Neoadjuvant Setting Research Articles

Abstract A009: Integrative drug screening and multi-omic characterization of patient-derived bladder cancer organoids reveals novel molecular correlates of chemotherapy response

Abstract Introduction: Predicting response to therapy for each patient’s tumor is critical to improving long-term outcomes for muscle-invasive bladder cancer (MIBC). Our objective is to establish ex vivo bladder cancer patient-derived organoid (PDO) models that are representative of patients’ tumors and determine potential efficacy of standard-of-care and curated experimental therapies. Methods: Tumor material was prospectively collected from consented patients with bladder cancer to generate short-term PDO models, which were screened against a panel of clinically relevant drugs in ex vivo 3D culture. Drugs were tested at the maximum plasma concentration (Cmax) in human trials, so as to provide physiologic relevance. When material was sufficient, cells were additionally tested using full dose response. The number of drugs screened was dependent upon amount of tissue available, with up to 34 drugs screened at Cmax and 9 drugs screened in dose response format. Multiomic profiling was utilized to validate the PDO models, establish the molecular characteristics of each tumor, assess gene expression (GEX) patterns between paired primary tissue and PDOs, and identify potential biomarkers of drug response using Pearson correlation coefficients and Kruskal-Wallis tests with Dunn’s post-hoc pairwise comparison testing. Results: 106 tumors were collected from 97 patients, with 65 samples yielding sufficient material for complete multiomic molecular characterization and PDO screening with 6 to 32 drugs/combinations. RNA sequencing and GSEA enriched pathways across organoids were compared to other published datasets, noting high levels of correlation between our organoid models and in particular the Cancer Cell Line Encyclopedia urethral lines. Moreover, analysis of subtype and mutation/copy number data further indicate that our organoid dataset is representative of the full spectrum of disease. RNA sequencing and subtyping of cultured organoids compared to patient tissue indicate that organoid models are representative of patient tissue and do not undergo subtype shifts in our short-term 3D cultures. Our drug screening results highlight the large spectrum of response to chemotherapies that in fact, clinically benefit only a small proportion of patients in the neoadjuvant setting. Utilizing an integrative approach, novel correlations between ex vivo drug responses and genomic alterations, GEX, and protein expression were identified, including a multiomic signature of gemcitabine response. Conclusions: Rapid organoid development, characterization, and drug screening allows for the prediction of therapeutic response in ~10 days following sample collection. Use of this technique on tissue provided during disease work-up may further guide selection of effective therapeutic agents in patients with bladder cancer, beyond the typical unranked lists derived from genomic analyses. This work would help maximize the overall benefits of standard of care therapies and could be used to identify alternative therapeutics for patients who progress on standard therapies. Citation Format: Nathan M. Merrill, Samuel D. Kaffenberger, Liwei Bao, Nathalie Vandecan, Laura E. Goo, Athena Apfel, Xu Cheng, Zhaoping Qin, Chia-Jen Liu, Armand Bankhead, Yin Wang, Varun Kathawate, Lila Tudrick, Habib Serhan, Zackariah Farah, Chad Ellimoottil, Khaled S. Hafez, Lindsey A. Herrel, Jeffrey S. Montgomery, Todd M. Morgan, Simpa S. Salami, Alon Z. Weizer, Peter J. Ulintz, Mark L. Day, Matthew B. Soellner, Phillip L. Palmbos, Sofia D. Merajver, Aaron M. Udager. Integrative drug screening and multi-omic characterization of patient-derived bladder cancer organoids reveals novel molecular correlates of chemotherapy response [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A009.

Efficacy and Toxicity Analysis of mFOLFIRINOX in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

High-grade neuroendocrine neoplasms (NENs) comprise both well-differentiated grade 3 neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) nearly always include poorly differentiated NEC as the neuroendocrine component. The efficacy and safety of frontline mFOLFIRINOX chemotherapy has never been investigated in patients with high-grade NENs. We conducted a multi-institutional retrospective analysis of patients with advanced high-grade NEN of the gastroenteropancreatic tract or of unknown origin seen between February 2016 and April 2023 who received treatment with frontline mFOLFIRINOX. A total of 35 patients were included (G3 NETs: n=2; NECs: n=25; MiNENs: n=8; stage III: n=5; stage IV: n=30). The objective response rate was 77% (complete response: 3%; partial response: 74%). Median progression-free survival was 12 months (95% CI, 9.2-16.2 months) and median overall survival was 20.6 months (95% CI, 17.2-30.6 months). No significant differences in efficacy were seen according to primary site, histopathology, and Ki-67 proliferative index. All 5 patients with stage III disease who received mFOLFIRINOX obtained an objective response and underwent radical surgery or definitive radiotherapy with curative intent, with a recurrence rate of 40%. Grade 3 or 4 adverse events were observed in 43% of patients (mainly neutropenia and diarrhea). Females were at significantly increased risk of developing severe toxicities. mFOLFIRINOX shows antitumor activity against high-grade NENs. Well-designed, prospective clinical trials are needed to assess the efficacy of mFOLFIRINOX in both the neoadjuvant and metastatic settings.

Multifactoral immune modulation potentiates durable remission in multiple models of aggressive malignancy.

Tumors typically lack canonical danger signals required to activate adaptive immunity and also frequently employ substantial immunomodulatory mechanisms that downregulate adaptive responses and contribute to escape from immune surveillance. Given the variety of mechanisms involved in shielding tumors from immune recognition, it is not surprising that single-agent immunomodulatory approaches have been largely unsuccessful in generating durable antitumor responses. Here we report a unique combination of immunomodulatory and cytostatic agents that recondition the tumor microenvironment and eliminate complex and/or poor-prognosis tumor types including the non-immunogenic 4T-1 model of TNBC, the aggressive MOC-2 model of HNSCC, and the high-risk MYCN-amplified model of neuroblastoma. A course of therapy optimized for TNBC cured a majority of tumors in both ectopic and orthotopic settings and eliminated metastatic spread in all animals tested at the highest doses. Immune responses were transferable between therapeutic donor and naïve recipient through adoptive transfer, and a sizeable abscopal effect on distant, untreated lesions could be demonstrated experimentally. Similar results were observed in HNSCC and neuroblastoma models, with characteristic remodeling of the tumor microenvironment documented in all model systems. scRNA-seq analysis implicated upregulation of innate immune responses and antigen presentation in tumor cells and the myeloid cell compartment as critical early events. This analysis also highlighted the potential importance of the autonomic nervous system in the governance of inflammatory processes. The data indicate that the targeting of multiple pathways and mechanisms of action can result in substantial synergistic antitumor effects and suggest follow-up in the neoadjuvant setting may be warranted.

Integrated management of stage III in nonsmall cell lung cancer: where do perioperative chemotherapy and immunotherapy fit?

Early-stage nonsmall cell lung cancer (NSCLC) accounts for 30% of the total NSCLC, being the stage III a heterogeneous disease that represents a challenge in the management of these patients. Multidisciplinary approach is essential for an adequate treatment strategy, with surgery being the only curative treatment. Neoadjuvant or adjuvant chemotherapy has been the standard of care for a long period, with modest results. Combination of chemotherapy and immunotherapy has revolutionized the neoadjuvant setting of resectable NSCLC, improving pathologic complete responses and survival outcomes in this scenario. Furthermore, perioperative treatment with immunotherapy has also recently shown promising results in several phase III trials. The landscape of early-stage resectable NSCLC has evolved in recent years, with an improvement in the survival of these patients since the incorporation of immunotherapy in this scenario.

Efficacy and safety of BRAF/MEK inhibitors in BRAFV600E-mutated anaplastic thyroid cancer: a systematic review and meta-analysis.

