HER2-negative Metastatic Breast Cancer Research Articles

Cyclin-Dependent Kinase 4/6 Inhibitors Beyond Progression in Metastatic Breast Cancer: A Retrospective Real-World Biomarker Analysis.

As the continuation beyond progression (BP) of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is becoming increasingly attractive for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), the definition of resistance factors is crucial. The aim of the study was to investigate the impact of CDK 4/6i BP and to explore potential genomic stratification factors. We retrospectively analyzed a multi-institutional cohort of patients with HR-positive HER2-negative MBC characterized for circulating tumor DNA through next-generation sequencing before treatment start. Differences across subgroups were analyzed by chi-square test, and survival was tested by univariable and multivariable Cox regression. Further correction was applied by propensity score matching. Among the 214 patients previously exposed to CDK4/6i, 172 were treated with non-CDK4/6i-based treatment (non-CDK) and 42 with CDK4/6i BP. Multivariable analysis showed a significant impact of CDK4/6i BP, TP53 single-nucleotide variants, liver involvement, and treatment line on both progression-free survival (PFS) and overall survival (OS). Propensity score matching confirmed the prognostic role of CDK4/6i BP both for PFS and OS. The favorable impact of CDK4/6i BP was consistent across all subgroups, and a differential benefit was suggested for ESR1-mutated patients. ESR1 and RB1 mutations were more represented in the CDK4/6i BP subgroup with respect to CDK4/6i upfront. The study highlighted a significant prognostic impact of the CDK4/6i BP strategy with a potential added benefit in patients with ESR1 mutations suggesting the need for an extensive biomarker characterization.

250P Liver Toxicity (LT) in patients (pts) with ER-positive HER2-negative metastatic breast cancer (MBC) treated with first-line Cyclin-Dependent Kinase 4/6 inhibitors (CDKi)

A meta-analysis of all Ph3 trials with CDKi plus endocrine therapy (ET) has established 13% incidence of LT of any grade (vs 5.4% with ET alone). However, the clinical characteristics of these pts and the predictive factors associated with developing LT remain unknown. All MBC pts treated with first-line CDKi in Vall d’Hebron Hospital from 2018 to 2022 were analyzed retrospectively. LT was defined as ≥G2 AST/ALT elevation. Clinical and laboratory characteristics, oncologic disease status, and evolution of liver function tests for those pts were registered. Among 472 pts treated, 26 (5.5%) developed LT, G2 in 11 (42%), G3 in 13 (50%) and G4 in 2(8%) without LT related-deaths. LT occurred in 3%, 8% and 11.6% of pts receiving palbociclib, abemaciclib and ribociclib, respectively. Baseline characteristics: median (M) age 61y, premenopausal 54%, overweight/obese 59%, 11.5% alcohol consumers, 27% current/former smokers, 27% stage IV de novo and 27% with liver metastases. As for cardiovascular risk factors: 32% had dyslipemia, 31% liver steatosis at CT scan and 26.9% arterial hypertension. Concomitant ET was letrozole 54%, fulvestrant 35% and anastrozole 11%. LT occurred after 7 cycles (M), and 218 days (IQR 37-399). Only 1 pt receiving abemaciclib had G4 bilirubin elevation without fulfilling Hy's Law criteria. In 88.5% LT returned to basal in 44 days (M) (IQR 26-61). CKDi was reintroduced in 58% of pts; 8% at the same dose, 54% at -1 dose level, and 38% at -2 dose level. Of them, 61.5% had a 2nd LT episode which resolved in 62.5% in 26 days (M) (IQR 14-49). The results by type of CDKi are shown in the table. Table: 250PCharacteristicsPalbociclibAbemaciclibRibociclibLT pts/Total pts8/2839/1129/77M days until LT1166398LT resolved87%75%100%M days to resolution282646Relapse of LT20%75%66%M days until relapse142011 Open table in a new tab In our cohort of pts 5.5% developed LT. LT reached G3 in 58% of cases, mainly with ribociclib. A high proportion of those pts had ≥25 BMI and 31% had liver steatosis. LT was mainly reversible with no fatal cases. These results could help to develop prediction scores to identify patients at risk of developing severe LT.

Efficacy and clinical outcome of chemotherapy and endocrine therapy as first-line treatment in patients with hormone receptor-positive HER2-negative metastatic breast cancer.

Endocrine therapy (ET) and ET-based regimens are the preferred first-line treatment options for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (HR+/HER2- MBC), while chemotherapy (CT) is commonly used in clinical practice. The aim of this study was to investigate the efficacy and clinical outcome of ET and CT as first-line treatment in Chinese patients with HR+/HER2- MBC. Patients diagnosed with HR+/HER2-MBC between January 1st, 1996 and September 30th, 2018 were screened from the Chinese Society of Clinical Oncology Breast Cancer database. The initial and maintenance first-line treatment, progression-free survival (PFS), and overall survival (OS) were analyzed. Among the 1877 included patients, 1215 (64.7%) received CT and 662 (35.3%) received ET as initial first-line treatment. There were no statistically significant differences in PFS and OS between patients receiving ET and CT as initial first-line treatment in the total population (PFS: 12.0 vs. 11.0 months, P = 0.22; OS: 54.0 vs . 49.0 months, P =0.09) and propensity score matched population. For patients without disease progression after at least 3 months of initial therapy, maintenance ET following initial CT (CT-ET cohort, n = 449) and continuous schedule of ET (ET cohort, n = 527) had longer PFS than continuous schedule of CT (CT cohort, n = 406) in the total population (CT-ET cohort vs. CT cohort: 17.0 vs . 8.5 months; P <0.01; ET cohort vs . CT cohort: 14.0 vs . 8.5 months; P <0.01) and propensity score matched population. OS in the three cohorts yielded the same results as PFS. ET was associated with similar clinical outcome to CT as initial first-line treatment. For patients without disease progression after initial CT, switching to maintenance ET showed superiority in clinical outcome over continuous schedule of CT.

