Moreno‐Aspitia, Alvaro

PURPOSEThere are numerous barriers to enrollment in oncology biomarker-driven studies.METHODSThe ELAINE 2 study (ClinicalTrials.gov identifier: NCT04432454 ) is an open-label phase 2 study of lasofoxifene combined with abemaciclib in patients with advanced or metastatic estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer with an ESR1 mutation. ELAINE 2 opened clinical sites by using a Traditional approach, which activated a site before patient identification, and the Tempus TIME Trial network, which opened a site only after identifying an eligible patient. This manuscript presents the operational metrics comparing the Traditional and TIME Trial site data.RESULTSThe study enrolled patients over 34 weeks and 16 sites (six Traditional and 10 TIME Trial) participated. Duration for full clinical trial agreement execution for Traditional sites and TIME Trial sites averaged 200.5 (range, 142-257) and 7.6 days (range, 2-14), respectively. Institutional review board approval time for Traditional sites and TIME Trial sites was 27.5 (range, 12-71) and 3.0 days (range, 1-12), respectively. Duration from study activation to first consent was 33.3 (range, 18-58) and 8.8 days (range, 1-35) for Traditional and TIME Trial sites, respectively. The first patient on study was at a TIME Trial site 115 days before a Traditional site and the first seven patients enrolled were at TIME Trial sites. Traditional sites consented 23 and enrolled 16 patients, while TIME Trial sites consented 16 and enrolled 13. The trial enrolled 29 patients in 8.5 months with the anticipated enrollment duration being 12-18 months.CONCLUSIONThe TIME Trial network opened earlier and enrolled the first study patients. These results demonstrate that the Just-in-TIME model, along with a Traditional model, can improve enrollment in biomarker-driven studies.

Abstract Background: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). This trial evaluated the efficacy of pembrolizumab and MEK inhibitor, binimetinib. Here we evaluated potential biomarkers in peripheral blood to predict response. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were enrolled. Treatment includes a 2-week run-in with binimetinib followed by pembrolizumab. There were 2 dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. A standard 3+3 design was used in phase I, and Simon’s two-stage Optimal design was used in phase II. Circulating tumor cells (CTC) and circulating cancer-associated macrophage-like cells (CAML) were isolated using CellSieve microfilters and immunofluorescently labeled with PD-L1 and p-ERK. Wilcoxon rank sum test and Cox regression model were used for analysis. Results: A total of 22 patients were enrolled, with a median age of 58 years old. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0, with grade 3 ALT abnormality, flank pain, and nausea. In the next 6 patients in DL -1, there was 1 DLT with grade 3 AST/ALT abnormality. There were 17 patients treated with DL -1 and were evaluable for response. The objective response rate (ORR) was 29.41% (95% CI: 10.31-55.9) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR ≥ 24 weeks) was 35.29% (95% CI: 14.21-61.67). ORR in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30), and CBR was 66.67% (95% CI: 29.93-92.51). There was no response observed in all 5 patients with liver metastases. Baseline mean CTC count was 1.3 cells, and CAML count was 8.9 cells/7.5 mL. Baseline PD-L1 in CAML (p 0.04) and decline in CAML size (p 0.02) after 1 cycle were significantly associated with CBR. However, baseline CTC count, CAML count (p 0.64), CAML size (p 0.46), p-ERK in CAML (p 0.23), and changes in CTC count, CAML count (p 0.83), p-ERK (p 0.07), and PD-L1 (p 0.08) in CAML were not significantly associated with responses. Using Cox regression analysis, a reduction in CAML count (p 0.02), CAML size (p 0.01), and PD-L1 in CAML (p 0.03) were associated with significant improvement in overall survival but not the reduction in p-ERK (p 0.6). Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Baseline PD-L1 expression, early reduction in CAML count, size, and PD-L1 expression were significantly associated with subsequent responses, providing potential noninvasive biomarkers to predict response to this combination. Future larger clinical trials are warranted to further evaluate the efficacy of this combination. Citation Format: Saranya Chumsri, Joseph J. Larson, Daniel L. Adams, Kathleen S. Tenner, Cha-Mei Tang, Morgan T. Weidner, Amanda N. Arnold, Dana L. Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-aspitia, Edith A. Perez, Keith L. Knutson. Peripheral blood biomarkers in Phase II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5454.