Approximately 45% of anaplastic thyroid cancer (ATC) patients harbor a BRAFV600E mutation and are eligible for target therapy (TT) with BRAF and MEK inhibitors (BRAFi/MEKi), nevertheless, few data advocate for this. Hence, we've conducted a systematic review and meta-analysis investigating the effectiveness and safety of BRAFi/MEKi in BRAFV600E ATC patients. PubMed, Embase, and the Cochrane Library were systematically searched for BRAFi/MEKi TT in BRAFV600E ATC patients. Outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response (DOR) and adverse events (AEs). Nine studies with 168 patients were included. Median follow-up ranged from 2.0 to 47.9 months. 75% of patients had stage IVc. In a pooled analysis, ORR was 68.15% (95% CI 55.31-80.99, I2 = 47%) and DCR was 85.39% (95% CI 78.10-92.68, I2 = 0), with a median DOR of 14.4 months (95% CI 4.6-14.4) and a median PFS of 6.7 months (95% CI 4.7-34.2). Moreover, 1-year OS rate was 64.97% (95% CI 48.76-81.17, I2 = 84%) and 2-years OS rate was 52.08% (95% CI 35.71-68.45, I2 = 79%). Subgroup analysis showed patients in the neoadjuvant setting had higher rates of 1 and 2-years OS and observational studies tended to report higher rates of ORR than clinical trials. No new or unexpected adverse events were found. Our study demonstrated BRAFi/MEKi have a decent activity for BRAFV600E ATC patients, especially in the neoadjuvant setting, with a tolerable safety profile. However, further clinical trials are warranted to investigate these findings.

Comparing niraparib versus platinum-taxane doublet chemotherapy as neoadjuvant treatment in patients with newly diagnosed homologous recombination–deficient stage III/IV ovarian cancer: study protocol for cohort C of the open-label, phase 2, randomized controlled multicenter OPAL trial

BackgroundMaintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, has been shown to extend progression-free survival in patients with newly diagnosed advanced ovarian cancer who responded to first-line platinum-based chemotherapy, regardless of biomarker status. However, there are limited data on niraparib’s efficacy and safety in the neoadjuvant setting. The objective of Cohort C of the OPAL trial (OPAL-C) is to evaluate the efficacy, safety, and tolerability of neoadjuvant niraparib treatment compared with neoadjuvant platinum-taxane doublet chemotherapy in patients with newly diagnosed stage III/IV ovarian cancer with confirmed homologous recombination–deficient tumors.MethodsOPAL is an ongoing global, multicenter, randomized, open-label, phase 2 trial. In OPAL-C, patients will be randomized 1:1 to receive three 21-day cycles of either neoadjuvant niraparib or platinum-taxane doublet neoadjuvant chemotherapy per standard of care. Patients with a complete or partial response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) will then undergo interval debulking surgery; patients with stable disease may proceed to interval debulking surgery or alternative therapy at the investigator’s discretion. Patients with disease progression will exit the study treatment and proceed to alternative therapy at the investigator’s discretion. After interval debulking surgery, all patients will receive up to three 21-day cycles of platinum-taxane doublet chemotherapy followed by niraparib maintenance therapy for up to 36 months. Adult patients with newly diagnosed stage III/IV ovarian cancer eligible to receive neoadjuvant platinum-taxane doublet chemotherapy followed by interval debulking surgery may be enrolled. Patients must have tumors that are homologous recombination–deficient. The primary endpoint is the pre–interval debulking surgery unconfirmed overall response rate, defined as the investigator-assessed percentage of patients with unconfirmed complete or partial response on study treatment before interval debulking surgery per RECIST v1.1.DiscussionOPAL-C explores the use of niraparib in the neoadjuvant setting as an alternative to neoadjuvant platinum-taxane doublet chemotherapy to improve postsurgical residual disease outcomes for patients with ovarian cancer with homologous recombination–deficient tumors. Positive findings from this approach could significantly impact preoperative ovarian cancer therapy, particularly for patients who are ineligible for primary debulking surgery.Trial registrationClinicalTrials.gov NCT03574779. Registered on February 28, 2022.

Abstract PO1-03-07: Revisiting the potential of pathological complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer at the trial-level

Abstract Background: Pathological complete response (pCR) has been used as a primary endpoint in neoadjuvant clinical trials for non-metastatic breast cancer and as a surrogate endpoint for long-term survival outcomes. The U.S. Food and Drug Administration (FDA) accepted pCR as a surrogate endpoint for the approval of new drugs in the neoadjuvant setting in high-risk early-stage breast cancer. However, though the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) pooled analysis in 2014 showed that at the patient level achieving pCR was associated with longer overall survival (OS) and event-free survival (EFS), at the trial-level the association between high pCR rate and better OS and EFS outcomes was weak (coefficient of difference [R2]; 0.03 and 0.24, respectively) among all subtypes of breast cancer. A recent study reported that this association at the trial-level was similarly weak among Human Epidermal Growth Factor Receptor-2 (HER-2) positive breast cancer (R2; 0.02 and 0.23, respectively). However, the potential surrogacy of pCR rate for OS and EFS in triple-negative breast cancer (TNBC) in the neoadjuvant setting has not been well studied in a comprehensive manner. Moreover, because of significant advances in systemic treatment strategies in TNBC over the past decade including a combination of immune checkpoint inhibitors (ICIs) with conventional cytotoxic agents, the trial-level surrogacy needs to be reassessed in recently published neoadjuvant clinical trials for TNBC. Our primary objective is to assess the association between pCR rate and survival outcomes in neoadjuvant clinical trials for TNBC by collecting data from articles published after the CTNeoBC article in 2014. Methods: We performed a systematic literature search based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed, Cochrane Library, and Web of Science databases. Articles published between January 1, 2014, and March 31, 2023, were searched. We included only randomized control trials of neoadjuvant treatments for clinical stage I-III TNBC that compared two or more regimens followed by curative intent breast surgery. The selected trials had data for odds ratio (OR) for pCR and hazard ratios (HRs) either for OS or for EFS or disease-free survival (DFS). We excluded trials including estrogen receptor positive, progesterone receptor-positive, or HER-2 positive diseases, and those without data enough to obtain ORs for pCR, HRs for OS, EFS, or DFS. Unpublished data as a full article was also excluded. If EFS could not be obtained from the articles, DFS was used in place of EFS. Two independent investigators (TY and TF) searched and extracted data. Any disagreement was resolved by discussion with the third author (ZZ). A linear regression model on a logarithmic scale weighted by the sample size of each trial was performed and the R2 was used to assess the trial-level association between OR for pCR and HRs for OS or EFS. Results: We identified eight trials with a total of 2,926 patients. Three of the eight trials used ICIs in the intervention arm. One trial did not provide OS data and was not included in the OS analysis. In four trials, EFS was not available and DFS was used for EFS analysis. The R2 was 0.191 (95% confidence interval [CI], 0.165 to 0.218) for OS and 0.193 (95% CI, 0.167 to 0.219) for EFS. Conclusions: Similarly to the previous reports, our findings suggest that the surrogacy of the pCR rate for OS and EFS in recent neoadjuvant clinical trials for TNBC is weak. At this moment, there is no strong evidence to support using pCR as a surrogate for long-term survival outcomes in neoadjuvant clinical trials for TNBC. Citation Format: Toru Yoshino, Zao Zhang, Ryota Sato, Stanley Lipkowitz, Takeo Fujii. Revisiting the potential of pathological complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer at the trial-level [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-07.

