56), TIW (n = 57), and QW (n = 60), respectively, showing no significant difference between QD and TIW arms (p = 0.9). Similarly, no differences were observed for estrone, total estrone and estrone sulfate between QD and TIW arms. The QW arm showed some modulation in all hormones, even though less significantly so. Among the secondary endpoints, Ki-67 and PgR were reduced in all arms, with a median change of -5% vs -7.5% for Ki-67(p = 0.124), and -9 vs -17 for PgR (p = 0.246) in the TIW vs QD arms, respectively. SHBG and HDL-cholesterol had a more favorable profile with the TIW dose compared to the daily dose. Adverse events, measured according to the CTCAE (v4), and menopausal symptoms according to MENQOL were similar in all arms, but the short treatment time may not be representative. Conclusions: Exemestane 25 mg TIW retains a comparable activity than 25 mg QD. This activity was similar in both arms throughout the primary and the main secondary endpoints. This new schedule should be further assessed in prevention studies and in women on adjuvant treatment who do not tolerate the daily dose. Clinical trial information: NCT02598557.

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.

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....

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

18610 Background: Pain is probably under-recognized and under-treated in the Elderly with advanced cancer disease but the effect of a therapy with high potency opioids is not studied so much in geriatric age people. To evaluate efficacy and tollerability of escalating doses of Transdermal Fentanyl (TTS-F) or equipollent doses of oral morphine long acting with Immediate Release Oral Morphine (IROM) as rescue medication for treatment of moderate-severe cancer pain, we have started a Multicentric Observational Analysis in four cancer centres of north-western Italy. Studies of oncological palliation using valid measures of quality of life show that patients may be willing to accept some side effects of treatment as long as they gain relief from tumor-related symptoms Methods: -TIQ (Therapy Impact Questionnaire) -VAS (Visual Analogic Scale): 0 to 10 -Toxicity (WHO criteria) -Geriatric Assessment for pts aged >70 yrs (only at time 0): CIRS (Comorbility Index) IADL/ADL (Instrumental Activities Daily Living/Activities Daily Living). Patients characteristics -159 pts -Total Median Age: 66 yrs (range 38–86) -Median ECOG PS: 1 (range 0–2) -Elderly (>70 yrs): 75. Pain Starting situation -Median starting VAS: 5.5 (range 3–9) -TIQ: depression 70 pts, cachexia 55 pts, dispnoea 40 pts -CIRS (Comorbidity index): comorbidity were present among 66 pts. TTS-Fentanyl starting dose: 25 mcg/h every 72 h (range 25–50 mcg) or oral morphine long acting 60–90 mg plus IROM 10 mg every 4–6 hours for breakthrough pain present in 38 pts Results: -Quickly pain VAS downloading during first two weeks of treatment (median VAS 1) -Analgesic doses were not significantly increased after two months and not exceeded WHO grade 2 -IROM rescue was similar to that observed for the overall population -TIQ, ADL and IADL were not influenced by therapy. Conclusions: High potency opioids (TTS-F or long acting morphine equipollent doses, plus Rescue-IROM) offers durable long term maintenance pain relief wild acceptable toxicity also in elderly people, is particularly useful for cancer pts with compliance problems and may be considered as first-line treatment for moderate/severe cancer pain. No significant financial relationships to disclose.

8234 Background: Cancer patients with moderate-severe pain often require opioid analgesics. Methods: From October 2002 to November 2003, 62 outpatients underwent transdermal treatment with Fentanyl (TDF). All pts had been previously treated with other drugs according to the WHO analgesic scale. Pts characteristics: median age 64 years (range 44–84), M/F 29/33, median ECOG PS 0 (range 0–2). Primary tumors: 24 breast, 8 lung, 9 colorectal, 7 pancreas, 7 prostate, 7 others. Somatic pain was reported in 35/62 pts (56%), visceral pain in 12/62 pts (19%), 15/62 pts (24%) showed both types, with neuropatic features in 10%. Breakthrough pain was present in 24/62 pts (38%) requiring rescue medication. 47/62 pts (75%) received palliative chemo-radiotherapy. All pts were evaluated weekly with VAS (Visual Analogic Scale) and TIQ (Therapy Impact Questionnaire). A Geriatric Assessment with CIRS (Comorbility Index), ADL and IADL was performed for pts aged over 65 years (23/62; 37%) at the beginning of treatment and afte...

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...