e24161 Background: Pertuzumab-induced gastrointestinal toxicities (PIGT), particularly diarrhea, is the most common adverse event reported in over 70% of patients receiving pertuzumab in combination with chemotherapy. PIGT can result in dose reduction, treatment delay, and discontinuation of chemotherapy. Rifaximin is a minimally absorbed oral antibiotic approved for gastrointestinal tract infections and bacterial overgrowth. Our aim was to evaluate the efficacy of rifaximin in reducing PIGT. Methods: Patients with stage I-III HER2-positive (HER2+) breast cancer who received pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCHP) were enrolled. PIGT included diarrhea, abdominal distention, abdominal pain, dyspepsia, stomach pain, and typhlitis. Patients with any PIGT ≥ grade 2 after the first cycle of TCHP received rifaximin 550 mg orally twice daily on days 1-5 in all subsequent cycles of chemotherapy. Patients with PIGT grade < 2 were observed without rifaximin. Simon's Two-Stage design was used. Results: Between 2018-2022, a total of 21 patients were enrolled. One patient was excluded due to significant anemia not meeting the eligibility criteria to proceed with rifaximin after the first cycle of TCHP. Of 20 patients, the median age was 52.5 (39-69) years. 18/20 (90.0%) patients had PIGT ≥ grade 2 after 1 cycle of TCHP with PIGT grade 2 in 15 (83.3%) and grade 3 in 3 (16.7%). PIGT ≥ grade 2 included diarrhea in 14 (70.0%) with grade 2 in 12 (60.0%) and grade 3 in 2 (10.0%), abdominal pain in 9 (45.0%) with grade 2 in 8 (40.0%) and grade 3 in 1 (5.0%), abdominal distension in 3 (15.0%), dyspepsia in 5 (25.0%), and stomach pain in 4 (20.0%) patients. Among 18 patients who received rifaximin, 15 (83.3%; 95% CI 0.586-0.964) had at least 1 cycle with a maximum PIGT grade < 2. This result surpassed the threshold of the Two-Stage analysis. Reduction of individual PIGT symptoms for patients who experienced > grade 2 at baseline after the first cycle of rifaximin was reported in 2/3 (66.7%) for abdominal distention, 8/9 (88.9%) for abdominal pain, 6/14 (42.9%) for diarrhea, 3/4 (75.0%) for stomach pain, and 4/5 (80.0%) for dyspepsia. No patients experienced > grade 2 typhilitis at baseline and during treatment. Treatment is well tolerated, with no significant grade 3+ adverse event related to rifaximin observed. Among patients who received rifaximin, there was no treatment delay or discontinuation of pertuzumab related to PIGT. Conclusions: PIGT is a debilitating side effect observed in most patients receiving pertuzumab. A short course of rifaximin after each cycle of treatment is a well-tolerated treatment option that significantly reduces PIGT in patients receiving pertuzumab in combination with chemotherapy. Clinical trial information: NCT04249622 .

