Citations

BackgroundThis multicenter, randomized phase 2 trial evaluated complete responses (CRs), efficacy, and safety with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib in patients with untreated, high‐risk follicular lymphoma (FL).MethodsPatients with grade 1 to 3a FL and either a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 with 1 lymph node >6 cm or an FLIPI score of 3 to 5 were randomized to arm A (ofatumumab, bendamustine, and maintenance ofatumumab) or to arm B (ofatumumab, bendamustine, bortezomib, and maintenance ofatumumab and bortezomib).ResultsOne hundred twenty‐eight patients (66 in arm A and 62 in arm B) received treatment. The median age was 61 years, and 61% had disease >6 cm; 29% had an FLIPI score of 2, and 71% had an FLIPI score of 3 to 5. In arm A, 86% completed induction, and 64% completed maintenance. In arm B, 66% and 52% completed induction and maintenance, respectively. Dose modifications were required in 65% and 89% in arms A and B, respectively. Clinically significant grade 3 to 4 toxicities included neutropenia (A, 36%; B, 31%), nausea/vomiting (A, 0%; B, 8%), diarrhea (A, 5%; B, 11%), and sensory neuropathy (A, 0%; B, 5%). The estimated CR rates were 62% (95% confidence interval [CI], 50%‐74%) and 60% (95% CI, 47%‐72%) in arms A and B, respectively (P = .68). With a median follow‐up of 3.3 years, the estimated 2‐year progression‐free survival (PFS) and overall survival (OS) rates were 80% and 97%, respectively, for arm A and 76% and 91%, respectively, for arm B.ConclusionsThe CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high‐risk FL. Although grade 3 to 4 toxicities were similar, more patients treated with bortezomib required dose modifications and early discontinuation.

5510 Background: Single agent aromatase inhibitor (AI) therapy is associated with limited clinical activity in ovarian cancer (OC) and endometrial cancers (EC). AI therapy was associated with a progression free survival (PFS) at 12 weeks of only 20% in relapsed OC (Bowman et al, 2002) and a median PFS of 1 month in relapsed EC (Rose et al, 2000). In Estrogen Receptor (ER) positive metastatic breast cancer, clinical studies had shown a significant prolongation of PFS with the addition of the cyclin kinase 4/6 inhibitor ribociclib to AI (Hortobagyi et al, 2016). Here, we report the results of a phase 2 clinical trial of the combination of ribociclib and letrozole in patients with relapsed ER positive OC or EC. Objectives: Primary endpoint was the proportion of patients with relapsed ER positive OC or EC alive and progression-free after 12 weeks of therapy (PFS12) with the combination of ribociclib given at a dose of 400 mg orally daily and letrozole 2.5 mg orally daily. A PFS of 45% was considered a favorable result based on the data referenced above from Bowman et al. Methods: Eligibility criteria included patients with relapsed ER positive OC or EC, with measurable disease, not previously treated with ribociclib or AIs. Xenografts were created from CT guided tumor biopsies at baseline to assess feasibility. Results: A total of 40 patients were enrolled (20 with OC and 20 with EC) ) with a median age of 61 years (range: 30-82) and 64.5 (range: 52-75) in the OC and EC groups respectively. Among the OC patients, 17 had high grade serous carcinomas and 3 had low grade serous carcinomas. 11 EC patients had endometrioid cancers (3 with grade 1 tumors) and 9 had high grade serous tumors. Ten out of 20 OC patients and 11/20 EC patients were alive and progression-free at 12 weeks (PFS12 of 50 and 55%, respectively). The most common grade 3 or higher adverse events (occurring in at least 5 pts) were leukopenia (18%), lymphopenia (18%), neutropenia (13%), and fatigue (13%). 34 tumor biopsies were suitable for injection into mice and 44% engrafted. ER expression persisted through multiple passages in mice. Two of three EC PDX models exhibited improved PFS with letrozole/ribociclib compared to letrozole alone. Conclusions: The combination of ribociclib and letrozole is associated with a promising 50% and 55% PFS12 in patients with ER positive relapsed OC or EC respectively. Creation of xenograft tumor models from CT guided biopsies of OC and EC tumors was feasible. Clinical trial information: NCT02657928.

