Giridhar, Karthik V.

Abstract Background: Cyclin dependent 4/6 kinase inhibitors (CDK4/6i) and endocrine therapy (ET) have improved progression-free survival (PFS) and overall survival in HR+ MBC, but progression of disease ultimately occurs. Apart from HR+ status, there are no clinically available biomarkers that enable oncologists to determine prognosis and predict response to CDK4/6i. An emerging biomarker is serum thymidine kinase 1 (TK1), a secreted marker of proliferation that is prognostic in pts with HR+ HER2- MBC. High levels of TKa are associated with inferior PFS, whereas pts with low TKa levels pretreatment, or TKa levels that decrease on ET and a CDK4/6i, have superior PFS. Notably, TKa levels rebound ≥ 5 days off Pb, with resumption of cell cycling. PROMISE (NCT0281902) is a prospective study that enrolled women with HR+ MBC starting Pb + letrozole (L) in the 1st line [FL] or Pb + fulvestrant in the 2nd line [SL] setting. The trial includes a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome to identify novel genomic variants and pathways associated with an early decline in TKa (measured after 2 months or end of cycle [C]2) and PFS. Here, we report the association between i) pre-treatment TKa (pre-TKa) levels and PFS (i.e. from registration to the 1st disease event) and ii) TKa levels at the end of C2 (C2-TKa) and PFS-2 (i.e. from the start of C3 to the 1st disease event).Methods: TKa testing was performed using the DiviTum assay (Biovica). TKa+ disease was defined as ≥ 200 Du/L and TKa- disease as below limit of detection to 200 Du/L. Log-rank test and univariate Cox modeling were used to assess the association between pre-TKa levels and PFS and between end of C2-TKa levels and PFS-2. The database was locked on June 28, 2021. Results: Of 68 pts enrolled, 4 were ineligible and pre-TKa data was unavailable for 4. Of the remaining 60 pts (45 FL, 15 SL), the percentage of pts with pre-TKa+ disease was 33.3% in FL (15/45, 95% CI: 20.0-49.0%), and 46.7% (7/15, 95% CI: 21.4-71.9%) in the SL. The median follow-up time for pts on study was 24 months (range: 2-42 months). There were 22 disease events (13 in FL, 9 in SL). In the FL setting, PFS was significantly shorter for preTKa+ pts compared to preTKa- pts (HR: 4.15, 95% CI:1.35-12.74; p=0.007), but not for SL pts (HR: 1.11, 95% CI: 0.30-4.18, p=0.875). End of C2 TKa data was obtained for pts while on Pb (n=5), or after stopping Pb as follows: 1-4 days (n=9), 5-8 days (n=28) and 9-36 days (n=11). PFS-2 was not associated with C2-TKa in the FL (p=0.834) or SL (p=0.454) settings. An analysis of TKa levels by metastatic site will be presented at the meeting.Conclusions: A secreted biomarker of proliferation (TK1) obtained prior to initiating CDK4/6i and ET for the treatment of HR+ MBC is associated with PFS in pts receiving 1st line Pb + L, but not in those receiving 2nd line Pb + fulvestrant. While the end of C2 TKa levels were not associated with PFS, the interpretability of these data are limited, given treatment delays (0-36 days) prior to starting C3 that may result in TKa rebound. Future studies evaluating the predictive nature of TKa and Pb response should focus on earlier timepoints while on drug. Citation Format: Ciara C O'Sullivan, Jun He, Jason Sinnwell, Vera J Suman, Krishna R Kalari, Peter T Vedell, Ann M Moyer, Xiaojia Tang, Kevin J Thompson, Abe Eyman Casey, Alvaro Moreno-Aspitia, Donald W Northfelt, Minetta C Liu, Tufia C Haddad, Saranya Chumsri, Brendan McMenomy, Prema Peethambaram, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Mattias Bergqvist, Adrian Nordmark, Richard M Weinshilboum, Liewei Wang, Matthew P Goetz. Serum thymidine kinase 1 activity (TKa) levels and progression-free survival (PFS) in patients (pts) with hormone receptor positive (HR+) HER2-negative metastatic breast cancer (MBC) on palbociclib (Pb) and endocrine therapy (ET) [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 P5-13-22.