Abstract Background: Previous studies demonstrated that activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Further in vivo study showed that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors (ICIs). Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were treated with pembrolizumab 200 mg every 3 weeks plus an oral MEK inhibitor binimetinib. Treatment was started with a 2-week run-in period with single-agent binimetinib. There were 2 dose levels in phase I, including dose level 0 (DL 0) with binimetinib at 45 mg orally twice daily continuously and dose level -1 (DL -1) at 30 mg twice daily. A standard 3+3 design was used in phase I to identify the recommended phase II dose (RP2D) and Simon’s two-stage Optimal design was used in phase II. Results: A total of 22 patients were enrolled. The median age was 58 years old (range 37-77). 14 (63.6%) patients had no prior systemic therapy in the metastatic setting and 8 (36.4%) patients had 1-2 prior lines of therapy. There were 4 patients treated in DL 0. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0 with grade 3 ALT abnormality in one patient and grade 3 flank pain together with grade 3 nausea and vomiting &gt; 48 hours despite anti-emetic therapy in the other patient. Binimetinib dose was reduced to DL -1. In the next 6 patients, there was 1 DLT observed with grade 3 AST/ALT abnormality. Thus, DL -1 was the RP2D, and an additional 12 patients were treated with DL -1 in phase II. Overall, 18 patients were treated in DL -1 and were included in phase II efficacy evaluation. 17 patients were evaluable for response. Objective responses were observed in 5 patients (29.41% 55.96) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR) was 35.29% (95% CI: 14.21 - 61.67) with 6 out of 17 having had CR, PR, or stable disease &gt;= 24 weeks. Since previous studies showed poor responses to ICIs in patients with liver metastases due to macrophage-mediated T cell elimination, we further conduct exploratory analysis to evaluate responses among patients with and without liver metastases. Among all 5 patients with liver metastases, no response was observed. The objective response rate (ORR) in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30) and CBR was 66.67% (95% CI: 29.93-92.51), when excluding 3 patients who discontinued treatment due to adverse events prior to follow-up scans. Median progression-free survival in DL 0 was 2.4 (95%CI: 0.5-NE) and in DL -1 was 8.3 (95% CI: 3.9-NE) months. Median overall survival in DL 0 was 7 (95%CI: 0.5-NE) and in DL -1 was 33.2 (95% CI: 10.3-NE) months. Among patients who responded, 3 out of 5 (60%) had a duration of response greater than 12 months and ongoing even after stopping treatment (range: 5.4 - 32.0 months). Adverse events (AEs) were mostly grade 1-2 including anemia, CPK increase, fatigue, diarrhea, nausea, peripheral neuropathy, acneiform rash, AST increase, cardiac troponin increase, and constipation. Additional correlative studies are ongoing and will be presented at the meeting. Conclusions: Pembrolizumab in combination with binimetinib at 30 mg twice daily appears to be safe with manageable toxicities. Promising activity with durable responses was observed with this combination without chemotherapy, particularly in patients without liver metastases. Future studies are warranted to further evaluate the efficacy of this combination. Citation Format: Saranya Chumsri, Joseph J. Larson, Kathleen S. Tenner, Jun He, Mei-Yin Polley, Morgan T. weidner, Amanda N. Arnold, Dana Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith A. Perez, Keith L. Knutson. Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-17.