Abstract PO5-18-02: A Population-Based Analysis of the Impact of Omission of Anthracyclines in the Neoadjuvant Setting on the Risk of Mortality

Abstract Background Most patients with high-risk non-metastatic breast cancer are treated with neoadjuvant chemotherapy (NAC), which includes the administration of anthracyclines. The omission of anthracyclines was shown to be associated with excellent outcomes in selected patients. However, the extent to which anthracyclines are omitted among a population of women treated with NAC and its impact on mortality remain unclear. Objective To investigate the extent to which anthracyclines are omitted among a population of patients with invasive breast cancer treated with NAC and to examine the impact of non-anthracycline NAC on risks of breast cancer-specific and all-cause mortality. Methods We performed a retrospective population-based cohort analysis using patient-level health administrative data. The cohort includes women aged ≥18 years with stage I – III invasive breast cancer diagnosed between January 2012 and December 2020, treated with NAC and surgery. Patients were excluded if they received < 50% of the planned chemotherapy regimen, had bilateral breast cancer and/or a previous malignancy. The exposure of interest was anthracycline versus non-anthracycline NAC regimen. The primary and secondary endpoints were breast cancer-specific mortality and overall (all-cause) mortality. Multivariable Cox proportional hazards models adjusted by propensity score, and clinical/pathologic variables including a measure of comorbidity was performed to examine impact of omission of anthracyclines on outcomes. Cumulative incidence curves were generated to calculate the 5-year cumulative incidence of breast cancer and all-cause mortality for the whole cohort and in subset analyses, stratified by stage and receptor subtype. Results The cohort includes 4,180 women. Median follow was 62 months (IQR 44-85) and median age was 51 years (IQR 43-60). Most patients had low co-morbidities (96.0%), Stage II (44.1%) or Stage III (47.7%) disease, underwent mastectomy (72.6%), had axillary node dissection (64.4%) and received post-operative radiotherapy (88.8%). 279 (6.7%) individuals were treated with a non-anthracycline NAC and 3,901 (93.3 %) received an anthracycline NAC. Women who received non-anthracycline NAC were older (median 62 years vs. 50 years; p< 0.001), more likely to have stage I-II disease (77.0% vs. 51.3%; p< 0.001), and more likely to have triple-negative breast cancer (TNBC) (14.0% vs. 24.4%; p< 0.001) than those who received anthracyclines.On propensity adjusted multivariable analysis, factors associated with an increased risk of BC mortality include Stage III (HR 9.3, 95%CI 4.5 - 19.2, p< 0.0001) or stage II at presentation (HR 2.57 95% CI 1.24, 5.34, p=.01) (ref: stage I) or triple negative subtype (HR 3.7 95% CI 3.03, 4.51, p< .0001) (ref: hormone positive/HER2-). There was no significant difference in the relative risks of BC death (HR 0.8, 95% CI 0.5-1.27) or all-cause mortality (HR 0.85, 95% CI 0.60-1.21) for patients selected for treatment without anthracyclines compared to those treated with anthracyclines.Overall, among individuals selected for treatment without or with anthracycline NAC there was no significant difference in the 5-year cumulative incidence of BC (15.4% vs 10.5%, P=.05) or all-cause mortality (16.4% vs 11.9%, P=.07). However, the 5-year cumulative incidence of BC specific death (31.8% vs 16.5%, p=.03) and 5-year cumulative incidence of all-cause death (31.8% vs. 18.2%, p=.06) was higher among 420 women with HER2+ Stage III breast cancer who received non-anthracycline versus anthracycline-based chemotherapy. No difference was observed for other subgroups. Conclusions The omission of anthracyclines in NAC for individuals with stage III HER2+ breast cancer was associated with higher cumulative risks of breast cancer and all-cause mortality but no difference was observed for other subgroups. Further research is warranted to better understand in whom anthracyclines can be safely omitted. Citation Format: Danilo Giffoni M. M. Mata, Rinku Sutradhar, Matthew Castelo, Lena Nguyen, Danielle Rodin, Ezra Hahn, Omolara Fatiregun, Cindy Fong, Sabina Trebinjac, Andrea Eisen, Lawrence Paszat, Katarzyna Jerzak, Eileen Rakovitch. A Population-Based Analysis of the Impact of Omission of Anthracyclines in the Neoadjuvant Setting on the Risk of Mortality [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-02.

Abstract PO5-17-04: Tolerability of pertuzumab in older adults with HER2 positive breast cancer: A single institution experience

Abstract Background: Tumor HER2 over-expression occurs in 10 to 15% of older adults with breast cancer (BC). Combination HER2-directed therapy (pertuzumab and trastuzumab) with chemotherapy (CT) is the standard treatment for early and advanced HER2-positive bc. However, a study of more than 1,300 Medicare beneficiaries showed that about half of patients (pts) aged 65 or older with stage I to III HER2 positive bc did not receive trastuzumab-based therapy. This is likely due to concern for tolerability as older women remain underrepresented in clinical trials of breast cancer making it difficult to extrapolate tolerability of these agents in these patients. In the Neosphere and TRYPHAENA studies, the mean age of pts were 49.8 and 50.6 years, respectively. We examined the real-world tolerability of pertuzumab in combination with trastuzumab and systemic ct in women over the age of 65 with HER2 positive bc. Methods: An IRB approved retrospective review of medical records was conducted evaluating pts over the age of 65 with early or advanced HER2 positive bc treated at The Ohio State University Comprehensive Cancer center from January 1, 2015 to May,1 2020. Descriptive statistics (means, standard deviations, medians and ranges for continuous variables and frequencies and percents for categorical variables) were used to summarize disease and patient characteristics for pts enrolled in this study and treated with pertuzumab. The total number of planned and completed cycles of treatment as well as the number of treatment delays and dose reductions were also summarized using frequencies and percentages. The same descriptive statistics were used to summarize the number of grade II or IV toxicities and pathologic complete response (pCR) in the neoadjuvant setting. Results: A total of 71 pts met inclusion criteria. Mean age was 76 years (SD 4.1). Of these pts, 62 had stage I-III disease and 9 had metastatic disease. Additionally, 68% (48/71) had estrogen positive (ER) disease whereas 32% (23/71) had ER negative disease. Neoadjuvant systemic therapy was provided to 81% (50/62) of non-metastatic pts and 19% (12/62) received adjuvant therapy. The median number of completed neoadjuvant cycles (ct plus trastuzumab and pertuzumab) was 5.4 (SD 1.5). Among those who received pertuzumab with systemic ct in the neoadjuvant setting, 46% (23/50) of pts achieved a pCR (56% for ER negative disease and 41% for ER positive disease) The median number of completed adjuvant cycles (ct plus trastuzumab and pertuzumab) was 4.9 (SD 2.0). Pts with stage I to III disease completed a mean of 8.6 (SD 5.0) targeted therapy cycles (pertuzumab/trastuzumab). Pts with metastatic disease had a median of 5.7 (SD 1.0) cycles of ct plus trastuzumab and pertuzumab and received a mean of 34.4 (SD 36.0) cycles of maintenance pertuzumab. Treatment delay by 7 or more days occurred in 11% (8/71) of pts whereas 25% (18/71) of pts discontinued pertuzumab early. Pertuzumab termination occurred due to toxicity in 44% (8/18), metastasis in 11% (2/18), and other causes in 44% (8/18) of cases. For toxicities, 2% (1/51) of patients reported grade 3 pain, 25% (2/8) reported grade 3 fatigue, and 12% reported grade 4 diarrhea (1/8) (Table 1). Conclusions: Our study showed that pertuzumab was well tolerated in older pts with bc in the real-world setting. However, 25 % of pts still discontinued pertuzumab early which illustrates the importance of identifying pts who are at higher risk for toxicities prior to starting treatment. Table 1 Reported adverse events in patients age 65 and older receiving pertuzumab Citation Format: Nicole Williams, Austin Warmbier, Dureti Doto, Marilly Palettas, Julie Stephens, Dionisia Quiroga, Kai Johnson, Ashley Pariser, Mathew Cherian, Sagar Sardesai, Daniel Stover, Margaret Gatti-Mays, Robert Wesolowski, Bhuvana Ramaswamy. Tolerability of pertuzumab in older adults with HER2 positive breast cancer: A single institution experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-17-04.

