Citations

3519 Background: An understanding of the mechanisms of acquired resistance to CDK4 & 6 inhibitors, either alone or with endocrine therapy (ET), is an unmet need. Abemaciclib is a CDK4 & 6 inhibitor approved for treatment of HR+, HER2- advanced breast cancer (ABC). Here we evaluated acquired genomic alterations detected in circulating tumor DNA (ctDNA) from patients (pts) treated with abemaciclib + nonsteroidal aromatase inhibitor (AI) or placebo + AI in MONARCH 3 or abemaciclib monotherapy in nextMONARCH 1. Methods: MONARCH 3 randomized postmenopausal women with HR+, HER2- ABC with no prior systemic therapy in the advanced setting to abemaciclib (150 mg Q12H) or placebo + AI. nextMONARCH 1 randomized women with HR+, HER2- metastatic breast cancer who had progressed on or after prior ET and CT to abemaciclib (150 mg Q12H) + tamoxifen, abemaciclib (150 mg Q12H), or abemaciclib (200 mg Q12H) + loperamide. Plasma from pts in the abemaciclib or placebo + AI arms (MONARCH 3) or abemaciclib monotherapy arms (nextMONARCH 1) was analyzed by the Guardant360 assay to identify potential tumor-related genomic alterations including point mutations, indels, amplifications, and fusions acquired at EOT in comparison with baseline. Results: For MONARCH 3, commonly acquired alterations at EOT included ESR1 (17%), TP53 (10%), EGFR (8%), FGFR1 (7%), and PDGFRA (7%) in the abemaciclib + AI arm, and ESR1 (31%), TP53 (10%), and BRCA1 (7%) in the placebo + AI arm. Acquired alterations more frequent for abemaciclib + AI pts included RB1 (6%), MYC (5%), and AR (5%), compared to 0% in the placebo + AI arm (p = 0.008 RB1; p = 0.015 MYC or AR). In contrast, acquired ESR1 alterations were less frequent with abemaciclib + AI vs placebo + AI (17% vs 31%, p = 0.038). In nextMONARCH 1, the most commonly acquired alterations with abemaciclib monotherapy were in TP53 (10%), EGFR (9%), RB1 (9%), MYC (9%), and MET (8%). In addition, acquired alterations in ESR1 (6%) and AR (3%) were also found. PIK3CA alterations were not frequently acquired (abemaciclib + AI 1%, placebo + AI 6%, abemaciclib monotherapy 5%). Conclusions: Acquired genomic alterations potentially associated with emerging mechanisms of resistance to abemaciclib alone or in combination with AI may include RB1, MYC, or AR alterations, while the acquisition of ESR1 alterations was less common in pts treated with abemaciclib + AI compared to placebo + AI. These findings are hypothesis-generating and provide insight into mechanisms of resistance to abemaciclib vs ET. Clinical trial information: NCT02246621, NCT02747004 .

Background The association among gallbladder disease, cholecystectomy, and pancreatic cancer is unclear. Moreover, time interval between gallbladder disease or cholecystectomy and pancreatic cancer diagnosis is not considered in most previous studies. Aim To quantify the association among gallbladder disease, cholecystectomy, and pancreatic cancer, considering time since first diagnosis of gallbladder disease or cholecystectomy. Methods We used data from nine case-control studies within the Pancreatic Cancer Case-Control Consortium, including 5760 cases of adenocarcinoma of the exocrine pancreas and 8437 controls. We estimated pooled odds ratios and the corresponding 95% confidence intervals by estimating study-specific odds ratios through multivariable unconditional logistic regression models, and then pooling the obtained estimates using fixed-effects models. Results Compared with patients with no history of gallbladder disease, the pooled odds ratio of pancreatic cancer was 1.69 (95% confidence interval, 1.51–1.88) for patients reporting a history of gallbladder disease. The odds ratio was 4.90 (95% confidence interval, 3.45–6.97) for gallbladder disease diagnosed <2 years before pancreatic cancer diagnosis and 1.11 (95% confidence interval, 0.96–1.29) when ≥2 years elapsed. The pooled odds ratio was 1.64 (95% confidence interval, 1.43–1.89) for patients who underwent cholecystectomy, as compared to those without cholecystectomy. The odds ratio was 7.00 (95% confidence interval, 4.13–11.86) for a surgery <2 years before pancreatic cancer diagnosis and 1.28 (95% confidence interval, 1.08–1.53) for a surgery ≥2 years before. Conclusions There appears to be no long-term effect of gallbladder disease on pancreatic cancer risk, and at most a modest one for cholecystectomy. The strong short-term association can be explained by diagnostic bias and reverse causation.