Abstract Background Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer (BC) defined by presence of both epithelial and mesenchymal components. Most are triple negative but are often chemo-refractory and associated with poor survival outcomes compared to non-metaplastic triple negative BC. Advances in therapy have led to improvements in survival outcomes of patients (pts) with BC over the last decade. Our multicenter retrospective study aims to assess (1) progression free survival (PFS) and overall survival (OS) (2) factors predictive of survival outcomes in MBC pts Methods We performed a retrospective analysis of pts diagnosed with MBC from 1997-2021 at Mayo Clinic (Florida, Arizona and Rochester) under IRB approval. Kaplan-Meier method was used to estimate OS and PFS at 1, 3 and 5 years. Cox regression models were used to examine the association between risk factors and survival outcomes. All tests were two-sided with p value &lt; 0.05 considered statistically significant Results We evaluated 158 pts with MBC. Median age and tumor size was 61 (range: 20-91) years and 2.8 (range: 0.5-21) cm, respectively, with 80% of pts being postmenopausal. At diagnosis, 14.6% of pts had clinical T3/T4 disease, 16.4% were clinically node-positive, and 6.3% (10 pts) had distant metastases (DM). Spindle cell histology was seen in 36 pts. Most MBC pts were triple-negative (68.3%), high grade (77.2%) and high Ki-67 (36/47; 76.5%). Of the 61 pts tested for germline mutation, 8 (13.1%) were positive, with BRCA1/2, PTEN, NBN, CHEK2, and BARD1 mutations. Most pts had lumpectomy (53.8%), followed by simple mastectomy (38.5), and modified radical mastectomy (7.7%). Majority of pts had sentinel lymph node biopsy (71.8%). Adjuvant radiation therapy was performed in 65.6% of pts. Pathologic complete response (pCR) was noted in 4/38 (10.5%) evaluable pts who received neoadjuvant chemotherapy (NACT). Residual cancer burden (RCB) scores of 2 and 3 were seen in 76.2% of evaluable pts. Median follow-up time was 2.2 years (range: 6 days-24.6 years). Overall, 1-, 3-, and 5-year OS was 93.3%, 81.7%, and 76.0%, while PFS was 80.8%, 67.9%, and 60.9%, respectively. The presence of DM at diagnosis [HR 38.55 (11.18, 132.93), p &lt; 0.001] and spindle cell histology (SC) [HR 2.57 (1.19, 5.53), p = 0.02] predicted worse OS in multivariable analysis. Inferior PFS was predicted by DM [HR 18.84 (6.53, 54.35), p &lt; 0.001], SC [HR 2.46 (1.25, 4.86), p = 0.009], and node-positivity at diagnosis [HR 3.65 (1.5, 8.89), p = 0.004]. The 5-year OS and PFS were 22.2% and 0% for DM pts versus 80.0% and 65.6% for non-DM pts. The 5-year OS and PFS were 71.5% and 54.7% for SC pts versus 81% and 66.6% for non-SC pts. 5-year OS and PFS for NACT pts was 67.3% and 52.6% for NACT pts versus 78.2% and 62.8% for non-NACT pts. Age at diagnosis, menopausal status, family history of BC, grade, stage, tumor size, hormone-receptor and HER2 status, and use of NACT were not found to be significantly associated with OS or PFS in multivariate analysis. Conclusion This study is one of the largest and most recent review of institutional experiences with MBC. Overall, OS at 5 years was improved compared to prior older studies of MBC but still remains very low for those with DM, representing an area of unmet clinical need. SC and DM correlated with worse outcomes for both PFS and OS. Additionally, node positivity at diagnosis was a predictor of worse PFS. In contrast, no association was seen between survival and tumor size, stage, hormone receptor-positivity, HER2 receptor-positivity. The low pCR rates following NACT in our study are consistent with reported literature. Further, use of NACT does not impact survival, suggesting pts with resectable disease should proceed with surgery first. Citation Format: Siven Chinniah, Raza Zarrar, Zhuo Li, Kostandinos Sideras, Alvaro Moreno-Aspitia, Saranya Chumsri, Rohit Rao, Sarah McLaughlin, James Jakub, Emmanuel Gabriel, Sanjay Bagaria, Laura Vallow, Santo Maimone, Pooja Advani. Clinical Factors associated with Survival Outcomes in Patients with Metaplastic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-25.