Abstract PO4-01-03: Dual anti-HER2 Therapy with Pertuzumab and Trastuzumab versus Trastuzumab Alone in Addition to Anthracycline and Taxane-Based Neoadjuvant Therapy in Patients with HER2-Positive Early-Stage Breast Cancer; Real-World Data

Abstract Background: When use in the neoadjuvant setting, anti-HER2 targeted therapy had improved pathologic complete response rate (pCR) in patients with HER2-positive early-stage breast cancer (EBC). Here we present real-world data on the use trastuzumab with or without pertuzumab on the backbone of anthracycline and taxanes-based NSAPB-B27 chemotherapy regimen. Methods: We retrospectively reviewed records of patients with HER2-positive EBC who received neoadjuvant therapy using the National Surgical Adjuvant Breast and Bowel Project (NSABP)-B27 protocol (4 cycles of adriamycin and cyclophosphamide, followed by 4 more cycles of docetaxel; all given every 3 weeks) with anti-HER2 therapy from Jan 2014 to September 2021, treated at a tertiary care cancer center. The clinicopathological features, treatment received, and outcome were collected from patients’ electronic medical records. We estimated 3-year disease-free survival (DFS), a validated endpoint in HER2-positive EBC, using Kaplan-Meier with recurrence and/or death as events. Outcomes were reported in subgroups based on known prognostic factors. Results: The study comprised 528 patients with a median follow-up of 36 months. Median age was 48 (21-80) years. Hormone receptors (HR) were positive in 379 (71.8%), lymph node-involvement prior to neoadjuvant therapy was reported in 402 (76.1%) patients and 319 (60,4%) had grade-3 disease. Majority (n= 482, 91.3%) were labeled HER2-positive based on immunohistochemistry staining (IHC+3) and the rest were based on IHC+2 with positive FISH/ISH. Dual anti-HER2 therapy (trastuzumab and pertuzumab) was used in 316 (59.8%) patients, single agent trastuzumab in 173 (32.8 %) patients, while 39 (7.4%) others did not receive any anti-HER2 therapy. Except for 9 (1.7%) patients who progressed while on treatment, all patients underwent surgery. Among the whole group, 225 (43.4%) achieved pCR; significantly higher (n=80, 53.7%) in HR-negative compared to 38.3% among those with HR-positive disease, p=0.002. Additionally, pCR was higher in patients who received dual anti-HER2 (46.2%) compared to 39.3% for those treated with trastuzumab and 28.2% for those who did not receive anti-HER2 therapy. Following surgery, 463 (89.4%) of the patients received adjuvant trastuzumab, however, none of them received pertuzumab or TDM1 in adjuvant sitting. Estimated 3-year DFS was 86.1% with dual anti-HER2 and 83.0% with trastuzumab alone, p=0.19. However, DFS was better among those with node-negative disease; 96.5% compared to 80.9% in node-positive disease, p= < 0.001. Patients who achieved pCR had significantly better 3-year DFS; 89.3% compared to 80.2% in patients with residual disease, p= 0.006. Conclusions: Even with the wide use of pertuzumab in the neoadjuvant setting, the DFS was not improved compared to trastuzumab alone, and this highlights the importance of switching trastuzumab to TDM1, or to continue with pertuzumab in the adjuvant setting in patient with residual disease. Citation Format: Baha' Sharaf, Faris Tamimi, Osama Salama, Anas Zayed, Osama El Khatib, Suhaib Khater, Malek Horani, Suhaib Al-Sawajneh, Yosra AL-Masri, Hikmat Abdel-Razeq. Dual anti-HER2 Therapy with Pertuzumab and Trastuzumab versus Trastuzumab Alone in Addition to Anthracycline and Taxane-Based Neoadjuvant Therapy in Patients with HER2-Positive Early-Stage Breast Cancer; Real-World Data [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-01-03.

Abstract PO3-03-11: Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative breast cancer

Abstract Background: Discordance in hormone receptor (HR) and/or HER2 status between matched primary tumors and residual specimens following neoadjuvant therapy is a known phenomenon. In the neoadjuvant setting, systemic treatment is primarily informed by the HR and HER2 status from the diagnostic biopsy. Current guidelines recommend additional adjuvant capecitabine and/or pembrolizumab and/or olaparib for patients with triple-negative breast cancer (TNBC) after neoadjuvant systemic therapy if residual disease is present at the time of surgery. Discordance in biomarker status between the initial diagnosis and residual cancer may impact postoperative systemic therapy recommendations. This study aims to investigate the discordance rate in HR and HER2 status after neoadjuvant chemotherapy (NAC) plus pembrolizumab in early-stage TNBC. Furthermore, given the emerging data in support of novel antibody-drug conjugates (ADCs) for HER2-low breast cancer, the prevalence of HER2-low disease following standard-of-care neoadjuvant therapy may have critical clinical importance. Methods: We performed a single-institution, retrospective study of early-stage TNBC patients diagnosed between February 1st, 2020 and December 1st, 2022 who were treated with neoadjuvant chemotherapy and pembrolizumab. Patients who had not undergone definitive surgery were excluded. Demographic information, clinical and pathologic characteristics, and treatment data were collected from an institutional database. Pathologic complete response (pCR) was defined as ypT0/Tis and ypN0. HR and HER2 status before and after neoadjuvant therapy were collected. This study was approved by an Institutional Review Board. Results: Among the 94 patients included the median age was 55 years (IQR 47.0-61.8). The majority of patients had invasive ductal carcinomas (90.4%), were clinical T2 stage (68.1%), and node negative (55.3%). On the core tumor biopsy, estrogen receptor (ER) was < 1% in 90 (95.7%) patients and 1-10% in 4 (4.3%) of patients. Progesterone receptor (PR) was < 1% in 91 (96.8%) of patients and 1-10% in 3 (3.2%) of patients. HER2 was 0 by IHC in 49 (52.1%) patients, 1+ in 30 (31.9%) patients, 2+ in 11 (11.7%) patients, and not performed in 4 (4.3%) patients. A pCR (ypT0/Tis ypN0) was achieved in 60 (63.8%) of the 94 patients. In the 34 patients with residual disease, 29 patients had ER status evaluated at the time of surgery. Of these patients, 4 had tumors with ER < 1% at baseline but >5% at surgery. 28 patients with residual disease had PR evaluated at the time of surgery. Of these patients, all had tumors with PR < 1% at the time of surgery. 28 patients had residual tumors with HER2 status evaluated at the time of surgery (table). Of these patients, 18 (64.3%) tumor specimens were HER2-ultra-low, 9 (32.1%) were HER2-low-positive, and 1 (3.6%) was HER2-positive. Conclusion: Receptor discordance from the time of initial biopsy to residual disease can occur in patients with early-stage TNBC treated with NAC with pembro. As additional systemic therapy is indicated in patients who do not achieve pCR, accurate tumor marker status is critical. This study highlights the potential impact of reassessment of HR and HER2 status on the surgical tumor specimen. Clinical trials that tailor adjuvant therapy recommendations based on residual biomarker analyses may further improve outcomes for women with high risk TNBC. Table. Discordance in HER2 Status Between Primary Tumor and Residual Specimen Citation Format: Alexis LeVee, Megan Wong, Sarah Flores, Nora Ruel, Heather McArthur, James Waisman, Joanne Mortimer. Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-11.

Abstract PO4-08-10: Genetic mutations and associated rates of pathologic complete response among a diverse patient population with early stage triple negative breast cancer