Abstract Background: Cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) and endocrine therapy (ET) have improved progression-free survival (PFS) and overall survival in hormone-receptor-positive (HR+) metastatic breast cancer (MBC), but endocrine resistance is a major challenge. PROMISE [NCT0281902; n=63] is a multicenter study that enrolled women with HR+ HER2- MBC commencing palbociclib (Pb) with letrozole (1st line [1L]) or fulvestrant (2nd line [2L]), and was designed to perform a comprehensive “omic” assessment of prospectively collected biospecimens (pre-treatment (M1), at 2 months (M2), and at disease progression). The goal is to identify novel genomic variants and pathways associated with resistance to CDK4/6i and ET and PFS outcomes. Here we report the association between the proteomic, metabolomics, and lipidomics data generated from pre-Pb and 2-month serum samples and PFS. Methods: Untargeted mass spectrometry data was generated from Metabolon, assaying 1308 metabolites and 831 lipids. Additionally, 1436 proteins were assayed on the Olink platform. Cox proportional hazard models were used to evaluate the univariate hazard ratio (HR) for all features with respect to PFS. The analyses were performed on samples from 45 patients (N=33 1Lwith 9 progression events and 12 2L with 8 progression events), obtained from M1 and M2 timepoints on Pb + ET. Enrichment analysis p-values are calculated using Fisher’s exact test. Results: Proteomics: In the M1 timepoint, 93 and 43 proteins were associated with PFS in the 1L and 2L settings, respectively; inflammation genes were enriched among the 1L setting (p= 0.034); 33 proteins presented HRs ranging between 0.026 and 0.56. The FABP9 protein (HR of 1.98, 95% CI 1.02-3.83) was associated with worse PFS. Conversely, inflammation genes were not observed to be enriched in 2L. In the M2 timepoint, we observed 60 and 21 proteins significantly associated with PFS, but no biological function was enriched in 1L and 2L. Metabolites: In the M1 timepoint, metabolism of the sulfur-containing amino acids (methionine, cysteine, SAM and taurine) were enriched in the 1L setting (p= 0.035, HR range 0.15-0.33); and the branched-chain amino acids (leucine, isoleucine, and valine) were significantly associated with PFS in the 2L setting (p= 0.028, HR range 0.013-0.33). At the M2 timepoint, the amino acids were no longer enriched, but fatty acid metabolism was significantly enriched for both 1L and 2L (p= 0.048 and 0.067, respectively). Pathways involving lipids, amino acids, and xenobiotics were enriched in metabolites related to PFS (p <0.05) for both treatment lines at M1 and M2. Lipidomics: In the M1 timepoint, 10 and 19 lipids were associated with PFS for 1L and 2L, respectively. The most notable lipid associated with worse PFS in the 1L was an 18 carbon phosphatidylinositol, PI(18:1/18:2), (HR 7.34 (CI 1.27-42.50); 8 triglycerides were associated with improved PFS (HR range 0.39 and 0.55). In 2L, the 19 lipids associated with PFS included 12 phosphatidylcholines (enrichment p = 5.6X10-8). In the M2 timepoint, 15 and 8 lipids were significantly associated with PFS for 1L and 2L. An enrichment of phosphatidylinositols was observed in 1L (p= 1.2X10-5); none were observed in the 2L.Future Directions: Networks are being constructed using the proximity scores of the proteins, lipids, and metabolites associated with PFS in M1 and M2 for 1L and 2L. Network similarities and analyses will be conducted.Conclusion: Distinct multi-omic changes identified in serum samples obtained from PROMISE participants M1 and M2 on Pb correlate with disease progression in both 1L and 2L settings. Additionally, validation studies will determine the significance of these findings. Citation Format: Krishna R. Kalari, Kevin J. Thompson, Jason Sinnwell, Xiaojia Tang, Vera J. Suman, Jun He, Seul Kee Byeon, Akhilesh Pandey, Abe Eyman Casey, Peter T. Vedell, Ann M. Moyer, Alvaro Moreno-Aspitia, Donald W. Northfelt, Minetta C. Liu, Tufia C. Haddad, Saranya Chumsri, Prema Peethambaram, Kathryn J. Ruddy, Karthik V. Giridhar, Roberto A. Leon-Ferre, Richard M. Weinshilboum, Liewei Wang, Ciara C. O’ Sullivan, Matthew P. Goetz. Multiomics data reveal novel biomarkers for CDK4/6 resistance [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 P4-01-03.