Abstract Background: SG was approved in 2020 for the treatment of metastatic triple negative breast cancer (TNBC). The most common grade 3/4 adverse event in the ASCENT trial was neutropenia (51.2%) with a 6% incidence of febrile neutropenia. 1 Package insert recommendations do not endorse primary prophylactic growth factor support, rather only initiating if severe neutropenia occurs on treatment.2 Objective: This study retrospectively reviewed the utilization of growth factor support in patients (pts) with metastatic TNBC initiated on SG at each Mayo Clinic Enterprise site. Methods: We performed a multi-center, retrospective review of all pts with TNBC who received SG from January 2021 to December 2021 at Mayo Clinic sites in Minnesota, Florida, Arizona, and its community-based health system network. Data collected included history of neutropenia with previous cycles of SG resulting in a treatment delay, number of cycles, grade of neutropenia and cycle/day of treatment plan when growth factor added. Pts who received only one dose of SG were excluded. The Fisher’s exact test was utilized to compare the difference in the use of primary prophylaxis between sites. Results: 67 pts received at least two doses of SG. Within this cohort, 42 pts (63%) received growth factor support during treatment with SG. Growth factor support was most often added during the first two cycles (59.5%). A total of 12 patients initiated growth factor with no history of delays related to neutropenia and without neutropenia at the time of administration. Eleven of these pts had growth factor support added on Cycle 1 as primary prophylaxis. Primary prophylaxis was most common at Mayo Clinic – Rochester compared to the other sites (Table 1), however there was not a statistically significant difference (p=0.27). There were 26 pts (39%) with a treatment delay due to neutropenia while receiving SG, of which 21 (81%) were managed with the addition of growth factor (13 pegfilgrastim, 8 filgrastim). The median number of cycles for all pts was 5 (range: 1-25). Pts who received growth factor were treated with a median of 5 cycles (range: 1-25) and pts who did not receive growth factor were treated with a median of 4 cycles (range: 1-19) (p=0.10). Conclusions: We observed wide variability in the use of prophylactic growth factor between Mayo Clinic sites with SG. The optimal practice of growth factor use with SG warrants further exploration. References: 1. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541 2. Immunomedics, Inc. Trodelvy (sacituzumab govitecan-hziy) [package insert]. Foster City, CA: Gilead Sciences; 2020. Table 1: Grade of neutropenia for patients receiving SG when growth factor initiated Citation Format: Kaylee Clark, Jamie L. Carroll, Alvaro Moreno-Aspitia, Brenda Ernst, Farah Raheem, Ashley Heil, Beth Boyer, Kristin Mara, Matthew P. Goetz, Roberto A. Leon-Ferre, Karthik V. Giridhar, Jodi Taraba. Mayo Clinic Enterprise patterns of growth-factor utilization for sacituzumab govitecan (SG)-induced neutropenia among patients with metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-56.

Abstract Background: We previously demonstrated that intrinsic subtypes were associated with prognosis for early recurrence risk in patients (pts) with early-stage HER2-positive (HER2+) BC treated with trastuzumab (H) in the N9831 trial. Here, we evaluated the prognostic value of Intrinsic subtypes and 21-gene assay and the risk of early and late recurrence in the N9831 trial. Methods: NanoString custom code set, which included PAM50 and housekeeping genes, was used to quantify mRNA and generated intrinsic subtypes and risk of recurrence (ROR) score from the N9831 trial in Arms A and C: Arm A chemotherapy alone and arm C concurrent H. Quantitative RT-PCR of 21 genes, calculation of the axis, including estrogen axis (ER, PGR, BCL2, SCUBE2), HER2 axis (GRB7, HER2), proliferation axis (Ki67, STK15, Survivin, CCNB1, MYBL2), invasion axis (MMP11, CTSL2), and recurrence score (RS) risk group assignment (RS group 1 and 2: RS &lt; 31 and RS group 3: RS ≥ 31) were performed using Oncotype DX assay. Cox regression models for RFS were used for analysis. Early recurrence was defined as a recurrence that occurred at ≤ 5 years, and late recurrence was defined as recurrence at &gt; 5 years. Results: A total of 783 patients (Arm A 409 and Arm C 374) were included in this analysis. Using multivariate Cox regression analysis to evaluate the risk of early recurrence in patients who received chemotherapy alone in arm A, both invasion genes (MMP11 HR 1.23, 95%CI 1.05-1.44, p 