Abstract Background: Combination treatment with chemotherapy and immunotherapy remains the standard of care for high risk, early-stage triple negative breast cancer (TNBC). Although the addition of immunotherapy improves rates of pathologic complete response (pCR) and event-free survival, approximately 50% of patients achieve pCR with neoadjuvant chemotherapy alone suggesting that some patients may safely avoid the potential toxicities of immunotherapy without compromising outcomes.1,2 Markers of immune activation including PD-L1 expression and tumor infiltrating lymphocytes have demonstrated prognostic significance; however, identifying a predictive biomarker to aid in selecting those patients most likely to benefit from immunotherapy remains an unmet need.3,4 Genetic mutations are suggestive of DNA susceptibility to damage and the role they may play as a potential marker of immune response is unclear.5,6 This study explores genetic analysis and mutation rates among a diverse cohort of patients with TNBC to identify patterns associated with and without pCR. Methods: We evaluated 105 women diagnosed with Stage I-III TNBC and treated with combination neoadjuvant chemotherapy and immunotherapy at Ochsner Cancer Center between December 2019 through June 2022. Exclusion criteria included ER+, PR+, HER2+, or unknown receptor status, no pembrolizumab in the neoadjuvant setting, no definitive surgery following neoadjuvant treatment, absence of documented race and age less than 18 years of age. Data was collected utilizing Epic Slicer Dicer program, in addition to chart review. Genetic analysis was performed using a variety of DNA-based next generation sequencing analysis platforms. Results: 91 patients met inclusion criteria. 17 patients were found to have pathogenic mutations (BRCA1/2, POLE and ATM), 38 patients had variants of undetermined significance (VUS) and 36 patients had neither. Among patients with pathogenic genetic mutations, 81.25% had a pCR following neoadjuvant treatment compared to 58.33% of those with a VUS and 47.06% of those with no known mutation (p=0.07). Before adjusting for age and stage, patients with a pathogenic mutation were 73% more likely to achieve pCR than those with no known genetic mutations (crude RR: 1.73, 95% CI: 1.13-2.65). After adjusting for age and stage, the relationship was not statistically significant (aRR: 1.15, 95% CI: 0.78-1.34). Among the 47 Black patients, 5 were found to have a pathogenic mutation and 29 had a VUS. 11 of the 39 White patients were found to have a pathogenic mutation while only 6 had a VUS. Across all genetic mutation categories, Black patients experienced lower rates of pCR than White patients. White patients with a known pathogenic mutation had the highest rate of pCR at 90.91%, while Black patients with no identified mutation had the lowest rate of pCR at 38.46%. The generalizability of these results may be limited due to small sample size. Conclusion: Our results demonstrating higher rates of genetic variants among patients achieving pCR regardless of race highlight the importance of better understanding how these variants correlate with tumor mutational burden (TMB) and further, the role this may play in predicting immune-response. Larger studies are needed to assess TMB as a predictive biomarker in early-stage TNBC as this may provide opportunities to further individualize treatment and minimize toxicity among this group of patients. Additionally, given differences in the prevalence of pathogenic mutations and VUS among Black patients, better understanding the relationship between mutation status and immune response is imperative to optimize outcomes in this high-risk population. Table. Citation Format: Caitlin Taylor, Melanie Sheen, Rabia Cattie, Victoria Chung, Melyssa Bratton, Meredith Lakey, Erin Biggs. Genetic mutations and associated rates of pathologic complete response among a diverse patient population with early stage triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-08-10.

Abstract PO3-23-08: Cancer and immune cells evolutionary trajectories under treatment with the aromatase inhibitor letrozole and the CDK4/6 inhibitor ribociclib

Abstract Cancer and immune cells evolutionary trajectories under treatment with the aromatase inhibitor letrozole and the CDK4/6 inhibitor ribociclib. Marie Fongaard1, Leonard Schmiester2, Salim Ghannoum1, Pål Marius Bjørnstad1, Tatjana Bosnjak3, Signe Meltzer Kleivbo3, Knut Selsås4, Stephanie Beate Geisler5, Kamilla Fjermeros5, Sameer Bhargava5, Manouchehr Seyedzadeh6, Unn-Cathrin Buvarp5, Aino Katri Rosenskiold5, Nam Thi Nguyen5, Torben Lüders7, Diether Lambrechts8, Marianne Lyngra9, Arnoldo Frigessi2, Vessela Kristensen1,10, Jürgen Geisler5,10,*, Xavier Tekpli1,* 1) Department of Medical Genetics, Oslo University Hospital, Oslo, Norway 2) University of Oslo, Oslo Centre for Biostatistics and Epidemiology (OCBE), University of Oslo, Norway 3) Novartis, Medical Affairs, Oslo, Norway 4) Department of Breast and Endocrine Surgery, Akershus University Hospital, Oslo, Norway 5) Department of Oncology, Akershus University Hospital, Oslo, Norway 6) Department of Radiology, Akershus University Hospital, Oslo, Norway 7) Department of Clinical Molecular Biology (EPIGEN), Akershus University Hospital, Oslo, Norway 8) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium 9) Department of Pathology, Akershus University Hospital, Oslo, Norway 10) University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway< * Jointly supervised the work, shared corresponding authors Background The recent introduction of CDK4/6 inhibitors is regarded as a major improvement in the field of breast cancer therapy. A growing body of evidence suggests that CDK4/6 inhibitors may impact on the recruitment of immune cells within the tumor microenvironment during therapy. Further, CDK4/6 inhibitors may potentially contribute to the extinction or survival of specific cancer cell clones through evolutionary pressure exerted on breast tumors. Clinical trial The NEOLETRIB-study is a multicenter, single-arm, open-label phase II clinical trial. Patients with locally advanced, LUM-A/LUM-B breast cancer, characterized by cT3-cT4 tumors and/or cN2-3 lymph node involvement, receive ribociclib (600 mg daily, 21 days on and 7 days off) in combination with letrozole (2.5 mg daily) for a duration of 6 months in the neoadjuvant setting. Patients with large cT2 tumors are also allowed to participate. Aim of the study Using single-cell analyses at different time points of treatment, we aim at studying the evolutionary trajectories of cancer and immune cells in 30 patients participating in the NEOLETRIB-trial. Methods Tumor biopsies taken before treatment (baseline) and during treatment (day 21 of ribociclib cycles 1 and 6, respectively), underwent single-cell RNA (scRNA), T cell receptor (TCR), and B cell receptor (BCR) sequencing. The sequencing data was first processed using cellRanger and Seurat . Results Initial clustering of the scRNA enabled the identification of the main cell types in breast tumors, which included T/NK cells, B cells, epithelial cells, cancer-associated fibroblasts, myeloid cells and endothelial cells. Focusing on epithelial cells, we were distinguished cancer cells from normal epithelial cells using the InferCNV algorithm. Further, by estimating the copy number events, we determined the genetic background of clones resistant or sensitive to combination therapies for each patient, revealing the dynamics of tumor heterogeneity evolution during treatment. Additionally, we examined CD4, CD8 and NK cell types, identified different cell states within these cell types and inferred pseudotime and immune cell type differentiation trajectories. ConclusionsWe identified the cell types present in tumor biopsies from the NEOLETRIB trial. We characterized the effects of therapies on the evolution of cancer and immune cells and gain insights into the factors influencing sensitivity and resistance to the combination of letrozole and ribociclib. Citation Format: Marie Fongård, Leonard Schmiester, Salim Ghannoum, Marius Bjørnstad, Tatjana Bosnjak, Signe Kleivbo, Knut Selsås, Stephanie Geisler, Kamilla Fjermeros, Sameer Bhargava, Manouchehr Seyedzadeh, Unn-Cathrin Buvarp, Aino Vuoriluoto, Nam Thi Nguyen, Torben Lüders, Diether Lambrechts, Marianne Lyngra, Arnoldo Frigessi, Vessela Kristensen, Jürgen Geisler, Xavier Tekpli. Cancer and immune cells evolutionary trajectories under treatment with the aromatase inhibitor letrozole and the CDK4/6 inhibitor ribociclib [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-23-08.