Abstract MM has a median age at presentation of 65–68 years, rarely occurring in pts before age 40. Here, we present clinical, laboratory and survival data in the largest ever-analyzed cohort of young pts compared with pts aged ≥ 40 years. 259 pts aged &lt; 40 and 8,296 aged ≥ 40 years were enrolled. These 8.555 pts were part of the cohort analyzed for the ISS staging project. Previously untreated pts entered into randomized trials with standard (SDT) or high dose treatment (HDT). Clinical data were available for all pts, 526 pts had karyotypic analysis and 454 pts testing for Del 13 testing by FISH. The Chi-Square test was used to identify significant prognostic factors. A maximum likelihood model was used to estimate relative excess risk (RER) for younger versus older pts treated with SDT or HDT. Observed survival was adjusted by life expectancy depending on age, gender, and nationality. Young pts had significantly lower ISS stage I than older pts (stage I; 39% vs. 28%, stage II: 28 vs. 39%, stage III 33% vs. 33%, p&lt;. 001, p&lt;001, p=0.863, respectively) due primarily to a lower prevalence of high ß2m levels and low albumin levels in the younger age group. Paradoxically, the younger pts more frequently presented with higher M-component levels and Durie Salmon stage III (65% vs. 54%, p&lt;0.001). Prevalence of other important prognostic parameters like Hb, platelet count, creatinine, calcium, CRP, LDH and bone marrow PC infiltration was similar in both groups. Younger pts had more frequently good ECOG performance status (PS) (0–2), (87% vs. 81%, p&lt;0.01). Karyotypic abnormalities and Del 13 were similarly distributed between both cohorts. Median OS was significantly longer in young pts (median: 4.8 years vs. 3.7 years; hazard ratio (HR): 1.46; 95%, CI (1.27, 1.68); p=&lt;0.001). Better outcome in the younger cohort was seen in all three ISS stages, independent of gender. Median OS survival was significantly longer after SDT in the young cohort (median: 49 months (mos) vs. 39 mos; HR 1.49; CI (1.27, 1.75); p&lt;0.001). Median survival: 86 mos in young and 68 mos in older pts on HDT; this did not translate into a statistical difference (HR 1.8; CI (0.81,1.44); p=0.6). Risk estimates in a maximum likelihood analysis revealed that, apart from ISS Stage, young age followed by female sex was statistical significant for a good outcome for pts treated with SDT (Age RER: 1.43, CI (1.20, 1.70), p&lt;0.001; Sex RER: 1.07, CI (1.02, 1.14); p &lt; 0.013). For pts treated with HDT, only ISS Stage was found to be a risk factor, but not age or gender. Conclusions: Patients &lt; 40 have better prognosis and survival than older patients. The most important features of young patients are low SßM, normal S. Alb, and good performance status.

Abstract Background: Combination treatments of CDK4 & 6 inhibitors (CDK4 & 6i) with endocrine therapy (ET) have improved outcomes in patients with HR-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Aside from estrogen receptor positivity (ER+), predictive biomarkers of clinical benefit from CDK4 & 6i in combination with ET remain elusive. We assessed clinical outcomes by genomic alterations detected in baseline circulating tumor DNA (ctDNA) from patients treated with abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) versus placebo plus NSAI in the Phase 3 study MONARCH 3 (NCT02246621). Methods: MONARCH 3 randomized 493 postmenopausal women with HR+, HER2- ABC who had no prior systemic therapy in the advanced setting to treatment with abemaciclib plus NSAI or placebo plus NSAI. Biomarker analysis of baseline ctDNA was an exploratory objective; plasma was analyzed by the Guardant360 next-generation sequencing (NGS)-based assay to identify potential tumor-related (i.e., somatic) genomic alterations including point mutations (SNV), indels, amplifications, and fusions in over 70 cancer-related genes. Genomic alterations