Citations

Abstract Background: Knowledge regarding risk of treatment-induced premature ovarian insufficiency (POI) is crucial for appropriate oncofertility counseling. While the gonadotoxicity of anthracycline- and cyclophosphamide-based chemotherapy (CT) in young breast cancer (BC) patients (pts) is well established, the impact of anti-HER2 agents remains largely unknown and limited conflicting evidence exists for taxanes. Anti-Mullerian hormone (AMH) is an established biomarker of ovarian reserve; its measurements during systemic therapies may aid in diagnosis and prediction of POI. The NeoALTTO trial represented a unique setting to explore the acute gonadotoxicity of anti-HER2 therapy alone and in combination with weekly paclitaxel in pts not previously exposed to any other potentially gonadotoxic anticancer treatment. Methods: NeoALTTO (NCT00553358) is a multicenter, open-label, randomized phase III neoadjuvant trial in HER2-positive early BC pts randomized to receive lapatinib (L), trastuzumab (T), or their combination (L+T) alone for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery.The present analysis included only premenopausal women aged ≤45 years with available frozen serum samples at baseline (i.e. before administering any anticancer treatment), at week 2 (i.e. “biological window” of anti-HER2 therapy alone) and/or at surgery (i.e. after completion of paclitaxel plus anti-HER2 therapy). Central AMH testing was performed at Erasme Hospital (Brussels, Belgium) with the Roche Elecsys® AMH Plus assay (LoD=0.010 ng/ml). AMH levels during anti-HER2 therapy alone and then combined with paclitaxel were assessed as a measure of treatment impact on ovarian reserve. The impact of different anti-HER2 agents (T and/or L), pts’ age and baseline AMH levels on treatment gonadotoxicity were also investigated. Results: The present analysis included 130 pts with a median age of 38 years (IQR: 33-42 years), of whom 86 (66.2%) were ≤40 years. At baseline, median AMH levels were 1.29 ng/mL (IQR 0.56 - 2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median value: 1.10 ng/mL, IQR 0.45 - 2.09 ng/mL, p<0.001; median cumulative decrease: -12.5%, IQR -37.6% - 12.4%). At surgery, there was a large significant decline in AMH levels (median value: 0.01 ng/mL, IQR 0.01 - 0.03 ng/mL, p<0.001; median cumulative decrease: -99.9%, IQR -100.0% - -98.7%). Type of anti-HER2 treatment (L vs. L vs. T+L) did not impact the results: there was no significant difference between treatment arms in degree of reduction in AMH levels at week 2 (p=0.763) or at surgery (p=0.700). Age and pre-treatment ovarian reserve had a major impact on treatment-induced gonadotoxicity risk, with a more profound decrease in AMH levels observed for older pts (p<0.001) and those with lower baseline AMH levels (p<0.001). Among pts aged <35 years, there was no significant difference in AMH levels between those with (n=7) or without (n=35) a subsequent pregnancy at baseline (p=0.316), week 2 (p=0.463) or at surgery (p=0.610). Conclusions: This biomarker analysis of the NeoALTTO trial showed for the first time the potential acute gonadal damage induced by anti-HER2 therapies alone and with the addition of weekly paclitaxel. We observed a small but significant reduction in AMH levels during T and/or L alone and then a profound reduction to almost undetectable levels following the addition of weekly paclitaxel, without differences by specific anti-HER2 regimen. Age and pre-treatment AMH levels strongly impacted gonadotoxicity risk. While this analysis is limited by lack of AMH measurement in longer term follow-up, findings have important implications for future research and oncofertility counseling of premenopausal women with HER2-positive BC. Citation Format: Matteo Lambertini, Marcello Ceppi, Richard A. Anderson, David A. Cameron, Marco Bruzzone, Maria Alice Franzoi, Claudia Massarotti, Sarra El-Abed, Yingbo Wang, Christophe Lecocq, Paolo Nuciforo, Rebecca Rolyance, Lajos Pusztai, Joohyuk Sohn, Jacopo Ligato, Maria Maddalena Latocca, Luca Arecco, Barbara Pistilli, Kathryn J. Ruddy, Alberto Ballestrero, Lucia Del Mastro, Fedro A. Peccatori, Ann H. Partridge, Cristina Saura, Michael Untch, Martine Piccart, Serena Di Cosimo, Evandro de Azambuja, Isabelle Demeestere. Impact of anti-HER2 therapy alone and in association with weekly paclitaxel on the ovarian reserve of young women with HER2-positive early breast cancer: Biomarker analysis of the NeoALTTO trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-05.