Abstract PO4-15-12: Personalized circulating tumor DNA monitoring to predict response to neoadjuvant therapy in patients with early-stage breast cancer

Abstract Introduction Longitudinal ctDNA testing offers a minimally invasive approach for monitoring treatment response in patients with breast cancer (BC). In this study, we evaluated whether serial ctDNA testing during neoadjuvant therapy (NAT) can provide an early indication of treatment response or resistance and disease progression. Methods In this real world study, longitudinal blood samples collected from 159 patients with stage I-III BC were analyzed using a personalized, tumor-informed ctDNA assay (SignateraTM bespoke mPCR-NGS assay). Of the 159 patients, 157 received standard of care NAT; the remaining 2 patients were treated with endocrine therapy only in the neoadjuvant setting. Blood samples were collected at the time of diagnosis from 71 patients (baseline) and longitudinally during treatment from 159 patients (median time between time points: 1.5 months). ctDNA status and dynamics were correlated with clinicopathological features and surgical outcomes available at the time of data cut off. Results At baseline, ctDNA was detected in 72% (51/71) of patients. Baseline ctDNA detection rates varied based on histologic subtypes: 82% (28/34) in patients with triple negative breast cancer, 88% (15/17) in patients with HER2+ disease and 40% (8/20) in patients with ER+HER2- BC. ctDNA was detectable at baseline in 72% (26/36) of patients with clinical T1-2 disease and 92% (11/12) of patients with T3-4 disease. ctDNA was detected in 64% (16/25) of patients with clinical N0, whereas among patients with at least one positive lymph node, ctDNA was detected in 92% (22/24). At baseline, 65% (31/48) of patients with low/intermediate-grade disease were ctDNA-positive, while 81% (25/31) of patients with high-grade disease were ctDNA-positive. Similarly, 83% (24/29) of patients with high levels (>20%) of Ki67 expression had detectable ctDNA prior to treatment initiation, while only 22% (2/9) of those with low level (< 20%) of Ki67 expression had ctDNA detected. Surgical outcomes were available for 22 patients of whom 16 had achieved pathologic complete response (pCR). While 3/16 pts were ctDNA negative at baseline, all of the remaining cases except one patient with baseline ctDNA detection and serial measurements (11/12) became ctDNA negative by the end of two months of treatment. Despite achieving pCR, one patient with inflammatory ER+HER2+ BC remained ctDNA positive before and after the surgery, which informed a change in the adjuvant treatment strategy. Among those with residual disease (pT1c-T3), 28% (7/25) remained ctDNA positive after two months of NAT. Association between ctDNA dynamics and surgical outcomes of the remaining 137 patients will be presented at the time of the conference. Conclusions This real world study demonstrates the prevalence of ctDNA detection and dynamics in patients with eBC treated with NAT. ctDNA monitoring during NAT can facilitate real-time assessment of treatment response and serve as an early indicator of subsequent pCR to NAT. Citation Format: Mridula George, Trishala Meghal, Coral Omene, Ekaterina Kalashnikova, Janie Fielder, Nisha Ohri, Shicha Kumar, Valeria Burkovskaya, Preena Patel, Ashley Young, Melanie Racenstein, Tinamarie Bauman, Wassim Mchayleh, Deborah Toppmeyer, Shridar Ganesan, Barry Rosen, Angel Rodriguez, Minetta Liu. Personalized circulating tumor DNA monitoring to predict response to neoadjuvant therapy in patients with early-stage breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-12.

Abstract PO3-03-07: Patterns of Chemotherapy Utilization among Elderly Patients with Early-Stage Triple-Negative Breast Cancer

Abstract Background: Patterns of adjuvant and neoadjuvant chemotherapy use among patients with breast cancer have changed over time. Historically, adjuvant chemotherapy has been the standard treatment approach for patients with triple-negative breast cancer after surgical resection, aiming to eliminate any remaining cancer cells and reduce the risk of recurrence. Advancements in treatment strategies, research findings, and clinical guidelines have contributed to shifts in cancer care approaches, with an increase in the use of neoadjuvant chemotherapy. In this study, we explore chemotherapy utilization in a large cohort of elderly patients diagnosed with early-stage triple-negative breast cancer (TNBC). Methods: Data were obtained from the SEER- and Texas Cancer Registry (TCR)-linked Medicare databases. We identified female patients aged 66 years or older, diagnosed with early-stage (localized or regional disease) TNBC between 2010 and 2017 with claims until 2019. We identified the use of chemotherapy using HCPCS codes from outpatient and physician’s carrier claims. We used descriptive statistics and analyzed overall chemotherapy utilization and time trends of neoadjuvant versus adjuvant use via the Cochran-Armitage trend test, and evaluated factors associated with chemotherapy use via logistic regression models. This study adhered to the STROBE reporting guidelines for cohort studies. Results: Among 8,848 patients with localized or regional stage TNBC (median age 74) a total of 5,159 (58%) were treated with chemotherapy. The rate of chemotherapy utilization increased yearly from 52% in 2010 to 66% in 2017 (p< 0.001). After multivariable adjustment, any chemotherapy use was associated with recent year of diagnosis (OR=1.77; 95%CI 1.54-2.04), regional stage compared to localized (OR=3.78; 95%CI 3.34-4.27), and Northeastern region compared to South (OR=1.2; 95%CI 1.06-1.37). Conversely, decreased chemotherapy use was associated with age ≥76 (OR=0.24; 95%CI 0.2-0.27), being single (OR=0.76; 95%CI 0.67-0.86), and higher comorbidity score (OR=0.69; 95%CI 0.61-0.78). Among chemotherapy-treated patients, 3,808 (73.8%) received it in the adjuvant setting, 722 (14.0%) received it in the neoadjuvant setting, and 629 (12.2%) received chemotherapy both preoperatively and postoperatively. Among those who were treated with any chemotherapy, the percentage of patients treated with neoadjuvant chemotherapy increased from 15.2% in 2010 to 37.4% in 2017 (p< 0.001). Among patients treated with chemotherapy, neoadjuvant chemotherapy use was associated with recent year of diagnosis (OR=3.38; 95%CI 2.77-4.12), regional stage (OR=3.28; 95%CI 2.86-3.77), and inversely associated with older age (OR=0.77; 95%CI 0.64-0.94), non-White, non-Hispanic, non-Black race or ethnicity (OR=0.64 95%CI 0.45-0.94), non-metro area (OR=0.61; 95%CI 0.5-0.74), and Northeastern region (OR=0.66; 95%CI 0.56-0.78). Conclusion: Our study highlights the significant changes in patterns of adjuvant and neoadjuvant chemotherapy use among elderly patients with early-stage TNBC. We observed an increasing trend in chemotherapy utilization, with a notable shift from adjuvant to neoadjuvant treatment. This transition reflects the evolving landscape of cancer care and the adoption of more personalized approaches to treatment, with increased utilization of neoadjuvant chemotherapy offering opportunities for better risk assessments and tailored treatment strategies. Citation Format: Catalina Malinowski, Xiudong Lei, Sharon Giordano, Marianna Chavez. Patterns of Chemotherapy Utilization among Elderly Patients with Early-Stage Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-07.