Abstract Background: Cyclin dependent kinase (CDK) 4/6 inhibitors (CDK 4/6i) can improve outcomes in ER-positive/HER2-negative (ER+/HER2-) breast cancer. The choice of CDK 4/6i selection and dose depends on clinical context and/or potential side effect of profile of each unique CDK 4/6i. The objective of this study was to evaluate practice patterns in patients initiated on CDK 4/6i and assess adherence to recommended laboratory monitoring in breast cancer patients in both an institutional and national dataset. Methods: The institutional cohort (IC) involved a retrospective chart review of patients newly initiated on palbociclib between May 8, 2018 - June 4, 2019 at Mayo Clinic, Rochester. The national cohort (NC) reviewed medical and pharmacy claims data from the OptumLabs Data Warehouse (OLDW) and included patients who were initiated on palbociclib (P), ribociclib (R) or abemaciclib (A) between February 6, 2015 - September 30, 2019. NC patients were required to have a minimum of 6 months baseline coverage, 6 months coverage after first prescription and Day 1 labs drawn. For both cohorts, patients were ≥18 years old with metastatic ER+/HER2- breast cancer. Data was collected for up to 6 cycles of treatment and included cycle start dates, doses, dates of lab draws and dose changes. Laboratory adherence was defined as a complete blood count being drawn +/- 3 days of the defined timepoint for the IC and +/- 5 days for the NC with a l4-day window for Cycle 1, Day 1 labs. Results: The IC included 81 patients and the NC 2600. In the NC, the most prescribed CDK 4/6i was P (90%), followed by A (6%) and R (4%). Prescription breakdown by geographic region was Midwest (26%), Northeast (14%), South (47%), West (13%). Ethnic breakdown of the group was White (68%), Black (15%), Hispanic (8%), Asian (3%) and unknown (6%). P practice pattern data were available for both the IC and NC, but R and A data in the NC only. In the IC, the initial P dose was 125 mg (95%), 100 mg (1%) and 75 mg (4%). In the NC, P (n=2329) dose was 125 mg (81%), 100 mg (15%) and 75 mg (4%). Dose reductions were common with 25% and 28% of patients requiring one dose reduction and 16% and 9% of patients requiring two dose reductions in the IC and NC, respectively. In NC patients initially treated with P, 5% were subsequently treated with A and 2% with R. In the NC, A (n=163) was initiated at 200 mg (7%), 150 mg (79%), 100 mg (10%) and 50 mg (4%). One dose reduction was required in 25% of patients and 6% required two dose reductions. Of those initially treated with A, 16% were subsequently treated with P and 1% with R. In the NC, R (n=108) was initiated at 600 mg (81%), 400 mg (8%) and 200 mg (11%). One dose reduction was required in 17% of patients and 2% required two dose reductions. Of those initially treated with R, 7% each were subsequently treated with P and 10% with A. Laboratory adherence was assessed for P only. For the IC, a total of 81 patients were included (mean age 61±13 years, 98% female and 95% White). The NC included 2329 patients (mean age 66±12 years, 99% female and 69% White). Laboratory adherence is listed in the table below: Conclusions: P was the most commonly prescribed CDK 4/6i. Dose reductions were less common with R. Adherence to laboratory monitoring was higher in our institutional cohort than in a national administrative claims database. Initiatives to ensure that labs are drawn at recommended timepoints during P therapy will be important for safety. ICNCC1D193%100%C1D1589%61%C2D191%71%C2D1558%55%C3D199%62%C4D190%55%C5D184%53%C6D178%50%C = cycle, D = day. Citation Format: Jodi Taraba, Kavya Swarna, Allison Golbach, Lindsey Sangaralingham, Kathryn Ruddy, Kristin Mara, Matthew Smith, Tufia Haddad, Karthik Giridhar. Evaluation of CDK 4/6 inhibitor practice patterns and institutional versus national adherence to palbociclib laboratory monitoring in breast cancer patients [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 P3-23-05.