detected in baseline ctDNA were associated with clinical outcomes including progression-free survival (PFS) and objective response rate (ORR). Results: Baseline ctDNA results were available for 295 patients (201 abemaciclib; 94 placebo) with 83% of patients harboring one or more detectable genomic alterations. Commonly altered genes of interest (% frequency) detected in baseline ctDNA included: PIK3CA (38%); TP53 (26%); EGFR (15%); FGFR1 (12%); NF1 (12%); MYC (9%); CCND1 (9%); ESR1 (5%).Overall, patients treated with placebo plus NSAI who harbored detectable ctDNA genomic alterations had shorter median PFS compared to patients without detectable genomic alterations, as shown in the Table (14.9 months [95% CI: 11.0-23.1] vs 19.2 months [95% CI 9.4-NR]). Moreover, genomic alterations in EGFR, FGFR1, MYC, and CCND1 were associated with median PFS &lt;12 months with placebo plus NSAI. However, consistent with the intent-to-treat population, the addition of abemaciclib to NSAI benefitted these genomic subgroups, regardless of ctDNA gene alterations. Additional genomic results, including alterations in cell cycle-associated genes, will be presented. Conclusions: In this exploratory subgroup analysis, the presence of detectable ctDNA genomic alterations was associated with shorter PFS with placebo plus NSAI. Consistently, abemaciclib added to NSAI improved outcomes for genomically identified subgroups. In contrast to prior studies, there was no subgroup (e.g., patients harboring FGFR1 alterations) that did not derive benefit from abemaciclib, supporting the efficacy of abemaciclib, including in difficult to treat tumors. These findings are hypothesis-generating and warrant further investigations in clinical studies of CDK4 & 6i in combination with ET. TableAbemaciclib + NSAIPlacebo + NSAIEvents, n/NMedian PFS (95% CI)Events, n/NMedian PFS (95% CI)Hazard Ratio (95% CI)OVERALLITT population170 / 32828.2 (23.7 - 33.9)123 / 16514.8 (11.2 - 19.2)0.52 (0.42 - 0.66)TR population93 / 20138.7 (31.1 - NR)71 / 9416.5 (11.7 - 23.1)0.45 (0.33 - 0.61)Any Gene AlterationDetected83 / 16634.1 (27.2 - 40.0)62 / 7914.9 (11.0 - 23.1)0.47 (0.34 - 0.66)Not detected10 / 35NR (36.4 - NR)9 / 1519.2 (9.40 - NR)0.31 (0.13 - 0.78)TP53Detected29 / 5327.0 (14.1 - NR)19 / 2315.4 (5.7 - 30.4)0.53 (0.30 - 0.95)Not detected64 / 14839.9 (34.1 - NR)52 / 7117.5 (11.7 - 24.2)0.42 (0.29 - 0.60)EGFRDetected10 / 26NR (32.4 - NR)16 / 1710.9 (2.1 - 24.7)0.20 (0.09 - 0.47)Not detected83 / 17536.4 (27.7 - NR)55 / 7717.6 (14.6 - 25.5)0.52 (0.37 - 0.73)FGFR1Detected15 / 2532.8 (10.1 - NR)10 / 117.6 (1.9 - 15.4)0.37 (0.16 - 0.85)Not detected78 / 17639.9 (31.1 - NR)61 / 8319.2 (14.6 - 26.5)0.45 (0.32 - 0.63)NF1Detected10 / 2435.9 (27 - NR)8 / 1014.6 (1.6 - 33.4)0.33 (0.13 - 0.84)Not detected83 / 17738.7 (30.8 - NR)63 / 8417.5 (11.7 - 24.2)0.47 (0.33 - 0.65)MYCDetected11 / 1720.1 (5.5 - NR)9 / 106.5 (1.2 - 15.7)0.33 (0.13 - 0.86)Not detected82 / 18438.9 (32.9 - NR)62 / 8419.2 (14.6 - 26.5)0.45 (0.32 - 0.63)CCND1Detected8 / 1632.8 (5.5 - NR)10 / 107.2 (3.6 - 9.0)0.28 (0.10 - 0.77)Not detected85 / 18538.7 (31.1 - NR)61 / 8417.6 (14.6 - 25.5)0.48 (0.34 - 0.67)n = number of patients with events; N = total number of patients in the corresponding population and treatment arm; NR = not reached. TR population consists of patients in the ITT population from whom a valid baseline ctDNA result has been obtained. Citation Format: Matthew P Goetz, J. Thaddeus Beck, Mario Campone, Sara Hurvitz, Seock-Ah Im, Stephen Johnston, Antonio Llombart-Cussac, Miguel Martin, Joohyuk Sohn, Masakazu Toi, Lacey M Litchfield, Hillary T Graham, Hong Wang, Sameera R Wijayawardana, Valerie M Jansen, Angelo Di Leo. Efficacy of abemaciclib based on genomic alterations detected in baseline circulating tumor DNA from the MONARCH 3 study of abemaciclib plus nonsteroidal aromatase inhibitor [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 PD2-06.