Abstract CT188: A phase Ib study of sapacitabine (sapa) and olaparib (ola) in patients (pts) with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer (MBC)

Abstract Background: PARP inhibitors (PARPi) are superior to chemotherapy in pts with BRCA1/2m MBC, with median PFS (mPFS) of 7 months with single-agent ola. Sapa is an oral nucleoside analog; the active metabolite, CNDAC, generates single-strand DNA breaks that are converted to double-strand breaks (DSB) during subsequent replication, resulting in cell death. CNDAC-induced DSB repair is dependent on homologous recombination. Sapa combined with ola may augment DNA damage compared to ola alone in BRCA1/2m tumors. Methods: We conducted a phase Ib study of sapa/ola in pts with BRCA1/2m HER2-negative MBC who were not previously PARPi-exposed. Primary objective was to determine the RP2D of sapa with ola. Secondary objectives included safety, tolerability and mPFS. RAD51 staining was performed on archival tissue. Serial blood samples were collected for circulating tumor DNA (ctDNA) analysis using low-pass WGS with targeted sequencing via the DDR Discovery Panel (Resolution Bioscience). Results: 10 women (median age 46) were enrolled before the study was terminated for hematologic toxicity. Germline BRCA1 and BRCA2 mutations were present in 3 and 7 pts, respectively. 4 pts had received prior platinum. All pts initially received standard dose ola (300 mg twice daily) with 100 mg (n = 3), 150 mg (n = 4), or 200 mg (n = 3) sapa once daily on days 1-5 and 8-12 of an every 28-day cycle. The RP2D was not determined. Hematologic AEs were common, including anemia (80%), neutropenia (80%), and thrombocytopenia (40%), with 1 DLT of G4 neutropenia lasting more than 7 days. The ORR was 50% (95% CI: 18.7% - 81.3%) with mPFS of 9.7 months (95% CI: 8.02 - NA). 3 pts had clinical benefit of 15+ months, exceeding expectations with olaparib alone, including 2 with PR, and 2 who remained on trial for 36+ months. 3 patients had confirmed PRs of short duration. Of the remaining patients, one withdrew consent early and the other 3 had non-CR/non-PD or SD of 4, 7 and 9 months. At progression, 2 pts had evidence of BRCA reversion mutation associated with an MMEJ signature; ctDNA also demonstrated MRE11 and PTEN amplifications in 1 of these pts, suggesting multiple resistance mechanisms. 3 pts had no evidence of reversion but had acquired putative non-reversion mechanisms of resistance, including changes suggesting enhanced MRN complex function, FANCD2 and ATR amplifications and PIK3CA mutation. The majority of tumors (6/10) were RAD51-negative. Other tumors with RAD51 foci demonstrated replication stress evidenced by high levels of pKAP1 and pRPA, suggesting benefit associated with sapa. Conclusions: Sapa/ola produces high rates of hematologic toxicity. However, the ORR of 50%, mPFS of 9.7 months, and durability of 3+ years in 2 pts suggest possible combinatorial benefit. Further exploration with different sapa schedules or with substitution of a PARP1-selective inhibitor to decrease hematologic toxicity is warranted. Citation Format: Filipa Lynce, Noah Graham, Bose S. Kochupurakkal, Huy Nguyen, Philip D. Poorvu, Victoria Attaya, Raechel Davis, Kavita Garg, Lee P. Lim, Mark Li, Cloud P. Paweletz, Nabihah Tayob, Geoffrey I. Shapiro, Sara M. Tolaney. A phase Ib study of sapacitabine (sapa) and olaparib (ola) in patients (pts) with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT188.

Abstract 4346: TFF1 and TFF3 predict response to CDK4/6 inhibitors in breast cancer patients

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with endocrine therapy (ET) have become the mainstay treatment for patients with hormone receptor (ER)-positive, HER2-negative metastatic breast cancer (BC). However, one-third of patients do not respond to the treatment (intrinsic resistance), leading to early tumor progression and treatment failure, and most patients eventually acquire resistance to therapy. The exact mechanisms of resistance to CDK4/6i are yet to be elucidated, and due to subsequent early (intrinsic) or late progression on CDK4/6i, long-term cures are not achieved. Methods: Transcriptomic profiles of BC cell lines that were sensitive or resistant to approved CDK4/6i, independent of subtype, were downloaded from the Cancer Cell Line Encyclopedia database. Bioinformatics analysis was performed by integrated Differential Expression and Pathway (iDEP) workflow. In parallel, transcriptomic profiles of metastatic biopsies from pre-CDK4/6i-treated BC patients (n = 54) were generated using RNA-Access technology. Key common biomarkers identified from the BC cell lines and patient tumor samples were validated by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) metastatic specimens from 73 patients prior to CDK4/6i therapy. Results: Transcriptomic profile comparisons of BC cell lines (n = 35) that were sensitive versus resistant to CDK4/6is identified Trefoil Factor 1 and 3 (TFF1 and TFF3) secretory proteins as top predictors of response. Correlation analysis showed a strong negative correlation between TFF1 and TFF3 levels to IC50 values of palbociclib and abemaciclib. Knockdown of TFF3 in CDK4/6i-sensitive BT20 cells with shRNA induced drug resistance in the cells. Transcriptomic data from 54 BC patients pre-treated with CDK4/6i showed the expression levels of TFF1 and TFF1/3 receptors (CCR4 and CCR7) were significantly increased in patients who developed late progression (&amp;gt; 6 months) compared to early progressors (&amp;lt; 3 months). In addition, IHC analysis of TFF1 and TFF3 expressions in 73 pre-treated BC patient samples showed significantly higher protein expression levels in late progressors than in early progressors. Conclusions: Our results identified and validated the common biomarkers, TFF1 and TFF3, as predictors of CDK4/6i response efficacy in ER-positive, HER2-negative BC patients. These findings provide a predictive tool capable of selecting de novo metastatic BC patients who will have the greatest benefit from the combination of CDK4/6i with endocrine treatment. Furthermore, our discovery of biomarkers in early versus late progression on CDK4/6i therapy will enable new therapeutic avenues and provide the rationale for future large-scale clinical trials. Citation Format: Linjie Luo, Yan Wang, Sophia Mastoraki, Akshara Singareeka Raghavendra, Juliana Navarro-Yepes, Nicole M. Kettner, Serena Kim, Debasish Tripathy, Kelly Hunt, Khandan Keyomarsi. TFF1 and TFF3 predict response to CDK4/6 inhibitors in breast cancer patients. [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 4346.

Abstract 4477: DIACC3010, optimized inhibitor of S6 kinase, combined with endocrine therapy, has potent antitumor activity in treatment-resistant ER-positive HER2-negative metastatic breast cancer