Abstract Background: FGFR dysregulation is observed in multiple cancers and targeting FGFR is an emerging therapeutic strategy with FDA approved treatments in bladder and cholangiocarcinoma. Here we examined the prevalence of FGFR mutations, fusions, and high-level amplifications in breast cancer, stratified by receptor subtype and local/metastatic status, in both Foundation Medicine (FM) and institutional Mayo Clinic (MC) cohorts. Methods: For the FM cohort, comprehensive genomic profiling (CGP) examining at least 324 genes for all classes of alterations, including FGFR1-4 was carried out for 32,048 breast cancers during the course of routine clinical care in a Clinical Laboratory Improvement Amendments (CLIA)-certified lab (Foundation Medicine Inc., Cambridge, MA, USA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb, microsatellite instability high (MSI-High) was determined on up to 114 loci and predicted ancestry from >10,000 SNPs. Estrogen receptor (ER) and HER2 status were available for a subset of FM samples. Additionally, 131 patients with metastatic breast cancer from a subset of patients at three Mayo Clinic sites (MC cohort) with clinical characteristics and cancer-panel DNA sequencing data from a CLIA-certified lab (Tempus, Chicago, IL) were included. Results: In the FM cohort, the prevalence of FGFR1-4 high-level amplification (CN≥10) was 10.1%, while mutations (1.5%) and fusions (0.72%) were rare. Most amplifications occurred in FGFR1 (9.2%); most fusions and mutations occurred in FGFR2 (0.46%, 0.77%). FGFR alteration prevalence was highest in ER+/HER2- subtype (14.4%) and lowest in HER2+ disease (7.7%). FGFR alterations were more common in IDC (11.7%) than ILC (7.7%), p<3E-08. FGFR alterations were more prevalent in the metastatic setting relative to breast-biopsied disease (13.6% v 10.1%; OR = 1.4; p=2E-17), especially in the HER2+ (OR =1.9, p=0.004) and ER-/HER2- (OR = 1.9, p = 0.05) disease; no enrichment was seen in the ER+/HER2- metastases (OR =1.0, p = 1). FGFR amplifications were observed at a higher prevalence in patients with predicted East Asian ancestry, relative to patients with European ancestry (12.1% v 10.0%; p = 0.03). Overall, the most common activating mutations in FGFR were FGFR2 N549K (n=85), FGFR1 N546K (n=78), FGFR4 V510M (n=28), FGFR2 K659E (n=28), FGFR4 V510L (n=20), and FGFR2 Y375C (n=15). The most common recurrent fusions were FGFR3:TACC3 (n=36), FGFR2:TACC2 (n=17), FGFR1:TACC1 (n=9), FGFR1:BAG4 (n=6), and FGFR2:ATE1 (n=5). In patients with FGFR amplifications, the most frequently co-occurring alterations were ZNF703 (78.4%), TP53 (51.5%), CCND1 (36.1%), FGF3/4/19 (32.9 - 34.4%), PIK3CA (30.7%), MYC (29.6%), ESR1 (17.2%), EMSY (16.3%), and PTEN (10.6%). Significant co-occurrence was observed for a number of genes including FGF3/4/19, CDK4, and CDK8 (all OR>2, p<1E-07); mutual exclusivity was observed with PIK3R1, BRCA1, and BRCA2 (all OR <0.5, p<4E-13), among other genes. In the 131 metastatic tumors from MC, the prevalence of FGFR1-4 high-level amplifications was 19.8% [FGFR1 (12.4%), FGFR2 (7.4%), and FGFR3 (0.8%)]. The prevalence of high-level FGFR amplifications did not differ by clinical subtypes: HR-/HER2- (7/31), HR+/HER2- (15/79), and HER2+ (2/11), p=0.68. Conclusions: High-level FGFR amplifications are observed in >11% of breast cancers, especially the ER+/HER2- subtype, while mutations/fusions are rare. These data support the ongoing studies evaluating targeted therapies for FGFR amplified ER + breast cancer. Correlations with clinical information (MC cohort) and associations with actionable alterations are ongoing and may inform potential combination strategies. Citation Format: Karthik V Giridhar, Ethan S Sokol, Peter T Vedell, Jason P Sinnwell, Aakash Desai, Tufia C Haddad, Ciara C O’Sullivan, Roberto A Leon-Ferre, Siddhartha Yadav, Kostandinos Sideras, Brenda Ernst, Minetta C Liu, Abe Eyman Casey, Xiaojia Tang, Zoe Fleischmann, Karthikeyan Murugesan, Krishna R Kalari, Matthew P Goetz. The frequency and somatic mutation landscape of Fibroblast growth factor receptor (FGFR) alterations in breast cancer [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 P3-08-02.