Abstract Background Patients (pts) with ER+ HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after neoadjuvant chemotherapy with dual HER2 blockade than pts with ER- HER2+ BC. Endocrine therapy (ET) plus trastuzumab is effective in advanced ER+ HER2+ BC, but pCR rate is low in the neoadjuvant setting. Inhibition of CDK4/6 and HER2 results in synergistic reduction in cell proliferation in preclinical studies. We therefore combined ET with CDK4/6 inhibition and trastuzumab in ER+ HER2+ BC as a chemotherapy-sparing regimen. Methods We evaluated the efficacy of palbociclib, letrozole, trastuzumab (PLT) in the neoadjuvant setting for pts with stages II or III ER+ HER2+ BC. Primary endpoint was pCR after 16 weeks of therapy. We assumed null of 15% pCR and pCR ≥ 30% warrants further investigation. To achieve 80% power at 1-sided 0.05 significance, 48 pts were to be enrolled. Evaluable population included pts who completed Cycle (C) 1 unless discontinued due to treatment-emergent adverse events (TEAEs) prior to completing C1. All who received one dose on study were considered evaluable for toxicity. Biopsies were collected at baseline (BL), C1 day 15 (C1D15), and surgery for RNA sequencing and central Ki67 assessment, for PAM50 subtype distribution, complete cell cycle arrest (CCCA: Ki67 ≤2.7%) at C1D15 and surgery, and treatment induced signaling changes. Results Accrual stopped early due to futility. 26 pts accrued were evaluable for efficacy and toxicity. pCR (residual cancer burden- [RCB] 0) was 7.7% (95% CI 0.9 - 25.1%) and RCB 0/I was 38.5% (95% CI 20.2 - 59.4%). TEAEs (n= 337) were seen in all pts (71.5% grade [G] 1, 19.3% G2, 8.6% G3, 0.6% G4); the most common were leukopenia (7.7%), neutropenia (7.1%), anemia (5.9%). G3/4 TEAEs occurred in 19 pts (73.1%). Among the 19, incidence of G3/4 neutropenia was 50%, hypertension 26.9%, leucopenia 7.7%. TEAEs (hypertension, ventricular tachycardia, pulmonary edema) leading to treatment discontinuation were reported in 1 pt. Two pts had at least one SAE. No treatment-related deaths occurred. Pt reported outcomes using NCI PRO-CTCAE revealed no differences in appetite, nausea, respiratory symptoms, edema, palpitations, rashes and dry skin, or concentration from BL to end of C4. Pts had worsening hair loss from BL to end of C4. Ki67 analysis indicated CCCA in 78% at C1D15, compared to 18% at surgery after only P had been discontinued approximately 4 weeks prior to surgery. RNA sequencing was performed on available biopsies collected at BL (N=16), C1D15 (N=5), and surgery (N=2) from 16 pts. Among 16 BL samples, PAM50 subtyping identified 5 (31.3%) basal-like, 2 (12.5%) HER2-E, 6 (37.5%) Lum B, and 3 (18.8%) normal. Subtype switching to Lum A at C1D15 (N=3, 1 each with HER2-E, Lum B, and normal at BL) or normal (N=2, 1 basal and 1 HER2-E at BL) was observed. 161 genes were differentially expressed (FDR p<0.05); 145 downregulated and 16 upregulated comparing C1D15 to BL. MKI67, TK1, CCNB1, AURKB, PLK1 were among the downregulated genes, consistent with CCCA for majority of the samples at C1D15 by Ki67. Analysis of the Molecular Signatures Database Hallmark gene-sets comparing C1D15 and BL samples demonstrated downregulated biological processes involved in proliferation (E2F targets, G2M checkpoint, MYC targets, mitotic spindle), signaling (Estrogen response, mTORC1 signaling), and DNA damage (DNA repair) at C1D15, consistent with the mechanisms of action of the study drugs. E2F targets were higher in BL samples of RCB II/III, compared to RCB I (FDR p=0.042). Conclusions PALTAN did not meet its primary endpoint of pCR. Neoadjuvant PLT showed a pCR of 7.7% but was well tolerated. RNA sequencing and Ki67 data indicated potent anti-proliferative effects of study treatments, despite significant heterogeneity of intrinsic subtypes. Clinical trial information: NCT02907918. Citation Format: Foluso O Ademuyiwa, Donald Northfelt, Tracey O'Connor, Ellis Levine, Jingqin Luo, Yu Tao, Jeremy Hoog, Marie Laury, Tracy Summa, Trish Hammerschmidt, Zhanfang Guo, Ashley Frith, Katherine Weilbaecher, Mateusz Opyrchal, Rebecca Aft, Katherine Clifton, Rama Suresh, Nusayba Bagegni, Ian S Hagemann, Cynthia X Ma. Phase 2 study of neoadjuvant palbociclib, letrozole, and trastuzumab in patients with ER+ HER2+ breast cancer (PALTAN) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-01.