Abstract Background: Ribosomal protein S6 kinase (S6K) is a key regulator of estrogen receptor (ER) function, and its high expression is associated with poor clinical outcomes in breast cancer (BC). Recent data have demonstrated that S6K is involved in resistance to CDK4/6 inhibitors in metastatic BC (MBC). DIACC3010 (formerly M2698) is an oral brain-penetrant potent inhibitor of S6K. By design, DIACC3010 also selectively inhibits AKT1 and AKT3, while sparing AKT2. DIACC3010 was previously evaluated in a phase 1 trial (NCT01971515). We performed exploratory correlative analyses of the phase 1 trial in ER+ HER2-negative MBC patients in addition to nonclinical experiments to evaluate its role in the CDK4/6 and endocrine therapy (ET) resistant setting. Methods: DIACC3010 was evaluated as monotherapy, or combined with either trastuzumab or tamoxifen, in a multicenter phase 1 trial that accrued 101 patients with advanced/refractory solid tumors (Tsimberidou et al, J Hematol Oncol 2021 14(1):127). The current analysis focused on patients with ER+ HER2-negative MBC and aimed to explore the efficacy of DIACC3010 according to ESR1 mutational status. DIACC3010 was also evaluated in tamoxifen resistant patient-derived xenograft (PDX) mouse models, both alone and combined with tamoxifen. Results: Twenty patients were evaluable at baseline for their tumor mutational status and included in the analysis. Median age was 60 years and median number of prior lines of therapy was 5.5. Twelve of 20 (60%) patients had received prior treatment with CDK4/6 inhibitors. Nine of 20 patients (45%) had ESR1 mutations, of whom 4 had received CDK4/6 inhibitor. Median progression free survival was 5.6 months in patients with ESR1 mutations, and 2.6 months in patients with ESR1 wild-type tumors. Among the 13 ER+ BC PDX models evaluated, 10 provided interpretable results and 4 were found resistant to tamoxifen. The combination of DIACC3010 and tamoxifen significantly reduced tumor growth in 6/10 (60%) of all PDX models, and in 4/4 (100%) of the tamoxifen-resistant PDX models. Conclusions: Exploratory analyses from the phase 1 trial, along with nonclinical efficacy in PDX models, demonstrate that DIACC3010 may have antitumor activity in MBC patients with ET resistance. Experiments are underway to assess nonclinical efficacy of DIACC3010 combination with elacestrant or CDK4/6 inhibitors in various models of ER+ MBC, including ET resistant. Citation Format: Christel Navarro, Apostolia Maria Tsimberidou, Cecile Bougeret, Elsa Borghi, Dominique Bridon, Helene Sicard. DIACC3010, optimized inhibitor of S6 kinase, combined with endocrine therapy, has potent antitumor activity in treatment-resistant ER-positive HER2-negative metastatic 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 4477.

Efficacy of front-line treatment for hormone receptor-positive HER2-negative metastatic breast cancer with germline BRCA1/2 mutation.

Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation. The ESME metastatic breast cancer platform (NCT03275311) is a French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1). A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR [95% CI] 1.26 [1.03-1.55]). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR [95% CI] = 1.54 [1.03-2.32]) and PFS1 (adjusted HR [95% CI] 1.58 [1.17-2.12]) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 [0.88-1.41], p = 0.350; PFS1: 1.09 [0.90-1.31], p = 0.379). In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.

Multi-omics fusion analysis models with machine learning predict survival of HER2-negative metastatic breast cancer: a multicenter prospective observational study.

Multi-omics fusion analysis models with machine learning predict survival of HER2-negative metastatic breast cancer: a multicenter prospective observational study.

Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells.

CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease. We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of CDKi-resistant mammary cancer cells by using the p16-INK-ATTAC mouse model of inducible senolysis. Palbociclib pretreatment of naïve mice increased lung seeding of CDKi-resistant syngeneic mammary cancer cells, and this effect was reversed by depletion of host senescent cells. RNA sequencing analyses of lungs from non-tumor-bearing p16-INK-ATTAC mice identified that palbociclib downregulates immune-related gene sets and gene expression related to leukocyte migration. Concomitant senolysis reversed a portion of these effects, including pathway-level enrichment of TGF-β- and senescence-related signaling. CIBERSORTx analysis revealed that palbociclib alters intra-lung macrophage/monocyte populations. Notably, lung metastases from palbociclib-pretreated mice revealed senescent endothelial cells. Palbociclib-treated endothelial cells exhibit hallmark senescent features in vitro, upregulate genes involved with the senescence-associated secretory phenotype, leukocyte migration, and TGF-β-mediated paracrine senescence and induce tumor cell migration and monocyte trans-endothelial invasion in co-culture. These studies shed light on how stromal senescence induced by palbociclib affects lung metastasis, and they describe palbociclib-induced gene expression changes in the normal lung and endothelial cell models that correlate with changes in the tumor microenvironment in the lung metastatic niche.

A phase I trial of palbociclib and bosutinib with fulvestrant in patients with metastatic hormone receptor positive and HER2 negative (HR+ HER2-) breast cancer refractory to an aromatase inhibitor and a CDK4/6 inhibitor

Standard treatment for metastatic hormone positive (HR+) breast cancer includes a combination of a CDK4/6 inhibitor and antiestrogen therapy. Despite durable responses, eventual endocrine resistance results in disease progression. The Src/Abl pathway has been shown to mediate endocrine resistance in breast cancer, thus providing a promising target for novel therapies. Bosutinib is a tyrosine kinase inhibitor that targets the Src/Abl pathway, which has been studied in hematologic malignancies. Preclinical data suggests that the addition of bosutinib to a CDK4/6 inhibitor and antiestrogen therapy has the potential to reverse endocrine resistance.This is a phase I, single arm, open-label clinical trial in which we evaluate the combination of palbociclib and fulvestrant with bosutinib in metastatic HR+ breast cancer. Patients with confirmed advanced HR+/HER2- breast cancer who have received no more than three lines of chemotherapy and have progressed on at least one aromatase inhibitor and one CDK4/6 inhibitor will be enrolled. Participants will be given a combination of palbociclib, fulvestrant and bosutinib over 28-day cycles. The primary objective of this study is to assess the safety and tolerability of bosutinib in combination with palbociclib and fulvestrant in the study population. Secondary objectives are to 1) determine the anti-tumor effect of this therapeutic combination by assessing overall response rate (ORR) and clinical benefit rate (CBR) after 6 months of treatment, 2) to determine the clinical pharmacology parameters of bosutinib in this regimen, and 3) to build a tissue repository at Georgetown Lombardi Comprehensive Cancer Center for further translational study.

Does Proton Pump Inhibitors Decrease the Efficacy of Palbociclib and Ribociclib in Patients with Metastatic Breast Cancer?