Abstract Background: FGFR gene amplifications are found in 18% of breast cancers (BCs), with FGFR1 amplifications occurring in ≈10% of cases, predominantly in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) MBCs. FGFR1 amplifications are associated with resistance to endocrine therapy, and in preclinical experiments, FGFR pathway inhibition has been shown to overcome resistance to hormone therapy in BC harboring FGFR1 amplifications. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown preclinical activity in BC xenograft models harboring FGFR1/2 amplifications. In a phase 1 study, futibatinib showed promising clinical activity and tolerability across tumor types, including MBC, harboring various FGFR aberrations. A multicohort phase 2 trial (FOENIX-MBC2; NCT04024436) was designed to evaluate futibatinib alone (cohorts 1-3) or in combination with fulvestrant (cohort 4) in patients with MBC harboring FGFR2 or FGFR1 amplifications, respectively. Here, we report preliminary safety data from cohort 4 of FOENIX-MBC2, including data from a safety lead-in. Methods: Cohort 4 of FOENIX-MBC2 enrolled adult patients with HR+ HER2− MBC harboring high levels of FGFR1 amplification (FGFR1:CEN8 ratio ≥5 or FGFR1 copy number ≥10 signals per cell), Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function. Patients were fulvestrant naive and had previously received 1-2 endocrine-containing therapies, ≤1 chemotherapy regimen, and a CDK4/6 inhibitor (if eligible). Cohort 4 began with a safety lead-in to assess dose-limiting toxicities (DLTs) during the first treatment cycle. Patients received oral futibatinib 20 mg once daily continuously, and intramuscular fulvestrant 500 mg was administered on days 1 and 15 of cycle 1 and day 1 of every subsequent 28-day cycle. Patients were treated until disease progression, unacceptable toxicity, or another discontinuation criterion was met. Results: As of data cutoff (March 31, 2021), cohort 4 had enrolled 8 female patients with HR+ HER2− MBC harboring high-level FGFR1 amplification. The median age was 55.5 years (range: 31-62 years), and all patients had received ≥2 prior therapies for advanced/metastatic BC. The median duration of treatment was 8.0 weeks (range: 3.0-32.7 weeks); 3 of 8 patients (38%) were continuing treatment at time of data cutoff. All patients experienced treatment-related adverse events (TRAEs; grade ≥3: 25%). The most common TRAE was hyperphosphatemia (88%), followed by constipation (62%), transaminase elevation (50%), dry mouth (38%), and alopecia (38%). Among these TRAEs, grade ≥3 events were only reported for hyperphosphatemia (12%), and no serious adverse events were reported. In this cohort, TRAEs led to dose reductions in 4 patients, dosing interruptions in 3 patients, and treatment discontinuation in 1 patient; no patients died due to TRAEs. DLTs were evaluated in 5 patients following 1 treatment cycle (1 patient was enrolled after data cutoff, and 4 of 9 patients were not evaluable for DLTs); DLTs were not experienced by any of the 5 evaluable patients. Conclusions: Based on these preliminary safety results, the combination of futibatinib and fulvestrant appears to be safe and tolerable in patients with HR+ HER− MBC harboring high-level FGFR1 amplification. The safety profile was consistent with the individual profiles of both drugs, and the treatment combination did not appear to result in synergistic toxicity. As no DLTs were observed in 5 evaluable patients, the recommended futibatinib dose in combination with fulvestrant is 20 mg once daily. Efficacy will be evaluated in the complete 28-patient post-lead-in cohort, in which enrollment is ongoing. Citation Format: Senthil Damodaran, Nisha Unni, Karthik V. Giridhar, Brooke Daniel, Sacha Howell, Luis Costa, Marta Ferreira, Masashi Shimura, Gareth Tomlinson, Maciej Gil, Nicholas Turner. Futibatinib in combination with fulvestrant in patients with metastatic breast cancer (MBC) harboring high-level FGFR1 amplification: Preliminary data from a phase 2 study [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 P1-18-35.