0.01 and CTSL2 HR 1.36, 95%CI 1.1-1.69, p 0.005) and invasion axis (HR 1.64, 95%CI 1.26-2.13, p &lt; 0.001) were associated with a higher rate of early recurrence. CD68 was associated with improved outcomes (HR 0.56, 95%CI 0.38-0.83, p 0.004). For the risk of early recurrence in patients treated with trastuzumab in arm C, ER (HR 0.85, 95%CI 0.74-0.97, p 0.02), PR (HR 0.78, 95%CI 0.64-0.94, p 0.008), and estrogen axis (HR 0.7, 95%CI 0.57-0.87, p 0.001) were associated with improved outcomes. Invasion axis (HR 1.61, 95%CI 1.08-2.41, p 0.02), Oncotype Dx risk group (3 vs. 1 and 2, HR 8.89, 95%CI 1.27-1124, p 0.02), and basal subtype (HR 2.77, 95%CI 1.1-5.95, p 0.03) were also significantly associated with worse outcomes. For risk of late recurrence, in arm A, ER (HR 1.22, 95%CI 1.04-1.44, p 0.02), PR (1.26, 95%CI 1.05-1.5, p 0.01), and estrogen axis (1.39, 95%CI 1.09-1.77, p 0.008) were associated with worse outcomes. Oncotype Dx risk group (3 vs. 1 and 2, HR 0.4, 95%CI 0.16-0.98, p 0.05) was associated with improved outcomes. However, neither individual gene, axis, nor intrinsic subtypes were associated with the risk of late recurrence in patients treated with trastuzumab. Conclusions: For risks of early recurrence, the invasion genes/axis were associated with increased risks of recurrence in patients with early-stage HER2+ BC regardless of trastuzumab treatment. Among patients treated with trastuzumab, ER genes/axis, Oncotype Dx risk group, and intrinsic subtype were prognostic for risks of recurrence in the first five years. For risks of late recurrence, ER genes/axis and Oncotype Dx risk group were prognostic but only in patients treated with chemotherapy alone. The ER genes/axis were associated with less recurrence in the first five years but worse after five years, reflecting a higher risk of late recurrence in ER/PR+ HER2+ BC patients treated with chemotherapy alone. However, none of the individual gene, axis, or intrinsic subtypes were associated with the risk of late recurrence in patients treated with trastuzumab. Therefore, future studies are needed to identify biomarkers for the risk of late recurrence in HER2+ BC patients treated with adjuvant trastuzumab. Support: BCRF-19-161; U10CA180821, U10CA180882, Genentech. https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifier: NCT00005970 Citation Format: Saranya Chumsri, Zhuo Li, Nadine Norton, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Keith L. Knutson, Antonio C. Wolff, Edith A. Perez, E. A. Thompson. Effects of Intrinsic Subtypes and 21-gene Assay on the Early and Late Recurrence Risks in Patients with Early Stage HER2+ Breast Cancer: An Analysis of the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-05.

Abstract Introduction: We performed matched case-control studies utilizing cohorts of postmenopausal women with ER+ breast cancer receiving adjuvant aromatase inhibitors (AI) on MA.27 [anastrozole, exemestane] or PreFace [letrozole] to assess the association between estrogen suppression after 6 months of treatment and an early breast cancer (EBC) event within 5 years of AI initiation (Clin Cancer Res 2020;26:2986-98). We found a significant 3.0-fold increase in risk of an EBC event for those taking anastrozole with levels of estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 pg/mL, but not for exemestane or letrozole. Given these findings we designed a prospective pharmacodynamic (PD) study to evaluate the impact of anastrozole (1 mg/day: ANA1) on E1 and E2 levels, and among those with inadequate estrogen suppression (IES: E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL), to evaluate the safety and PD efficacy of high-dose anastrozole (10 mg/day: ANA10), which has been found to be safe in prior clinical trials (Cancer 1998;83:1142-52). Methods: Post-menopausal women with stage I-III, ER ≥1% positive/HER2-negative breast cancer who were candidates for anastrozole were eligible after completion of locoregional therapy and chemotherapy, as clinically indicated. Women who were pre-menopausal at diagnosis were not eligible. All patients received 8-10 weeks of ANA1, after which those with adequate estrogen suppression (AES: E1&lt; 1.3 pg/mL or E2&lt; 0.5 pg/mL) came off study. Those with IES went on to receive ANA10 for 8-10 weeks, followed by letrozole (2.5 mg/day: LET) for 8-10 weeks. All patients were managed at their treating oncologist’s discretion following study discontinuation. E1 and E2 blood levels were measured pre-treatment and after completion of each treatment cycle by a CLIA-approved liquid chromatography with