Background and Objectives: This investigation aimed to determine the impacts of concurrent proton pump inhibitors (PPIs) on progression-free survival (PFS) in patients with hormone receptor-positive and HER2-negative metastatic breast cancer managed with palbociclib or ribociclib as either the initial or subsequent line of therapy option. Materials and Methods: In this retrospective study, patients were classified as "concurrent PPIs" if PPIs were given for at least two-thirds of the palbociclib or ribociclib therapy period, and "no concurrent PPIs" if no PPIs were given during the period of palbociclib or ribociclib therapy. Each patient was also classified as endocrine-sensitive or endocrine-resistant according to the duration of previous endocrine responses. "Concurrent PPIs" and "no concurrent PPIs" groups were compared with each other in terms of PFS. This comparison was performed for both ribociclib and palbociclib groups. Results: The research included 220 patients in total. The PFS of 57 patients on palbociclib using concomitant PPIs was 14.4 months. Among 63 patients using palbociclib without concomitant PPIs, the PFS was 15.8 months. No statistically significant difference was found with PPI use (p = 0.82). Among 29 patients using ribociclib concurrently with PPIs, the PFS was 22.4 months. Among 71 patients using ribociclib without PPIs, the PFS was 20.2 months. No statistically significant difference was found with PPI use (p = 0.40). Conclusion: The results of our investigation showed that concomitant use of the most commonly used PPIs in the study (lansoprazole, pantoprazole, and esomeprazole) with palbociclib or ribociclib did not have any detrimental effects on PFS. Where appropriate, PPIs can be used concurrently with palbociclib and ribociclib. However, the effect of PPIs on cycling-dependent kinase 4/6 inhibitors deserves further investigation.

Pegylated liposomal doxorubicin (Duomeisu®) monotherapy in patients with HER2-negative metastatic breast cancer heavily pretreated with anthracycline and taxanes: a single-arm, phase II study

PurposeTo evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) heavily pretreated with anthracycline and taxanes.MethodsIn this single-arm, phase II study, patients with HER2-negative MBC previously treated with anthracycline and taxanes as second- to fifth chemotherapy received PLD (Duomeisu®, generic doxorubicin hydrochloride liposome) 40 mg/m2 every 4 weeks until disease progression, unacceptable toxicity, or completion of six cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety.ResultsOf 44 enrolled patients (median age, 53.5 years; range, 34–69), 41 and 36 were evaluable for safety and efficacy, respectively. In total, 59.1% (26/44) of patients had ≥ 3 metastatic sites, 86.4% (38/44) had visceral disease, and 63.6% (28/44) had liver metastases. Median PFS was 3.7 months (95% confidence interval [CI] 3.3–4.1) and median OS was 15.0 months (95% CI 12.1–17.9). ORR, DCR, and CBR were 16.7%, 63.9%, and 36.1%, respectively. The most common adverse events (AEs) were leukopenia (53.7%), fatigue (46.3%), and neutropenia (41.5%), with no grade 4/5 AEs. The most common grade 3 AEs were neutropenia (7.3%) and fatigue (4.9%). Patients experienced palmar-plantar-erythrodysesthesia (24.4%, 2.4% grade 3), stomatitis (19.5%, 7.3% grade 2), and alopecia (7.3%). One patient displayed a left ventricular ejection fraction decline of 11.4% from baseline after five cycles of PLD therapy.ConclusionPLD (Duomeisu®) 40 mg/m2 every 4 weeks was effective and well-tolerated in patients with HER2-negative MBC heavily pretreated with anthracycline and taxanes, revealing a potentially viable treatment option for this population.Trial registration Chinese Clinical Trial Registry: ChiCTR1900022568.

Abstract P4-01-14: Changes in the Genomic Spectrum of Actionable Alterations in HER2 Negative Metastatic Breast Cancer in Serial Cell Free DNA (cfDNA) Analysis

Abstract Background: Serial cell free DNA (cfDNA) analysis in metastatic breast cancer (MBC) is a noninvasive method for tracking tumor evolution and the emergence of new somatic alterations through the course of the disease. The detection of new actionable alterations may impact treatment selection; thus, serial cfDNA collection is increasingly being performed in the clinic. However, it is not well-understood how often serial cfDNA testing identifies new actionable alterations. We evaluated changes in the genomic spectrum of actionable alterations in serial cfDNA analysis of HER2 negative (HER2-) MBC. Method: Patients with HER2- MBC who underwent plasma-based cfDNA testing (Guardant360, 74-gene assay) between February 2015 and February 2021 at an academic institution were included. A retrospective review of records was conducted to identify subtype, demographics, lines of therapy, and cfDNA results. At baseline cfDNA testing, all cfDNA alterations were considered new. For patients with serial draws, new cfDNA alterations in each draw, compared to previous draws, were quantified and characterized. The pathogenicity of new alterations was determined using the OncoKB precision oncology database. New pathogenic alterations were further classified as actionable alterations (AA) using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Alterations that met the ESCAT I (alteration-drug match was associated with improved outcomes in clinical trials) or ESCAT II (alteration-drug match was associated with antitumor activity) criteria were considered as AA. Results: 344 patients with hormone receptor positive (HR+) MBC and 95 patients with triple negative (TN) MBC had a baseline cfDNA draw. Among the HR+ cohort, 139, 79 and 48 patients had 2nd, 3rd, and 4th serial cfDNA draws, respectively. Among the TN cohort, 33 and 18 patients had 2nd and 3rd serial cfDNA draws, respectively. Table 1 depicts the prevalence of AA found in each of these draws, as well as the median number of prior therapies at each point of collection and the mean time between serial draws. The median number of new genomic alterations was lower in subsequent draws compared to the baseline, regardless of subtype (HR+: 4 vs. 2, TN: 4 vs. 1.5-3, at baseline vs. subsequent draws, respectively). In the HR+ cohort the proportion of patients with new AA (ESCAT I/II) decreased from 63% at baseline to 27-33% in the 2nd-4th draws. While some of the new AA in subsequent draws were new actionable variants in the same genes that were known to be altered in previous draws (in 19%, 68% and 57% of patients with new AA in the 2nd, 3rd and 4th draws, respectively), the remainder were new AA in previously unaltered genes. In the TN cohort 25% of patients had new AA at baseline and this proportion of TN patients with new AA continued to decrease in subsequent draws (9% and 0% in the 2nd and 3rd draws, respectively). PIK3CA and ESR1 were the most frequent genes with new AA in the ER+ cohort, regardless of draw number. In the TN cohort, PIK3CA was the most frequent gene with new AA in the first draw, and in the second draw, new AA in PIK3CA, BRCA2, and ERBB2 were present at an equal frequency. Conclusion: While the proportion of patients with HER2- MBC identified to have new AA in serial cfDNA decreased with time for both HR+ and TNBC, new alterations continue to emerge, particularly for patients with HR+ MBC. Further research is needed to determine the impact of serial cfDNA testing on the selection of genotype-matched therapy and outcomes. Table 1. Citation Format: Yael Bar, Jennifer C. Keenan, Lianne Ryan, Dejan Juric, Jennifer Shin, Seth A. Wander, Laura M. Spring, Beverly Moy, Leif Ellisen, Steven J. Isakoff, Aditya Bardia, Neelima Vidula. Changes in the Genomic Spectrum of Actionable Alterations in HER2 Negative Metastatic Breast Cancer in Serial Cell Free DNA (cfDNA) Analysis [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 P4-01-14.