Abstract PO2-19-11: NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer

Abstract Background The standard of care for patients with early triple-negative breast cancer (TNBC) is neoadjuvant chemotherapy followed by surgery. Recently, immune checkpoints inhibitors (ICI) added to neoadjuvant chemotherapy have shown efficacy. Among TNBC, BRCA mutations and other homologous recombination deficiency (HRD) signals are relatively frequent. As opposed to other types of breast cancer, TNBC show a high neoantigen load, a large number of tumour infiltrating lymphocytes (TILs), and a high PD-L1 expression. In BRCA/HRD breast cancer, PARP inhibitors (PARPi) exhibit a distinct anticancer activity. In addition, they show immunomodulatory effects by promoting PD-L1 expression and DNA damage, increasing neoantigen load. Chemotherapy-free regimens combining PARPi and ICI result in promising synergistic activity as shown in the metastatic setting, supporting investigation in the neoadjuvant setting. Trial design NOBLE is an EORTC phase 2, randomized, international, multicentre, open label, clinical trial. Eligible patients will undergo central screening for tumoral BRCA/HRD (Institute Curie, 455 patients), 152 patients will be randomized 1:1 between olaparib vs olaparib and durvalumab for 4 cycles (16 weeks) of neoadjuvant treatment. Thereafter, patients will undergo surgery. All patients will be followed-up to 2 years (y) after surgery. The trial will be conducted in 3 steps (screening/randomization): Step 1 – Feasibility (60/20): to assess the central testing failure rate, the turn-around time for central testing and the prevalence of tBRCA/HRD; Step 2 (193/64) – Futility; and Step 3 (202/152) – Expansion of recruitment. The primary endpoint is the rate of pathologic complete response (pCR) at the time of surgery, defined as ypT0/is ypN0. Secondary endpoints are response based on RECIST v1.1, surgery rate, 2-y event-free-survival, 2-y overall survival, safety, and quality of life. The study is expected to be activated in early autumn 2023 and the primary endpoint will be available approximately 5 years after the screening of the first patient. Main inclusion criteria Histologically confirmed primary TNBC, defined as: - ER and PgR ≤ 10% - HER2-negative per ASCO CAP guidelines Stage T1c-T2 N0-N1 M0 BRCA mutation and/or HRD based on methylation as determined by central testing ECOG status 0-1 Written informed consent Age ≥18 years No prior systemic therapy nor surgery for the current Main exclusion criteria Previous treatment with a PARPi or an immune-checkpoint inhibitor History of previous invasive breast cancer Bilateral and/or multifocal and/or multicentric BC Autoimmune or inflammatory disease Specific aims The aim of this study is to provide a safe and effective neoadjuvant treatment free of chemotherapy to a distinct subpopulation among patients with TNBC. We will evaluate the pCR after neoadjuvant treatment with olaparib alone and with olaparib in combination with durvalumab in patients with TNBC showing a BRCA1/2 mutation or HRD based on methylation. Statistical methods The sample size was calculated based on the minimax Simon two-stage design including an interim analysis for futility of the primary endpoint. Decision rules are pre-specified in the study protocol. Each treatment arm will be analyzed independently. There will be no formal comparison between the two experimental treatment arms. A minimization technique will be used for random treatment allocation stratifying for the type of HRD alteration, PD-L1 expression level and for TILs. Accrual We expect to start recruiting in September 2023. We aim to screen 455 patients to randomize 152 patients. Contact information for people with a specific interest in the trial Etienne Brain (study coordinator): etienne.brain@curie.fr Anne-Sophie Hamy-Petit (study co-coordinator): anne-sophie.hamy-petit@curie.fr Citation Format: Emanuel Buhrer, Eleni Xenophontos, Anne-Sophie Hamy-Petit, Jose Casas-Martin, Céline Callens, Thomas Meyskens, Coralie Poncet, Anastasia Lanzi, Etienne Brain. NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-11.

Abstract PO5-15-07: Integrative proteomics, phosphoproteomics, and RNA profiling revealed novel timeline-dependent vulnerabilities in HER2-positive breast cancer

Abstract Background: Most personalized breast cancer therapies leverage biomarkers identified in the pre-treatment setting. They do not always reflect the dynamic nature of early indicators of treatment response/resistance. Herein, we have a unique cohort of newly diagnosed HER2-positive breast tumors treated with a single low dose of trastuzumab (50mg), and the corresponding residual tumors that did not achieve pathologic complete response (pCR) to HER2-targeted neoadjuvant therapy. We hypothesize that integrative molecular profiling with proteomics and transcriptomics of these breast tumors could reveal novel time-course dependent contributors of therapy response and resistance. Method: This correlative biomarker study was a secondary objective of a parent study that evaluated 64uc-DOTA-trastuzumab PET imaging to predict response to trastuzumab and pertuzumab-based neoadjuvant therapy in HER2-positive breast cancer patients. Eighteen newly diagnosed breast cancer patients were enrolled, and pCR was achieved in 13 patients (72%). This correlative biomarker study was performed on breast tumors collected within 72 hours following administering a low dose trastuzumab (50mg) to the subjects prior to imaging and neoadjuvant therapy. Deep expression proteomics and phosphoproteomics data acquisition were performed on a Thermo Orbitrap Eclipse mass spectrometer. RNA profiling was performed using Nanostring breast cancer profiler. Results: Our multi-omic approach identified increased abundance or activity in the pCR group on the following (p < 0.05): Her2 protein and ERBB2 transcript levels, increased phosphorylation of ERBB2 (T1052), increase in Golgi trafficking activities, posttranslational modification with protein glycosylation, and lipid biosynthesis. Interestingly, compared to the non-pCR group, the pCR group showed lower activity level in ERBB2’s downstream pathways, such as MAPK, SRC, and PI3K. In the non-pCR group, the residual tumor showed decrease in the following (p < 0.05): Golgi trafficking, glycosylation, antigen processing, and Her2 protein and phosphorylation (T1166). The pCR group had a negative enrichment for SGK1, a kinase which mediates PI3K pathway independently of AKT. SGK1 abundance was highest in residual tumors following neoadjuvant therapy. Conclusion: Using integrative proteomic and RNA profiling, we identified several in-vivo biological pertubations following administration of low dose trastuzumab. Increased Her2 abundance and ERBB2 transcript levels are associated with pCR, in keeping with previous reports of known pCR predictors. Decreased abundance of ERBB’s downstream signaling proteins in the pCR group suggests that early treatment response to trastuzumab may be a predictor of pCR. Our integrative approach identified other dynamic biomarkers. For example, compared to non-pCR group, Golgi trafficking is more active in pCR group tumors, and lowest in residual tumors following neoadjuvant therapy. This suggests that novel Golgi-targeting agents may be best utilized in neoadjuvant setting. Further, we identified SGK1 may be an important kinase for mediating therapy resistance early in treatment course, since its level is higher in non-pCR group following early exposure to trastuzumab compared to pCR group, with highest level detected in the residual tumors. These findings warrant orthogonal validation using in-vitro functional assays. Citation Format: Christina Wei, Lixin Yang, Krystine Mansfield, Jessica Liu, Ritin Sharma, Russell Rockne, Raju Pillai, Patrick Pirrotte, Joanne Mortimer. Integrative proteomics, phosphoproteomics, and RNA profiling revealed novel timeline-dependent vulnerabilities in HER2-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-15-07.

Abstract PO3-17-08: SAFETY AND TOLERABILITY OF SUBCUTANEOUS TRASTUZUMAB AS A TREATMENT IN PATIENTS WITH EARLY HER 2 POSITIVE BREAST CANCER : EXPERIENCE OF A CANCER CENTER IN PERU

Abstract BACKGROUND: About 15% to 20% of breast cancers express positivity for human epidermal growth factor receptor 2 (HER2), a more aggressive breast cancer subtype with shorter survival. Trastuzumab, a humanized monoclonal antibody was approved by the U.S. Food and Drug Administration (FDA) for therapeutic use in metastatic breast cancer in 1998 and HER2-positive early breast cancer in 2006. HER2 overexpression is associated with more aggressive tumor growth and worse prognosis compared to HER2-negative tumors. HER2-positive tumors occur more frequently in younger women and node-positive women and are often less responsive to cytotoxic therapies. The primary objective of this study was to evaluate the tolerability of the subcutaneous formulation of trastuzumab in real life at the national institute of neoplastic diseases LIMA-PERU in patients with epidermal growth factor receptor 2 (HER2)-positive early breast cancer; efficacy was a secondary objective. METHOD: Female patients aged 18 years or older diagnosed between 2018-2019 with early epidermal growth factor receptor 2 (HER2)-positive breast cancer who received at least 1 dose of trastuzumab subcutaneously in a neo/adjuvant setting with or without chemotherapy were included. The treatment indication is 600 mg at a fixed dose every 3 weeks for 18 cycles. RESULTS: A total of 70 patients who received treatment with subcutaneous trastuzumab were included in the analysis. The mean age of the population was 52.6 ± 12.4 years, with the majority of patients being older than 50 years (54.29%). The mean number of subcutaneous trastuzumab cycles received was 11.4 ± 4.2. Adverse effects such as arthralgia (47.62%), diarrhea (9.52%), fatigue (9.52%) and injection site reaction (9.52%) occurred in 30% of patients. The mean number of cycles received until the first occurrence of adverse effects was 5.2 ± 2.1. It was observed that 97.14% completed treatment with trastuzumab subcutaneously, and 2.86% had to discontinue treatment. Cardiotoxicity and hypertension were the reasons why patients discontinued treatment. Of the patients included in the study, 63.77% received subcutaneous trastuzumab in the neoadjuvant setting, while the remaining 36.23% received it in the adjuvant setting. Of the patients, 45.71% started treatment with trastuzumab intravenously and received an average of 6 ± 3 cycles before switching to the subcutaneous presentation. After 3 years of follow-up, 7.14% developed disease progression; 57.1% had progression at the cerebral level, 28.6% at the local level and 14.3% at the pulmonary/hepatic level. 98.57% of patients are alive. CONCLUSIONS: In a real-life setting, subcutaneous trastuzumab is a well-tolerated and effective treatment option for patients even in patients who started treatment with the intravenous presentation and made the switch during treatment. Table 1: General clinical characteristics of patients XX XX Citation Format: Iris Otoya, Natalia Valdivieso, Zaida Morante, Carlos Castañeda, Silvia Neciosup, Mónica Calderón, Henry Gómez. SAFETY AND TOLERABILITY OF SUBCUTANEOUS TRASTUZUMAB AS A TREATMENT IN PATIENTS WITH EARLY HER 2 POSITIVE BREAST CANCER : EXPERIENCE OF A CANCER CENTER IN PERU [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-08.