tandem mass spectrometry in the Immunochemical Core Laboratory at Mayo Clinic. With a sample size of 29 patients with IES after ANA1, a one-sided binomial test of proportions with a significance level of 0.05 will have an 87% chance of rejecting the proportion with AES after ANA10 is at most 25% (Ho) when the true proportion is at least 50%. Specifically, the null hypothesis is rejected if the number of women with AES after ANA10 is 12 or more. Data lock was July 6, 2022. Results: Of the 161 women enrolled from April 2020 through May 2022, 3 withdrew consent prior to start of ANA1 and 2 were ineligible; thus, 156 women comprised the study cohort. Median patient age was 64 years (range 44-86), 10% of patients were of Hispanic ethnicity and/or non-white race, and 15% received chemotherapy. Six patients remain on ANA1, and 10 discontinued ANA1 due to refusal (7), adverse event (AE) (2), or COVID-19 (1). Forty-one of the remaining 140 patients (29.3%; 95%CI: 21.9-37.6%) had IES with ANA1. Nine of these 41 patients did not go on to ANA10 due to refusal (6) or AE (3). Of the 32 patients who started ANA10, 8 remain on treatment, 5 discontinued due to refusal (3) or AE (1-grade 2 urinary tract infection; 1-grade 1 palpitations), and 19 had a blood draw 45 days or more after starting ANA10. No grade 3-5 AEs or grade 2 hot flashes or arthralgias were reported. Of these 19 patients, 14 achieved AES with ANA10 (73.7%; 95%CI: 48.8-90.9%). All 19 patients switched to LET of which 3 remain on treatment, 1 is missing E1/E2 data, and 15 had a blood draw 45 days or more after starting LET. Of these 15 patients, 10 maintained AES, 2 acquired AES with LET, and 3 no longer had AES. Anastrozole and letrozole drug levels will be reported at the meeting. Conclusions: Approximately 29% of postmenopausal women with ER+/HER2- BC receiving adjuvant anastrozole 1 mg/daily had IES. A majority of these patients achieved AES with dose escalation to ANA10 without tolerability issues. E1 and E2 levels are logical biomarkers given the mechanism of action of anastrozole, and further study utilizing them to determine the optimal dose of anastrozole for a given patient should be performed. Citation Format: Tufia C. Haddad, Vera Suman, Karthik V. Giridhar, Alvaro Moreno-Aspitia, Donald Northfelt, Brenda Ernst, Kostandinos Sideras, Ciara C. O’Sullivan, Ravinder Singh, Zeruesenay Desta, Jodi Taraba, Barbara Goodnature, Matthew P. Goetz, Liewei Wang, James N. Ingle. Anastrozole dose escalation for optimal estrogen suppression in postmenopausal early stage breast cancer: A prospective trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-04-02.

Abstract Purpose To determine if the COVID‐19 pandemic has further exacerbated racial disparities in late‐stage presentation of breast, colorectal, lung, and prostate cancers. Methods We conducted a registry‐based retrospective study of patients with newly reported diagnoses of breast, colorectal, lung, and prostate cancers between March 2019–June 2019 (pre‐COVID‐19) and March 2020–June 2020 (early‐COVID‐19). We compared the volume of new diagnoses and stage at presentation according to race between both periods. Results During the study period, a total of 3528 patients had newly diagnosed cancer; 3304 of which had known disease stages and were included in the formal analyses. 467 (14.1%) were Blacks, and 2743 were (83%) Whites. 1216 (36.8%) had breast, 415 (12.6%) had colorectal, 827 (25%) had lung, and 846 (25.6%) had prostate cancers, respectively. The pre‐COVID‐19 period included 2120 (64.2%), and the early‐COVID‐19 period included 1184 (35.8%), representing a proportional 44.2% decline in the volume of new cases of breast, colorectal, lung, and prostate cancers, p < 0.0001. Pre‐COVID‐19, 16.8% were diagnosed with metastatic disease, versus 20.4% early‐COVID‐19, representing a proportional increase of 21.4% in the numbers of new cases with metastatic disease, p = 0.01. There was a non‐significant proportional decline of 1.9% in Black patients diagnosed with non‐metastatic breast, colorectal, lung, and prostate cancers early‐COVID‐19 ( p = 0.71) and a non‐significant proportional increase of 7% in Black patients diagnosed with metastatic disease ( p = 0.71). Difference‐in‐difference analyses showed no statistically significant differences in metastatic presentation comparing Black to White patients. Conclusion While we identified substantial reductions in the volume of new cancer diagnoses and increases in metastatic presentations due to the COVID‐19 pandemic, the impact was similar for White and Black patients.