Abstract P4-01-41: Clinical outcome and toxicity profile of Cyclin-dependent kinase 4/6 inhibitors in combination with hormonal treatment in management of metastatic breast cancer patients: A Middle-East Real World Experience

Abstract Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with hormonal treatment is the standard of care in the management of hormone receptor positive, human epidermal growth factor receptor-2 (Her2) negative metastatic breast cancer (MBC) patients. Data coming from the Middle east region is very rare and our patients’ population were poorly represented in the CDK4/6 inhibitors landmark clinical trials, This retrospective study is to evaluate our real-world experience with this treatment combination in our patients’ population. Patients and methods: A retrospective study was conducted in a middle eastern tertiary institution, where the clinical data of treatment outcome and toxicity were collected from the electronic medical records of 164 patients with hormone receptor positive, Her2 negative MBC who were managed with CDK4/6 inhibitors in combination with hormonal treatment, at and beyond first line of treatment. Progression free survival (PFS) was the study primary objective, Objective response rate (OR), Overall survival (OS), and toxicity profile were the secondary objectives. Results: From January 2017 to April 2021, 164 patients (5 men and 159 women) were managed with CDK4/6 inhibitors in combination with hormonal treatment for MBC, median age was 52 years (IQR: 45-59), 63% of patients were postmenopausal, 60% had luminal type B tumors, 22% had Her2 expression of 2+ by IHC, 55% had de Novo metastases, 67% had visceral metastases, 61% defined to have endocrine resistant disease (13% primary and 48% secondary resistance), CDK inhibitors (46% Palbociclib, 54% Ribociclib) were given as 1st, 2nd and beyond 2nd line in (48%, 28% and 24% respectively), at a median duration of follow up of 25.3 months (IQR: 13.8-33.9 months), the median PFS for the overall group was 14.2 months (CI 09.8-18.7), it was highest for 1st line treatment 19 months vs 15 and 5 months for the 2nd and beyond 2nd line treatment respectively. The median overall survival was 51.6 months (CI 35.8-67.5) for the whole group, 50.3 and 51.6 months for 1st and 2nd line vs 33.1 months for beyond 2nd line treatment. 5% of patients had achieved complete response, 37% partial response, and 24% had stable disease, with a clinical benefit rate of 74%. A body mass index (BMI) &amp;lt; 30, KI67 &amp;lt; 20%, luminal type A, de Novo metastases, Ribociclib as a CDKi, Aromatase inhibitor (AI) as the hormonal partner, and introducing the treatment combination in early treatment lines (1st and 2nd lines) were all associated with significantly higher PFS in univariate analysis. BMI and AI were the only factors associated with significantly higher PFS in multivariate analysis. Efficacy was consistent regardless of the menopausal status, type of endocrine resistance, and site of metastases. The most common toxicities were neutropenia, fatigue, vomiting, diarrhea, QTC prolongation and hepatic toxicity, the most common G3&amp;4 toxicity were Neutropenia 56%, hepatic toxicity 5.4% and QTC prolongation in 4.3%. Treatment was permanently stopped because of toxicity in 12 patients (7.3%). Conclusion: Our real-life data came consistent with the pivotal clinical trials’ results, encouraging and supporting the use of CDK 4/6 inhibitors in combination with hormonal treatment in our patient population with metastatic breast cancer, especially in the early treatment lines, deferring the start of more toxic therapies to a later stage. Citation Format: Ahmed Mostafa Gad, Adhar AlSayed, Aisha AlShibani, Taher Twegieri, Kausar Suleman, Dahish Ajarim. Clinical outcome and toxicity profile of Cyclin-dependent kinase 4/6 inhibitors in combination with hormonal treatment in management of metastatic breast cancer patients: A Middle-East Real World Experience. [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 P4-01-41.

Abstract P4-01-13: A retrospective study of anlotinib in patients with HER-2 negative metastatic breast cancer after prior two or more lines treatment

Abstract Background: Anlotinib is a novel small molecule antiangiogenic drug that can inhibit multiple tyrosine kinase receptor activities. It has demonstrated antitumor activity in various cancers. This retrospective study explored the efficacy and safety of anlotinib combined chemotherapy in HER-2 negative metastatic breast cancer patients who have disease progressed after prior two or more lines of therapy. Methods: This retrospective study enrolled twenty-two HER-2 negative metastatic breast cancer patients including TNBC and HR+ subtypes. These patients pretreated with at least two lines of chemotherapy and/or endocrine drugs before receiving anlotinib. These patients received anlotinib combination with investigator-selected chemotherapy agents, including docetaxel, vinorelbine, gemcitabine, etoposide, alibrine and so on. Anlotinib was administered 12mg d1-d14 for a 21-day cycle. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. The treatment continued until disease progression or intolerability or the patient withdraw informed consent. Results: The enrolled breast cancer patients received anlotinib with a median age of 52.5 (rang 30 to 73). The patients with multiple metastases were 59.1% (13/22). All patients were evaluated and the ORR was 50% (95% Cl 0.282-0.718), DCR 95.5% (95% Cl 0.772-0.999) and the mPFS was 8 months (95% Cl 5.15-10.85). We also analyzed the efficacy of anlotinib combination with chemotherapy in different subtypes. For HR+HER2- metastatic breast cancer patients, the ORR was 77.8% (95% Cl 0.4-0.972), DCR 100% (95% Cl 0.664-1.0) and the mPFS was 8.5 months (95% Cl 7.217-9.783). And for TNBC patients, the ORR was 30.8% (95% Cl 0.091-0.614), DCR 92.3% (95% Cl 0.640-0.998) and the mPFS was 6 months (95%Cl 4.405-7.595). The most common adverse events were grade 1/2 including fatigue, hand-foot syndrome and thrombocytopenia et.al., and no serious adverse events occurred. Conclusion: Anlotinib is safe and effective in patients with HER-2 negative metastatic breast cancer after prior two or more lines treatments, and it is well tolerated. Citation Format: Jing Sun, Yijun Tang, Xiaohui Liu, Jiangli Li, Jin Xia, Liang xu, Junlan Guo, Jing Wang, Shengnan Guo, Zhaojie Sheng, Yanfang Zhang, Yuan Yuan. A retrospective study of anlotinib in patients with HER-2 negative metastatic breast cancer after prior two or more lines treatment [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 P4-01-13.