Abstract Background: Breast cancer incidence and mortality rates are increased in patients’ older than 65 years. However, there are limited reports on age-specific efficacy, safety, and drug tolerability, particularly in elderly patients older than 75 years old. Abemaciclib demonstrated clinically meaningful progression-free survival (PFS) improvement in combination with endocrine therapy (ET) in HR+, HER2- advanced breast cancer patients in the Phase 3 studies, MONARCH 2 and 3. Here we report exploratory subgroup analyses of MONARCH 2 and 3 to provide age-specific outcomes. Methods: In MONARCH 2 (NCT02107703), patients progressing while on prior ET received abemaciclib (or placebo) plus fulvestrant; in MONARCH 3 (NCT02246621), postmenopausal women with no prior systemic therapy for recurrent or metastatic breast cancer received abemaciclib (or placebo) plus letrozole or anastrozole. Exploratory outcome analyses of MONARCH 2 and 3 studies were performed for three age groups (women aged &lt;65, 65-74, and ≥75 years). Using pooled safety data, we performed age-specific subgroup analyses of the most common treatment-emergent adverse events (TEAEs) associated with either ET or ET plus abemaciclib. To assess the impact of age on efficacy, a subgroup analysis of PFS was performed using a Cox model for each trial independently. Results: Pooled safety data were available for 1152 patients treated in MONARCH 2 and 3 trials, including 59.7% pts &lt;65 years, 28.7% pts between 65 and 74 years, and 11.5% pts ≥ 75 years. Of those, 768 women received abemaciclib plus ET and 384 women received placebo plus ET. The most frequent TEAE was diarrhea and the most common Grade ≥3 TEAE was neutropenia. While diarrhea (any grade) occurred with similar incidence in abemaciclib-treated patients across age groups, clinically relevant diarrhea (Grade 2/3) was higher in the elderly (&lt;65, 39.5%; 65-74, 45.2%; ≥75, 55.4%); however, in the ≥75 group, diarrhea (Grade 2/3) incidence was also higher for placebo plus ET (&lt;65, 6.8%; 65-74, 4.5%; ≥75, 16.0%). Similarly, nausea and decreased appetite were moderately higher (by 10-20%) in the 2 abemaciclib-treated elderly subgroups. Fatigue (any grade) was higher in the 2 abemaciclib-treated elderly subgroups (&lt;65, 34.8%; 65-74, 48.4%; ≥75, 51.8%), while no differences were found across the 3 placebo subgroups. In contrast, the rates of Grade 3/4 neutropenia did not differ as a function of age in either the abemaciclib plus ET arm (&lt;65, 25.8%; 65-74, 27.4%; ≥75, 18.1%) or placebo plus ET arm. For efficacy, a consistent PFS benefit was observed with abemaciclib plus ET versus placebo plus ET across all three age-specified subgroups in both studies (Table). Conclusion: Abemaciclib in combination with ET demonstrates a tolerable safety profile and consistent efficacy benefit across all age subgroups examined, supporting the use of this combination in elderly patient populations. Despite the limited number of patients in the ≥75 group with potentially confounding comorbidities, the safety data suggest that patient education and appropriate management of toxicities, including dose adjustments and use of supportive medication for gastrointestinal toxicities, could maximize the benefit of abemaciclib. Table: Age-specified PFS outcomes from MONARCH 2 and 3MONARCH 2MONARCH 3Age GroupAbemaciclib + ETPlacebo + ETHR (95% CI)P-value *Abemaciclib + ETPlacebo + ETHR (95% CI)P-value *Events/NEvents/NEvents/NEvents/N&lt;65140/29192/1330.52 (0.40, 0.68)0.69581/18065/910.48 (0.35, 0.67)0.63465-7461/11442/600.63 (0.43, 0.94)40/10631/540.64 (0.40, 1.02)≥7521/4123/300.62 (0.34, 1.11)17/4212/200.54 (0.26, 1.13)Abbreviations: CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; PFS, progression-free survival.*P-value corresponds to the interaction test between age and treatment. Citation Format: Matthew P. Goetz, Meena Okera, Hans Wildiers, Mario Campone, Eva-Maria Grischke, Luis Manso, Valerie Anne Marie Andre, Amy Lee Chong, Belen San Antonio, Masakazu Toi, George W Sledge Jr. Safety and efficacy of abemaciclib plus endocrine therapy (ET) in elderly patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+, HER2-) advanced breast cancer: An age-specific subgroup analysis of MONARCH 2 and 3 trials [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 P1-19-10.