Abstract Background: There is no clinical equipoise on the best upfront management of patients with early-stage hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer (BC) that is high-risk by clinicopathologic criteria, and low-risk based on molecular profiling. These patients are unlikely to respond to chemotherapy. However, these patients still have risk, often risk of late recurrence, despite standard adjuvant endocrine therapy. Novel endocrine-based strategies that are more effective and tolerable than current standard therapies are needed for this population. Next-generation orally-bioavailable selective estrogen receptor degraders (oSERDs) with improved pharmacokinetic (PK) properties are promising potential therapies for HR+ BC. The oSERD amcenestrant has demonstrated a favorable safety profile and encouraging efficacy in a phase I/II dose escalation and expansion trial for heavily pre-treated patients with HR+ metastatic BC and is an attractive agent for assessment in the neoadjuvant BC setting. The neoadjuvant setting offers a unique opportunity to study novel agents and to assess early biological endpoints. However, one of the challenges in studying endocrine-based strategies in the neoadjuvant setting is the lack of a robust surrogate endpoint to reliably predict response and benefit. The I-SPY2 Endocrine Optimization Protocol (EOP) is a pilot sub-study within the main I-SPY2 TRIAL that will test amcenestrant alone or in combination with abemaciclib or letrozole. EOP will test the feasibility of using the I-SPY2 platform to test novel endocrine-based strategies in the neoadjuvant setting in patients with clinical high-risk, molecular low-risk, HR+/HER2- tumors, and will generate a rich database of imaging, molecular, and pathologic correlative endpoints that may potentially inform the improved assessment of response to neoadjuvant endocrine therapy. Trial Design/Eligibility/Accrual: The I-SPY2 EOP is a prospective, randomized, open-label trial specifically for patients with HR+/HER2-negative MammaPrint (MP) low-risk tumors that are at least 2.5 cm in size. Eligible patients are identified during the screening process for the parent I-SPY2 trial. The planned total accrual for the EOP is 120 patients. Patients are randomized 1:1:1 to one of 3 oral treatment arms: 1) amcenestrant 200 mg daily; 2) amcenestrant 200 mg daily + abemaciclib 150 mg bid; 3) amcenestrant 200 mg daily + letrozole 2.5 mg daily. Patients are treated for 6 months prior to surgery. Premenopausal women must receive concomitant monthly ovarian suppression. Serial breast MRIs, breast biopsies, blood, and patient reported outcomes (PROs) are being collected, and patients will be followed for 10 years for recurrence and survival. Serial dedicated breast PET (dbPET) scans and PKs will be assessed in a subset of patients. Objectives/Statistics: The primary objective of the EOP is to investigate the feasibility of enrolling and treating molecularly-selected patients with early stage HR+/HER2- MP low-risk BC in a randomized neoadjuvant trial using an oral-SERD backbone. Treatment will be determined to be feasible if ≥75% of enrolled patients complete ≥75% of assigned study therapy. Secondary objectives include the safety, tolerability, PROs, and PKs related to amcenestrant +/- abemacilcib and letrozole, as well as the assessment of imaging, pathologic, and molecular correlative endpoints as potential biomarkers of response to neoadjuvant endocrine therapy. Status: This study opened in May 2021. Accrual is ongoing. Citation Format: A. Jo Chien, Kevin M Kalinsky, Julissa Molina-Vega, Rita Mukhtar, Karthik Giridhar, Olufunmilayo I Olopade, Amrita Basu, Smita M Asare, Paul Henderson, Gillian Hirst, Ruixiao Lu, Ella Jones, Nola Hylton, Lamorna Brown-Swigart, Laura J van 't Veer, Douglas Yee, Ingrid Mayer, Laura J Esserman. I-SPY2 endocrine optimization protocol (EOP): A pilot neoadjuvant endocrine therapy study with amcenestrant as monotherapy or in combination with abemacicilib or letrozole in molecularly selected HR+/HER2- clinical stage 2/3 breast cancer [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 OT1-10-02.