Abstract P3-05-45: Circulating tumor cells, immunohistochemical subtypes, and genes mutation as prognostic markers in HER2 negative metastatic breast cancer patients candidates to chemotherapy

Abstract Background: In the era of targeted therapies, chemotherapy (CT) is still a valuable treatment option for patients (pts) with HER2 negative metastatic breast cancer (MBC). The identification of predictive and prognostic markers might improve treatment response and survival. Here we investigated the role of tumor subtypes, circulating tumor cells (CTCs), and mutations in genes or pathways of interest, in predicting response to CT and prognosis of HER2 negative MBC pts within AARES trial. Methods: AARES is an open label multicentric randomised phase 2 trial comparing a DNA-damaging (arm A: cisplatin 25 mg/m2/day, day 1-3 + cyclophosphamide 600 mg/m2 day 1) versus (vs) a non-DNA-damaging (arm B: capecitabine 1000 mg/m2 bid/day, day 1-14 + vinorelbine 60 mg/m2/day, day 1,8) CT regimen in pts with HER2 negative MBC. Archival tumor tissue samples and blood samples were collected at baseline. The Cell SearchTM system was used for CTCs isolation and enumeration and a cut-off of 5 CTC/7,5 ml was used. Tumor subtypes were based on locally assessed hormone receptors and HER2 status. The luminal-like subtype (Lum) was defined by ER or PR positivity, while the triple negative subtype (TN) by ER, PR, and HER2 negativity. Tissue samples were used for DNA extraction and next generation sequencing analysis using a target enrichment panel of 170 genes (TruSight 170, Illumina). Primary endpoint was objective response rate (ORR) assessed for the two treatment arms. Progression free survival (PFS) and overall survival (OS) were evaluated as secondary endpoints, and estimated with the Kaplan-Meier method. ORR, PFS and OS were correlated with CTC counts, tumor subtypes, and mutational status of genes/pathway of interest (PIK3CA, TP53, BRCA1, BRCA2, PI3K/AKT pathway (PI3K/AKT)). Results: AARES enrolled 102 pts from 2011 to 2016 across 9 Italian centers. Of these, 77 pts were evaluable for ORR. Median follow up was 32 months. Overall, median age was 57. The majority of pts had Lum tumors (73%), while 27% had TN. 86% of pts had visceral metastases, and 52% had 3 or more metastatic sites. 48% of pts received the study treatment as 1st line, 32% as 2nd line, and 19% as 3rd line. Out of the 77 pts with ORR data, 41 (53%) were CTC- and 36 (47%) CTC+. A larger proportion of pts with Lum tumors were CTC+ (54% n=30), while TN tumors were mainly CTC- (71% n=15). 49 pts had adequate tumor tissue for sequencing analysis. TP53 mutations (mut) were found in 33% of pts, BRCA1/2 mut in 14%, PIK3CA mut in 35%, and PI3K/AKT mut in 47%. ORR was 24% and 37% in arm A vs arm B, respectively (p= 0.2), and no difference in ORR was observed by tumor subtypes (Lum vs TN), and CTCs count (+ vs -). PFS and OS were assessable on the whole population (n=102) and did not significantly differ by treatment arms. Median OS (mOS) was higher in Lum pts compared to TN (24 months (mo) vs 15.4 mo, p=0.048) while median PFS (mPFS) did not differ according to tumor subtypes (p=0.28). Overall, CTCs count was not significantly associated with mPFS or OS however in pts with TN tumors and CTC-, mPFS and mOS were significantly longer (mPFS: 4.44 mo vs 2.56 mo in CTC- and CTC+ subgroups, respectively, p=0.00087 and mOS: 22.07 mo vs 3.57 mo in CTC- and CTC+ subgroups, respectively, p&amp;lt; 0.0001). On the other hand, no differences were observed in Lum pts categorized according to CTC status (p=0.83 for mPFS, p=0.54 for mOS). Finally, pts with PI3K/AKT mut had a significantly worse PFS compared to wild type in the overall population (p=0.0091) as well as in Lum (p=0.034) and TN pts (p=0.0052). Conclusions: CTCs and tumor subtypes were not predictive of response to CT regimens in HER2 negative MBC pts. A number of CTC &amp;gt;5 in TN MBC, and mutations in the PI3K/AKT pathway, identified a subgroup of pts with worse prognosis, potentially candidates for alternative treatments. Further studies are needed to confirm these results in a larger population. Citation Format: Emanuela Risi, Marta Pestrin, Chiara Biagioni, Dario Romagnoli, Ilenia Migliaccio, Francesca Galardi, Francesca De Luca, Matteo Benelli, Erica Moretti, Giuseppina Sanna, Luca Livraghi, Silvia Cappadona, Roberta Di Marsico, Domenico Amoroso, Angelo Martignetti, Angela S. Ribecco, Elena Rota Caremoli, Luigi Coltelli, Fabio Puglisi, Luca Malorni, Laura Biganzoli. Circulating tumor cells, immunohistochemical subtypes, and genes mutation as prognostic markers in HER2 negative metastatic breast cancer patients candidates to chemotherapy [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 P3-05-45.

Abstract P1-03-04: Visceral fat area as a predictive factor in metastatic HER2 negative breast cancer patients treated by first line chemotherapy with weekly paclitaxel and bevacizumab

Abstract Background Obesity has previously been correlated with poorer survival in both early and metastatic breast cancer. Adipose tissues release proangiogenic factors such as Insulin-like Growth Factor and Vascular Endothelial Growth Factor that may ultimately promote tumor growth. CTscan can be used to measure the visceral fat area (VFA) and the subcutaneous fat area (SFA) on the same section. High VFA has been shown to independently predict poorer outcome in patients given first-line bevacizumab-based treatment for metastatic colorectal cancer and metastatic renal cell carcinoma. The prospective multicenter COMET trial included metastatic HER2 negative breast cancer patients receiving bevacizumab and paclitaxel as fist-line chemotherapy. This study was designed to identify and validate reliable factors to predict benefit of bevacizumab and allow for a more personalized use of this antiangiogenic agent. Our aim was to evaluate the prognostic value of BMI (Body Mass Index), VFA and SFA in the COMET cohort and their impact on the quality of life. Patients and Methods Out of the 510 patients included in the COMET trial from 9/2012 to 3/2016, 480 received bevacizumab and paclitaxel as first-line treatment and 360 had available CTscan data. VFA and SFA were measured retrospectively on the CTscans performed before chemotherapy initiation, at the level of the umbilicus with the patient in the supine position. ImageJ software was used to measure pixels with densities in the -190 HU to -30 HU range in order to delineate the subcutaneous and visceral compartments and to compute the cross-sectional area of each in cm2. These measurements were performed by a radiologist blinded to patients’ characteristics and outcomes. For VFA and SFA, we used a threshold at the median value. VFA and SFA levels were tested for their association with progression-free survival (PFS) and overall survival (OS). The impact on quality of life was based on the Global Health Status, the Physical functioning, the Emotional functioning, Fatigue and Pain scores. Results The mean age at inclusion was 57 years (range: 28-83). At initial diagnosis, the main histological type was invasive ductal carcinoma (n = 247, 80.7%). Most patients had received prior neoadjuvant/adjuvant chemotherapy (n = 245, 68.1%) and a large majority (95.4%) had less than 3 metastatic sites. One hundred and forty patients (46.7%) had histological grade II and 41% had grade III tumors. The majority of the patients had positive hormone receptor tumor (n = 238, 79.3 %) and 62 (20.7%) had triple-negative tumor subtype. The median BMI was 24.7 (range : 17-46). After a median follow-up of 60.6 months (95%CI, 60-61.3), median PFS was 9.5 months (95CI, 8.6-10.3). There was no significant correlation between BMI (p = 0.69), VFA (p = 0.24) or SFA (p = 0.58) and PFS in the univariate analysis. The median OS was 29.6 months (95CI, 25.9-32.4). BMI, VFA and SFA were not correlated with OS. Out of the 360 patients, 328 had available data regarding the quality of life. There was no impact of the VFA or the SFA on the different quality of life scores. Conclusions In our prospective cohort of 360 patients with metastatic breast cancer receiving bevacizumab and paclitaxel as first-line treatment, high VFA or high SFA were not associated with a poorer survival. VFA and SFA had no impact on quality of life. Citation Format: Séverine Guiu, Boris Guiu, Marion Chevrier, Oumar Billa, Christelle Levy, Olivier Trédan, Isabelle Desmoulins, Marc Debled, Jean-Marc Ferrero, Christelle Jouannaud, Anthony Gonçalves, Maria Rios, Marie-Ange Mouret-Reynier, Frédérique Berger, Fatima-Zohra TOUMI, Jérôme Lemonnier, Jean-Yves Pierga, Sandrine Dabakuyo, Sophie Gourgou. Visceral fat area as a predictive factor in metastatic HER2 negative breast cancer patients treated by first line chemotherapy with weekly paclitaxel and bevacizumab [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 P1-03-04.