Abstract Background Transcriptomic immune-related gene signatures have been associated with achievement of pathologic complete response (pCR) and prognosis in the neoadjuvant setting. I-SPY 2 is a multicenter, phase 2 platform trial using response-adaptive randomization within subtypes defined by receptor status (HR/HER2) and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Given racial disparities in mortality from breast cancer and the paucity of racial demographic data from clinical trials, we aimed to evaluate the association between racial groups and baseline characteristics, including expression-based subtypes and immune signatures, treatment response, and prognosis of patients enrolled in the I-SPY 2 TRIAL. Methods Our study population included 990 I-SPY 2 patients. 15 patients identified as part of a racial group with <10 patients enrolled in the trial and were excluded from analysis. Pre-treatment expression data was available for 971 patients. Follow-up data was available for 907 patients; median follow-up time of 4.4 yrs. Chi-square test was used to assess associations between racial groups and pre-treatment SBR grade, HR/HER2 defined subtypes, intrinsic subtype (defined by BluePrint 80-gene molecular subtyping) and residual cancer burden (RCB) class. Logistic regression was used to evaluate race association with pCR. Cox proportional hazard modeling was used to assess the association between racial groups and event free survival (EFS) in a univariate setting, adjusting for pCR status. Association between racial groups and 28 expression signatures related to immune, proliferation, ER and HER2 pathway was analyzed using ANOVA with post-hoc Tukey test in the overall population and in each receptor subtype. Results Of 975 patients included in our analysis, 787 (81%) were White, 68 (7%) were Asian, and 120 (12%) were Black or African American. No significant associations between race and pre-treatment SBR grade (p=0.49), HR/HER2 defined subtypes (p=0.09), or expression-based subtypes (p=0.25) were observed. pCR rates do not significantly differ by racial groups (Odds ratio of pCR relative to White: 1.00 for Asian and 0.89 for Black or African American); and no significant differences in RCB class distribution by race was observed (p=0.88). Event free survival was not associated with patient racial group in a univariate Cox model (Hazard ratio relative to White: 1.10, p=0.73 for Asian and 1.37, p=0.13 for Black or African American). Among the 28 expression signatures evaluated, four were differentially expressed among racial groups within the overall population (F-test p<0.05): IFN module, B cell signature, Dendritic cell signature, and Mitotic score. Pairwise comparisons between racial groups with post-hoc Tukey test identified significant differences in IFN module expression between Black or African American vs. White (p=0.019) and Dendritic cell signature expression between Asian vs White (p=0.047). Among patients in the TNBC subtype, three signatures (dendritic cell signature, macrophage signature and ERBB2 module) were differentially expressed between Black or African American and White patients (p=0.002, 0.016 and 0.007). Conclusion Our analysis demonstrates that among women with high risk breast cancer, race does not affect subtype specific response rates nor event free survival. Distribution of subtypes previously shown to be associated with pCR in the I-SPY2 trial did not significantly differ among racial groups indicating race is less likely than tumor biology to predict response. The decreased expression of immune signatures observed in Black or African American women with TNBC suggests possible differential sensitivity to immunotherapy plus combination chemotherapy. Tumor immune multiplex studies are underway to further investigate. Citation Format: Beverly Kyalwazi, Christina Yau, Olufunmilayo Olopade, A. Jo Chien, Anne Wallace, Andres Forero-Torres, Lajos Pusztai, Erin Ellis, Kathy Albain, Anne Blaes, Barbara Haley, Judy Boughey, Anthony Elias, Amy Clark, Claudine Isaacs, Rita Nanda, Hyo Han, Rachel Yung, Debu Tripathy, Kristen Edmiston, Rebecca Viscusi, Donald Northfelt, Qamar Khan, Ashish Sanil, Scott Berry, Smita Asare, Amy Wilson, Gillian Hirst, Nola Hylton, Michelle Melisko, Jane Perlmutter, Hope Rugo, Fraser Symmans, Laura van ‘t Veer, Donald Berry, Laura Esserman. Analysis of clinical outcomes and expression-based immune signatures by race in the I-SPY 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-02.