Abstract Objective: The established link between estrogen and breast cancer occurs via both estrogen receptor (ER)-mediated and non ER-mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including estrogen catechols and quinones, which have been linked to breast carcinogenesis in post-menopausal women. Recent data showed that childhood obesity is associated with significantly higher levels of genotoxic estrogens in the blood compared with lean children, raising the possibility of a potential pathogenic roles of these metabolites in breast cancer starting even prior to the onset of puberty (Mauras et al: J Clin Endocrinol Metab. 100:2322, 2015). A finding of higher levels of genotoxic estrogens associated with oral estradiol may have breast cancer prevention implications.We hence aimed to assess if the route of administration of 17β estradiol (E2) affects the accumulation of genotoxic estrogen metabolites in a model of ovarian failure in young girls with Turner Syndrome. Methods: Stored plasma were used from 40 adolescents with Turner's who participated in a previous 12 months randomized controlled trial of the metabolic impact of E2 orally (2mg/d) vs. transdermally (100μg/d). The doses of oral and transdermal E2 were determined to result in similar plasma levels of unconjugated E2. Previously we had reported that despite the similar plasma levels of unconjugated E2, the oral E2 administration route was associated with higher levels of biologically active estrogen activity than the transdermal route (Torres-Santiago L et al:J Clin Endocrinol Metab. 98:2716, 2013). In this study, we measured 12 estrogen metabolites (conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison. Results: After treatment, least square mean (SE) total (conjugated plus unconjugated) E2 and estrone (E1) concentrations were higher in the oral vs. transdermal group (p<0·0001), as were catechol-estrogens 4-OH-E2 (149 vs. 28 (49) pmol/L), 2-OH-E2 (300 vs 76 (52)), 4-OH-E1 (450 vs 105 (113)), 2-OH-E1 (304 vs 740 (684)) and 16α-OH-E1 (3007 vs 157 (534)) (<0·001 between groups). Levels were much closer to controls in the transdermal group. Conclusions: Common feminizing doses of oral estradiol for 12 months result in greater accumulation of unphysiologic, genotoxic estrogens than transdermal estradiol, expanding concerns about oral estrogens' first hepatic passage contributing to the accumulation of these metabolites. These metabolites have the potential for inducing breast cancer in post-menopausal women. These results suggest the potential benefit of preferential use of transdermal versus oral estrogens as replacement and possibly contraceptive options, in the prevention of breast cancer. Further studies to assess long-term risks of these metabolites in women taking different forms of estrogen replacement are needed. Citation Format: Colon-Otero G, Torres-Santiago L, Santen R, Mericq V, Ross J, Damaso L, Hossain J, Wang Q, Mesaros C, Blair IA, Mauras N. Impact of route of administration of estradiol (oral vs. transdermal) on genotoxic estrogens concentrations in girls with ovarian failure due to Turner syndrome: Potential implications for breast cancer prevention [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 P4-10-14.

Abstract Purpose: Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown. Experimental Design: A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated. Results: In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28–0.66; P < 0.001; and age > 40; HR, 0.56; 95% CI, 0.45–0.69; P < 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29–0.68; P < 0.001; and age > 40; HR, 0.42; 95% CI, 0.33–0.54; P < 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor–positive subset, but not the hormone receptor–negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years. Conclusions: Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.

AbstractObjectiveThe established link between oestrogen and breast cancer occurs via both oestrogen receptor (ER)‐mediated and non ER‐mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including oestrogen catechols and quinones, which have been linked to breast carcinogenesis in post‐menopausal women. We aimed to assess whether the route of administration of 17β oestradiol (E2) affects the accumulation of genotoxic oestrogen metabolites in a model of ovarian failure in young girls with Turner syndrome.MethodsStored plasma samples obtained at 0 and 12 months were used from 40 adolescents with Turner syndrome who participated in a 12 months randomized controlled trial of the metabolic impact of E2 orally (2 mg/d) vs transdermally (100 µg/d); dose escalation allowed matching of unconjugated E2 levels in the parent study. We measured 12 oestrogen metabolites (total concentrations = conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison.ResultsAfter treatment, least square mean (SE) total E2 concentrations were higher in the oral vs transdermal group (6784 pmol/L vs 1123 [1614], P < 0.0001), as was oestrone (E1) (91 060 pmol/L vs 19 278 [16 534], P < 0.0001). Also, higher after oral treatment were catechol‐oestrogens 4‐hydroxy‐E2 (149 vs 28 [±49] pmol/L), 2‐hydroxy‐E2 (300 vs 76 [±52]), 4‐hydroxy‐E1 (450 vs 105 [±113]), 2‐hydroxy‐E1 (3094 vs 740 [±684]) and 16α‐hydroxy‐E1 (3,007 vs 157 [±534]) (<0.001 between groups). Levels were much closer to controls in the transdermal group.ConclusionsCommon feminizing doses of oral oestradiol for 12 months result in substantial accumulation of unphysiologic, genotoxic oestrogens compared to transdermal oestradiol, expanding concerns about oral oestrogens’ first hepatic passage. Further studies assessing long‐term risks of these metabolites in women taking different forms of oestrogen are needed.