Abstract Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT; RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257; 46.0%), CMT (n = 184; 32.9%), CT alone (n = 47; 8.4%), observation (n = 37; 6.6%), rituximab and RT (n = 19; 3.4%), and rituximab alone (n = 15; 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites &gt;2 were associated with worse PFS (P &lt; .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites &gt;2 (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments.

The aim of the study was to evaluate the effect of severe short‐term nutritional deprivation (ND) on the fractional synthesis rates (FSR) specific proteins and protein pools in the diaphragm muscle (DiaM). Male rats were divided into two groups: 20% of usual food intake for 4 days (ND) with water provided at libitum and free‐eating control (Ctl). [U‐13‐C] leucine was continuously infused through the jugular vein for 3–3.5 h after a priming dose of the isotope. Blood samples were collected from the carotid artery at baseline and every 30 min at precursor pool plateau. DiaM was excised at the end of the isotope infusion. Mixed muscle protein (MMP), myosin heavy chain (MHC), sarcoplasmic (Sarco) and mitochondrial (Mito) proteins were extracted from DiaM and the incorporation of the label into each protein(s) was determined using mass spectrometry. The FSR of MMP, MHC, Sarco and Mito in the rat DiaM were calculated using the precursor‐product relationship. ND resulted in the reduction of the FSRs of MMP (71%), MHC (69%), Sarco (44%) and Mito (55%) in DiaM. In summary, short‐term ND is associated with a global decrease in the synthetic rate of DiaM proteins, suggesting a compromise in the ability of the DiaM to synthesize functionally important proteins in the ND state. The underlying mechanisms for this depressed state of protein synthesis in DiaM related to ND remain to be elucidated.

Background: Evidence-based, procedure-specific guidelines for prescribing opioids are urgently needed to optimize pain relief while minimizing excessive opioid prescribing and potential opioid diversion in our communities. A multidisciplinary panel at our institution recently developed procedure-specific guidelines for discharge opioid prescriptions for common orthopaedic surgical procedures. The purpose of this study was to evaluate postoperative opioid prescription quantities, variability, and 30-day refill rates before and after implementation of the guidelines. Methods: This retrospective cohort study was conducted at a single academic institution from December 2016 to March 2018. Guidelines were implemented on August 1, 2017, with a recommended maximum opioid prescription quantity for 14 common orthopaedic procedures. Patients who underwent these 14 procedures during the period of December 2016 to May 2017 made up the pre-guideline cohort (n = 2,223), and patients who underwent these procedures from October 2017 to March 2018 made up the post-guideline cohort (n = 2,300). Opioid prescription quantities were reported as oral morphine equivalents (OME), with medians and interquartile ranges (IQRs). Four levels were established for recommended prescription maximums, ranging from 100 to 400 OME. Results: In the pre-guideline cohort, the median amount of prescribed opioids across all procedures was 600 OME (IQR, 390 to 863 OME), which decreased by 38% in the post-guideline period, to a median of 375 OME (IQR, 239 to 400 OME) in the post-guideline cohort (p < 0.001). The 30-day refill rate did not change significantly, from a rate of 24% in the pre-guideline cohort to 25% in the post-guideline cohort (p = 0.43). Multivariable analysis demonstrated that guideline implementation was the factor most strongly associated with prescriptions exceeding guideline maximums (odds ratio [OR] = 9.9; p < 0.001). Age groups of <80 years (OR = 2.0 to 2.4; p < 0.001) and males (OR = 1.2; p = 0.025) were also shown to have higher odds of exceeding guideline maximums. Conclusions: Procedure-specific guidelines are capable of substantially decreasing opioid prescription amounts and variability. Furthermore, the absence of change in refill rates suggests that pain control remains similar to pre-guideline prescribing practices. Evidence-based guidelines are a readily employable solution that can drive rapid change in practice and enhance the ability of orthopaedic surgeons to provide responsible pain management.