Abstract Background: Previous studies showed conflicting results regarding association between stromal tumor infiltrating lymphocytes (sTIL) and outcome in HER2+ breast cancer. While sTIL were not associated with outcome in patients (pts) treated with trastuzumab in N9831, immune functions genes are linked to outcome in these pts. TLS is an organized form of ectopic lymphoid aggregates (LA) with secondary lymphoid organ structure. Several studies showed that TLS associates with improved outcome in multiple cancers. However, distinguishing TLS and simple LA is challenging, particularly when germinal center is absent. In this study, we evaluated integrated pathological quantification and genomic data to assess functional TLS. Methods: Pathological evaluation of LA in H&E slides from pts treated in Arm A (chemotherapy alone) and Arm C (chemotherapy with concurrent trastuzumab) in N9831 was performed. NanoString was used to quantify mRNA. Wilcoxon rank sum test, Chi squared test, Kaplan-Meier method and Cox regression model were used to evaluate association between LA and baseline characteristics as well as outcomes. Results: LA was quantified in 1011 pts (526 Arm A, 485 Arm C). Greater number of LA was significantly associated with higher tumor grade, ER/PR negativity and increasing sTIL, but not age, tumor size or lymph node status. Increasing numbers of LA were associated with improved RFS in both arms combined (p 0.028). However, using multivariable Cox regression analysis in each treatment arm, LA (≥ 1 vs 0) was associated with improved RFS only in Arm A (HR 0.6, 95%CI 0.43-0.84, p 0.003) but not Arm C (HR 0.72, 95%CI 0.47-1.1, p 0.134). Further evaluation of expression of TLS-related immune genes including IFNG, ICOSLG, CXCL13, CXCR3, BCL6, IL21R, ICOS, PDCD1, CXCR5, CXCL9, TBX21, CD38, CXCL10, CLXCL11, IL21, CD200 was carried out among 252 pts in Arm C with LA ≥ 1. Among these 16 TLS-related immune genes, as a continuous variable, higher expression of BCL6 (HR 0.61, 95%CI 0.41-0.92, p 0.019) and IL21R (HR 0.78, 95%CI 0.62-0.98, p 0.03) were associated with improved RFS in Arm C pts with LA ≥ 1. However, these genes were not significantly associated with outcome in Arm C pts without LA with BCL6 HR1.07 (95%CI 0.67-1.71, p 0.776) and IL21R HR 0.96 (95%CI 0.71-1.29, p 0.775). Conclusion: Similar to sTIL, greater number of LA was associated with improved outcome in HER2+ pts treated with chemotherapy alone but not chemotherapy in combination with trastuzumab. Using histogenomic integration with the combination of pathological LA and TLS-related immune genes, we identified that pts with functional TLS with LA ≥ 1 and higher expression of BCL6 or IL21R had significantly improved outcome when treated with trastuzumab. Future studies are needed to further confirm these findings. Support: U10 CA180821, U24 CA196171, https://acknowledgments.alliancefound.org; Genentech; Clinicaltrials.gov Id: NCT00005970 Citation Format: Saranya Chumsri, Tracy R. Shachner, Zhuo Li, Nadine Norton, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Edith A. Perez, E. A. Thompson, Aziza Nassar, Keith L. Knutson. Functional tertiary lymphoid structure (TLS) and outcome in HER2-positive (HER2+) breast cancer in NCCTG N9831 (Alliance) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5627.