Abstract Background Anthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC. Methods Intravenous pixantrone was administered at 180 mg/m2 every 3 weeks (group A) versus 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population. Results Forty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%). Conclusion Pixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: NCT01086605).

Background Chemotherapy-induced peripheral neuropathy is a common and often severe side effect from many chemotherapeutic agents, with limited treatment options. There is no literature on the use of topical cannabinoids for chemotherapy-induced neuropathy. Case Presentations The current manuscript presents a case series of patients presenting in oncology clinics at Sutter Health, CA and Mayo Clinic, Rochester, MN from April 2019 to December 2020 with chemotherapy-induced peripheral neuropathy who used topical creams containing the cannabinoids delta-nine-tetrahydrocannabinol (THC) and/or cannabidiol (CBD). Conclusions This case series suggests that topical cannabinoids may be helpful for patients with chemotherapy-induced peripheral neuropathy. This paper also discusses the potential mechanisms of action by which topical cannabinoids might alleviate established CIPN symptoms. A randomized placebo-controlled trial using a standardized product is planned to study the actual efficacy of such treatment.

Abstract Background: DNIV accounts for 6%–10% of newly diagnosed breast cancer cases. Despite widespread mammography screening, its incidence is increasing in the United States and survival of this disease has only modestly improved since the late 1970s. As patient data accumulates in EHR, it’s promising to generate practice-based evidence through utilization of observational data sources. However, assembly of a DNIV cohort based on EHR data is challenging, as key pathologic and staging information are stored in unstructured clinical narratives and not available as structured data. In this study, we developed a rule-based algorithm to phenotype DNIV using natural language processing (NLP) techniques, and implemented the algorithm on our institutional EHR to extract potential DNIV cases. Methods and Results: We defined DNIV as those with either (1) M1 disease identified at time of initial presentation or M1 disease identified within 4 months after definitive surgery. We first developed a reference case list of DNIV verified by physician chart review of the EHR. We next refined the algorithm on a training dataset containing 51 positive and 38 negative reference cases. Next we tested the performance on the testing data containing 23 positive and 55 negative cases. The phenotyping algorithm identified key data elements using NLP, i.e., stage IV breast cancer, definitive surgery, stage 0-III, recurrent breast cancer and associated dates. To identify DNIV cases, phenotyping algorithm integrated temporal relations among the key data elements. The following steps were conducted in the following sequential order: (1) Identification of patients with breast cancer diagnosis using ICD-9 and ICD-10 codes. (2) Patients are positive cases if there are explicit mentions that delineate DNIV from recurrent metastatic breast cancer, such as “de novo stage IV” or “primary intact” detected by NLP at time of diagnosis. (3) Otherwise, patients with definitive surgery are selected if stage IV was within 5 years before definitive surgery or within 4 months after definitive surgery, along with patients with stage IV but without definitive surgery. (4) We further excluded patients with stage 0-III detected within 5 years after stage IV. (5) We further excluded patients with recurrent breast cancer detected before or at time of detection of stage IV. The remaining patients were left as positive cases. Precision of the algorithm was 70%, recall was 87% and F1, the weighted average of precision and recall, was 77%. We implemented our algorithm to interrogate 10 million clinical documents in a cohort of 56,548 patients with breast cancer diagnosis codes who presented to our institution between 2004 and 2018 and had research authorization. We identified 1918 potential DNIV cases. Conclusion: Our future focus is on algorithm refinement. An algorithm-generated cohort could serve as a data source for further study on outcomes related to DNIV and ideally as automated data abstractor and staging process. Citation Format: Liwei Wang, Karthik Giridhar, Kimberly Corbin, Brenda Ernst, Sadia Choudhery, Emmanuel Gabriel, Feichen Shen, Hongfang Liu, James Jakub. Identifying de novo stage IV breast cancer (DNIV) cases in Electronic Health Records (EHR) using natural language processing [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-050.