Abstract HER2-05: HER2-05 Comprehensive genomic characterization of HER2-low breast cancer

Abstract Background: About half of all breast cancers exhibit low HER2 expression. Despite lack of ERBB2 amplification, HER2-low tumors respond to trastuzumab deruxtecan (T-DXd), leading to the NCCN recommendation of T-DXd both for patients with HER2+ and HER2-low metastatic breast cancer (MBC). It remains however unclear if HER2-low represents a distinct molecular entity, as compared to HER2-0 MBC. Here, we compare the genomic landscape of HER2-low versus HER2-0 breast cancers in a large, single institution cohort. Methods: We identified consecutive patients with MBC seen at Dana-Farber Cancer Institute between 07/2013 and 12/2020. Patients were included if they had HER2-negative MBC per ASCO/CAP Guidelines and had undergone next generation sequencing (NGS) testing with a targeted, tumor-only platform (OncoPanel). Based on the HER2 status of the specimen tested by NGS, patients were divided into 2 groups: (i) HER2-low if immunohistochemistry (IHC) 1+ or 2+ non-amplified, or (ii) HER2-0 if IHC 0. Mutations of interest detected on NGS were classified as oncogenic using the OncoKB tool and additional annotation. Genomic profiles of HER2-low and HER2-0 tumors were compared using Chi-Square and Kruskal-Wallis tests. To determine genomic event enrichment between the two HER2 groups, logistic regression models were used, accounting for background rate and estrogen receptor (ER) expression. ERBB2 copy counts were calculated for tumors with recorded histology-estimated purities and copy-number segmentation using a simple model of allelic gain/loss. Results: Among 1847 patients with HER2-negative MBC, 1043 underwent NGS testing on a HER2-low (n=489, 47%) or HER2-0 sample (n=554, 53%). Most samples were metastatic (71%, n=743) while 29% (n=300) were from primary tumors. 73% had ductal histology, 13% were lobular and 14% had mixed or other histology. ER expression was enriched among HER2-low vs. HER2-0 tumors (76% vs. 60%; p&amp;lt; 0.001). Focusing on the most commonly occurring genetic mutations, no major differences were observed in HER2-low vs. HER2-0 tumors, after correcting for ER status (Table 1). Among all mutational events, any mutation in MPL, CYLD, and MAP3K and oncogenic mutations in TP53 and NF1 were more common in HER2-0, while any mutation in MTOR, RAD21, DNMT3A, and PDGFRA were enriched in HER2-low patients, when controlling for ER status and background mutational rate (p&amp;lt; 0.05). However, no mutation reached significance after accounting for multiple hypothesis testing. Similarly, no deep deletion or high amplification CNV events reached significance for either group. Analysis of tumor mutational burden in HER2-low vs. HER-0 tumors revealed no significant differences (median: 7.26 muts/Mb vs. 7.60 muts/Mb, p=1.00), including when accounting for ER status. Finally, among tumors with sufficient tumor purity for ERBB2 copy count analysis (n=374 and 419 for HER2-low and HER2-0, respectively), HER2-low tumors had a significantly higher number of ERBB2 alleles as compared to HER2-0 (&amp;lt; 2 copies, 15.0% vs. 30.9%, 2 copies 67.4% vs. 60.5%, and &amp;gt;2 copies, 17.6% vs. 8.6%; p&amp;lt; 0.001 by Kruskal-Wallis). Conclusions: To our knowledge, this is the largest comprehensive genomic analysis of HER2-low MBC to date. In our cohort of patients with HER2-negative MBC, the genomic landscape of HER2-low and HER2-0 tumors did not differ significantly, apart from a higher number of ERBB2 alleles. These data further support the notion that HER2-low, as currently defined, is not a distinct molecular subtype of breast cancer. Citation Format: Paolo Tarantino, Hersh V. Gupta, Melissa E. Hughes, Janet L. Files, Sarah Strauss, Gregory Kirkner, Anne-Marie Feeney, Yvonne Y. Li, Ana C. Garrido-Castro, Romualdo Barroso-Sousa, Brittany Bychkovsky, Laura MacConaill, Neal Lindeman, Bruce Johnson, Matthew Meyerson, Sheheryar Kabraji, Rinath Jeselsohn, Xintao Qiu, Rong Li, Henry W. Long, Eric Winer, Deborah A. Dillon, Giuseppe Curigliano, Andrew Cherniack, Sara Tolaney, Nancy U. Lin. HER2-05 Comprehensive genomic characterization of HER2-low 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 HER2-05.