Background and objectives Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. Methods Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%–74% agreement. Results Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. Conclusion By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia.

Background The association of social isolation or lack of social network ties in older adults is unknown. This knowledge gap is important since the risk of heart failure (HF) and social isolation increase with age. The study examines whether social isolation is associated with incident HF in older women, and examines depressive symptoms as a potential mediator and age and race and ethnicity as effect modifiers. Methods and Results This study included 44 174 postmenopausal women of diverse race and ethnicity from the WHI (Women's Health Initiative) study who underwent annual assessment for HF adjudication from baseline enrollment (1993–1998) through 2018. We conducted a mediation analysis to examine depressive symptoms as a potential mediator and further examined effect modification by age and race and ethnicity. Incident HF requiring hospitalization was the main outcome. Social isolation was a composite variable based on marital/partner status, religious ties, and community ties. Depressive symptoms were assessed using CES‐D (Center for Epidemiology Studies‐Depression). Over a median follow‐up of 15.0 years, we analyzed data from 36 457 women, and 2364 (6.5%) incident HF cases occurred; 2510 (6.9%) participants were socially isolated. In multivariable analyses adjusted for sociodemographic, behavioral, clinical, and general health/functioning; socially isolated women had a higher risk of incident HF than nonisolated women (HR, 1.23; 95% CI, 1.08–1.41). Adding depressive symptoms in the model did not change this association (HR, 1.22; 95% CI, 1.07–1.40). Neither race and ethnicity nor age moderated the association between social isolation and incident HF. Conclusions Socially isolated older women are at increased risk for developing HF, independent of traditional HF risk factors. Registration URL: http://www.clinicaltrials.gov ; Unique identifier: NCT00000611.

PURPOSE Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome–negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome–negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome–negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.

AbstractIntroductionSlower mobility is associated with mild cognitive impairment (MCI) and dementia. We examined the interaction of endurance with gait speed on prevalent MCI and dementia.MethodsCross‐sectional multinomial regression in the ARIC cohort (n = 2844 participants; 71 to 94 years; 44% men; 18% Black persons) with cognitive status (normal/MCI/dementia), 4 m gait speed, and endurance (2 minute walk [2MW]).ResultsFaster gait speed (up to but not above 1 m/s) and better 2MW were separately associated with lower dementia risk. Good performance in both (2MW = 200 m, gait speed = 1.2 m/s) was associated with 99% lower dementia (Relative Prevalence Ratio [RPR] = 0.01 [95% CI: 0.0 to 0.06]) and 73% lower MCI, RPR = 0.27 (0.15 to 0.48) compared to poor performance in both (2MW = 100 m, gait speed = 0.8 m/s). Models incorporating a gait speed‐by‐2MW interaction term outperformed gait speed‐only models (P < .001).DiscussionGait speed relationships with dementia diminish at faster gait speeds. Combining endurance with gait speed may yield more sensitive markers of MCI and dementia than gait speed alone.