Abstract PO3-12-11: A phase-3 randomized controlled study to evaluate the role of hydroxyprogesterone in prevention of chemotherapy induced neurotoxicity in women with breast cancer

Abstract Introduction Chemotherapy induced peripheral neuropathy (CIPN) is seen in 60% breast cancer patients who receive paclitaxel-based chemotherapy with no conclusively known pathophysiology. Hydroxyprogesterone is known to have neuroprotective and neuro-regenerative potential. We conducted a randomized controlled trial assessing the role of hydroxyprogesterone in reducing the incidence and severity of CIPN. Methodology Histologically proven, post-menopausal, non-metastatic breast cancer patients without pre-existing neuropathy, planned to receive paclitaxel (with or without trastuzumab) in the adjuvant or neoadjuvant setting were screened and consented. They were randomized to receive depot hydroxyprogesterone injection 500 mg followed by 250 mg injection every 2 weekly (trial arm) versus 1 ampoule (2 ml) of vitamin-B complex (B1-100mg, B6-100mg and B12-1000µg) injection every 2 weekly (control arm) during the entire course of paclitaxel-based chemotherapy. The primary end point was cumulative incidence of grade II-IV CIPN, at the last cycle of chemotherapy as assessed by CTCAE-V4. Secondary end point was EORTC-QLQ-CIPN20 assessment 8 weeks after last cycle of chemotherapy. Patients were stratified for stage, diabetes mellitus, and frequency of paclitaxel administration. Sample size was calculated for a 20% reduction in CIPN from 60% with α-0.05 and power of 80%, for 2-sided significance of p-0.05, with a drop-out rate of 10%. Results A total of 240 patients were randomized between November 2015 and February 2023- 120 each on the trial and control arm. The median age was 54 (43-73) and 55 (43-74) years; 35% and 31.7% patients were early breast cancer (cT1-2, N0-1) in the trial and control arms respectively. The median pT size was 2.6 cm and 65% patients were node positive overall. The incidence of grade II-IV CIPN (motor and/or sensory) at the end of chemotherapy was 55.9% and 56.8% in the trial and control arms respectively (p=0.90, 95%CI-0.12-0.13). Overall, chemotherapy related adverse events (CTCAE-V4) were seen in 41.39 and 39.9% in trial and control arms respectively. The average EORTC-QLQ-CIPN20 score at 8 weeks after last cycle of chemotherapy for motor neuropathy was 11.18 (0-70) and 13.53 (0-74), for sensory neuropathy was 8.51 (0-76) and 9.27 (0-81) and that for autonomic neuropathy was 4.94 (0-67) and 4.65 (0-67) in the trial and control arms respectively (p=NS). Conclusion Hydroxyprogesterone did not reduce the incidence of paclitaxel related CIPN when assessed immediately post-chemotherapy. The absolute incidence of CIPN (any grade) was 61% in our study which is like that reported in literature. Long term follow-up of these patients will assess the recovery of CIPN and long-term impact of the study interventions on CIPN. The study was approved by Institutional Review Board and Drug Controller General of India (CTRI/2015/11/006381). Citation Format: Rajendra Badwe, Shalaka Joshi, Rohini Hawaldar, Tejal Panhale, Nita Nair, Sandesh Sawant, Vaibhav Vanmali, Mitchelle Engineer, Anuradha Daptardar, Vani Parmar, Seema Gulia, Sudeep Gupta. A phase-3 randomized controlled study to evaluate the role of hydroxyprogesterone in prevention of chemotherapy induced neurotoxicity in women with breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-11.

Abstract PO5-17-05: Recommendations of a panel of experts from the Brazilian Society of Mastology on breast and axilla clipping: when, how and for whom?

Abstract Background: The precise location of the tumor site is essential for obtaining free margins and success of surgical treatment, reducing the rates of reoperation and local recurrences. Neoadjuvant chemotherapy (NAC) is a challenge for preoperative tumor localization, due to the different patterns of locoregional response, limitations related to imaging methods, and the possibility of a pathological complete response (pCR). In addition, there are several divergent approaches regarding preoperative axillary evaluation, lymph node marking methods and approaches when facing cN1. Thus, the knowledge and attitudes of the affiliated members of the Brazilian Society of Mastology (SBM) regarding breast and axilla marking were evaluated and a consensus regarding management and treatment was reached. Methods: This is an online survey conducted between June and December 2022. All 1.742 active mastologists affiliated to SBM were anonymously invited to participate in the study. The online form contained 28 objective questions, of which 22 were formulated on a Likert scale. These questions addressed several relevant aspects related to breast and axilla marking in the neoadjuvant setting. Responses that reached 70% agreement were considered consensual. Statistical analysis was performed using the SPSS program. Post hoc analysis was performed when appropriate and, in all analyses, the significance level of p < 0.05 was adopted. Results: A total of 468 mastologists answered the questionnaire (26.8%), with a predominance of professionals aged between 40-49 years (32.1%), male (50.4%), and residents of state capitals (63.9%). Most professionals were board-certified (84,8%), 87.7% for more than five years. The indication of tumor marking in the breast prior to NAC was consensual (96.4%) and the metal clip was the preferred method (69.7%). If available, the US-visible clip is preferred (86.5%). With respect to the marking of the breast and axilla prior to NAC, 93.3% of the mastologists considered relevant issues related to the techniques and materials. There was no consensus regarding the indication of pre-NAC histologically positive lymph node marking (49.8% disagree and 42.8% agree), however there was consensus that the clinical and imaging evaluation is insufficient for staging the axilla as N1 (71.6 %). The contraindication of breast and node marking in T4b tumors (71.2%) was consensual. There was consensus on the indication of sentinel lymph node biopsy (SLNB) for initially cN1 (92.3%) or cN2 (72.7%) tumors that became cN0 after NAC, with 67.5% opting for dual staining with technetium and patent blue. There was also consensus on the indication of axillary lymphadenectomy (89%) after NAC when double marking with technetium and patent blue for SLNB is not available. In addition, 41.0% of mastologists perform axillary lymphadenectomy when less than three lymph nodes are found in the SLNB. Among the 28 questions, consensus was reached on only 11 (39.3%); with some consensus variations according to age group, sex, geographic location of residence, place of professional activity (public or private), and professional experience. Conclusion: The indication of pre-NAC breast marking is consensual among Brazilian mastologists, although axillary nodal marking is not. There is a great divergence of attitudes among Brazilian surgeons in relation to the many issues related to pre-NAC breast and axilla marking, indicating the need to establish continuing education programs on the subject. Citation Format: Henrique Couto, Augusto Hassan, Dalton Steinmacher, Eduardo Pessoa, Eduardo Millen, Felipe Zerwes, Francisco Pimentel Cavalcante, Giuliano Tosello, Gustavo Badan, José Francisco, Leonardo Soares, Lucas Budel, Luciano Chala, Raquel Fernandes, Ruffo Freitas-Junior, Vilmar Oliveira, Vinicius Budel, Andre Mattar. Recommendations of a panel of experts from the Brazilian Society of Mastology on breast and axilla clipping: when, how and for whom? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-17-05.