Abstract OT3-07-01: Real-World Data on First-line Treatment of HR-positive, HER2-negative, Metastatic Breast Cancer in Brazil (BRAVE Study/LACOG 0221)

Abstract Background: It is estimated that 50 thousand patients live with metastatic breast cancer (MBC) in Brazil. A recent Brazilian registry (LACOG 0312) on MBC demonstrated a median overall survival (OS) by breast subtype of 15 months for triple negative, 23 months for HER2 positive, and 42 months for Luminal tumors, which are very similar to developed countries except the HER2 positive group which have limited access to targeted agents in the public health system. Recently, CDK 4/6 inhibitors were approved for the treatment of HR+ HER2-negative MBC with an improvement in progression-free survival (PFS) and ribociclib and abemaciclib demonstrating benefit in OS over endocrine therapy alone, establishing the standard of care in first-line setting for this BC subtype. In Brazil, disparities exist in the incorporation of novel anticancer agents between public and private health systems limiting treatment options for patients with HR+ HER2- negative MBC in the public system, which covers most of the population. The BRAVE study aims to describe the patient journey and current patterns of care for HR+ HER2-negative MBC to identify possible gaps and how health insurance type influences treatment patterns in Brazil. Trial Design: This is an observational, retrospective cohort study. All patients diagnosed with mBC (either de novo or recurrent) in the period of January 2018 to December 2020 at participating centers will be included. Data will be collected from medical records. No interventions are proposed. Enrollment of a total of 300 patients (150 patients from public health care system and 150 patients from private health care system) is planned. ClinicalTrials.gov identifier: NCT05034393. Eligibility: Inclusion criteria: women ≥18 years old; histologically confirmed HR-positive HER2-negative invasive breast cancer; HR-positive, defined as 1% to 100% of tumor nuclei positive for ER and/or PgR as per ASCO/CAP Guideline 2020 or Allred score of ≥3; HER2-negative, defined as IHC result is 0/1+ or 2+ with ISH negative as per ASCO/CAP Guideline 2018; diagnosed with de novo or recurrent metastatic breast cancer between January 2018 and December 2020. Exclusion criteria: male BC; first-line treatment for mBC received through clinical trial. Specific Aims: Primary objective is to describe the first-line (1L) treatment of HR-positive, HER2-negative mBC in Brazil. Secondary objectives are to describe progression-free survival (PFS) in the 1L setting until month 24; describe and compare the 1L treatment of HR-positive, HER2-negative mBC and PFS until month 24 according to the health care coverage (public vs. private); describe timelines from symptoms, histopathological diagnosis, molecular test, and treatment; describe the mBC pathological characterization; describe frequency of diagnostic tests to define breast cancer molecular subtypes; describe the subsequent line of treatment and corresponding PFS; describe overall survival (OS); evaluate PFS and OS according to visceral vs. non-visceral metastatic disease, primary endocrine resistance vs. acquired endocrine resistance, de novo versus recurrent disease, public vs. private health system and pre vs postmenopausal status. Statistical Methods: No a priori sample size calculation was performed. The expected sample size of 150 patients in each group allows description of the proportion of patients using CDK 4/6 inhibitors with two-sided 90% confidence interval ranging from 53.4% to 66.6% when the expected proportion is 60% in the private health system. Present Accrual and Target Accrual: A total of 12 sites of 14 planned were activated. The first patient was enrolled on February 8, 2022. As of June 24, 2022, a total of 122 patients were enrolled, 86 from public and 36 from private health system. The target accrual of 300 patients is expected to be completed by November 2022. Results are expected to be presented by April 2023. Funding: Novartis. Acknowledgements: SAS. Citation Format: Gustavo Werutsky, Tomás Reinert, Daniela D. Rosa, Romualdo Barroso-Sousa, Heloísa Resende, Poliana A. Signorini, Juliana G. Martins Fagundes, Jose Marcio B. Figueiredo, Eduardo Cronemberger, Aline C. Vieira, Jorge Henrique Santos Leal, Luiza Nardin Weis, Ludmila Thommen, Rafaela G. Jesus, Gustavo Gössling, José Bines. Real-World Data on First-line Treatment of HR-positive, HER2-negative, Metastatic Breast Cancer in Brazil (BRAVE Study/LACOG 0221) [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 OT3-07-01.

Abstract P5-02-42: Soluble CD163 may be a predictive biomarker of the efficacy of nivolumab plus chemotherapy in patients with HER2-negative metastatic breast cancer (WJOG9917BTR)

Abstract Background: We have conducted a phase II trial (WJOG9917B) to evaluate efficacy of triple therapy with nivolumab, paclitaxel and bevacizumab in patients (pts) with HER2-negative metastatic breast cancer (MBC). Although soluble CD163 has been reported as a potential biomarker for predicting the efficacy of nivolumab in melanoma, however the data is limited in breast cancer. In an ancillary study (WJOG9917BTR), serum level of soluble CD163 were evaluated to elucidate this question. Methods: The main study enrolled 57 pts and showed that median Progression-free survival (PFS) and overall survival (OS) was 14.0 months and 32.5 months, respectively, with a median follow-up of 29.5 months. We have collected blood samples from consenting patients. Serum samples were collected at pretreatment, cycle 1 day 8 and other time points, which were used to measure the concentrations of cytokines, chemokines, and other surrogate proteins. PFS, OS, and response were analyzed in association with the biomarker data using the Kaplan–Meier method, log-rank tests as appropriate. Results: Biomarker study included 50 pts (36 with recurrent BC and 14 with de novo stage IV BC). The median amount of soluble CD163 before treatment was 562.3 (pg/ml) (range: 158.7-1518.0), and the baseline CD163 levels were higher in pts with recurrent than de novo stage IV (p = 0.0099). Other clinical factors including tumor subtypes, liver metastasis, response, PFS or OS were not significantly associated with the baseline CD163 levels. The kinetic changes in serum soluble CD163 after treatment were divided into two groups; one group (30 patients, CD163 increased group) had increased soluble CD163 immediately after administration (Cycle 1 Day 8), with a median PFS of 18.2; the other group (20 patients, CD163 decreased group) had decreased CD163 immediately after administration, with a median PFS of 13.6. There was a significantly difference in PFS between these two groups (hazard ratio 0.50 [0.26-0.93], log-rank test, p = 0.0263), but not in OS (p = 0.0548). These results suggested that the early change of serum soluble CD163 may be a predictive biomarker of efficacy of nivolumab plus chemotherapy in pts with HER2-negative MBC. Conclusions: Soluble CD163 may be a predictive biomarker for early detection of the efficacy of nivolumab plus chemotherapy in pts with HER2-negative MBC. (UMIN000029590) Citation Format: Toru Mukohara, Yukinori Ozaki, Shigehisa Kitano, Makiko Yamashita, Daiki Ikarashi, Junji Tsurutani, Tsutomu Iwasa, Masato Takahashi, Norikazu Masuda, Manabu Futamura, Hironobu Minami, Koji Matsumoto, Yuko Tanabe, Hidetaka Kawabata, Kenichi Yoshimura, Toshimi Takano. Soluble CD163 may be a predictive biomarker of the efficacy of nivolumab plus chemotherapy in patients with HER2-negative metastatic breast cancer (WJOG9917BTR). [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 P5-02-42.