Metastatic Breast Cancer Population Research Articles

A single center retrospective cohort study of patients with metastatic breast cancer and leptomeningeal disease: Updated survival data and subgroup analyses by breast cancer subtype.

1108 Background: Patients (pts) with metastatic breast cancer (MBC) and leptomeningeal disease (LMD) have a poor prognosis with limited therapies. We previously reported data from our retrospective LMD registry; here we provide an update with additional pts and subgroup analyses highlighting differences in treatment and survival by breast cancer subtype. Methods: In this single center retrospective cohort study, we identified pts with MBC and LMD who received care from 2000-2024 and abstracted key clinical, treatment, and overall survival (OS) data. Results: We identified 111 pts with MBC and LMD, including pts with the following subtypes: HR+/HER2- (n=53, 47.7%), HER2+ (n=30, 27.0%), and triple negative breast cancer (TNBC; n=28, 25.2%). The majority of pts had concurrent brain metastasis (n=82, 73.9%). Median time from diagnosis of MBC to LMD was 16.4 months (mo) (range 0-101.3 mo). Pts received a median of 3 lines of therapy prior to the diagnosis of LMD (range 0-10) and 1 line after the diagnosis of LMD (range 0-4). Most pts received central nervous system-directed (CNS)-directed therapy (n=94, 84.7%), including intrathecal (IT) therapy (n=42, 37.8%) and/or CNS radiation (n=70, 63.1%). Median OS from the diagnosis of LMD to death was 4.1 mo (range 0.1-78.1 mo) and varied by subtype, with pts with HR+/HER2- or HER2+ MBC and LMD living longer than those with TNBC and LMD (4.2 and 6.8 mo respectively vs. 2.0 mo, p<0.01, HR 2.15, 95% CI 1.36-3.39). There was no difference in OS by histology ductal vs. lobular or by presence or absence of concurrent parenchymal brain metastases. Pts who received IT therapy survived longer than those who did not (7.1 vs. 2.7 mo, p=0.01, HR 0.60, 95% CI 0.40-0.90). There was difference in OS by receipt of CNS-directed radiation therapy. Pts diagnosed with LMD from 2015-2024 lived longer than those diagnosed from 2000-2014 (6.4 vs. 2.9 mo, p=0.04, HR 0.67, 95% CI 0.46-0.99). On multivariable analysis, having TNBC was associated with shorter OS from time of LMD to death (p=0.004, HR 2.03, 95% CI 1.25-3.30). Conclusions: This study represents one of the largest case series of pts with MBC and LMD, including the most pts diagnosed after 2015 to our knowledge. Pts with lobular histology, HER2+ BC, TNBC, and those with de novo MBC were over-represented compared to the general MBC population. Pts with HR+/HER2- or HER2+ disease, LMD diagnosed after 2015, and those who received IT therapy survived longer than their respective cohorts. Novel diagnostic and therapeutic strategies for pts with MBC and LMD remains an area of unmet clinical need.

Abstract PO2-16-10: Characterising HER2-low status in metastatic breast cancer: a real-world retrospective study of patients at a metropolitan cancer centre in Australia

Abstract Background: Traditionally, breast cancer subtyping has described patients as HER2-negative or HER2-positive, with the latter being those in whom HER2-directed therapies are utilised. A proportion of HER2-negative cancers can be classified as “HER2-low” as they express IHC 1+ or 2+ and are non-amplified on in-situ hybridisation (ISH). Until recently, our widely available HER2-targeted therapies have proven to be ineffective in this subtype. The DESTINY-BREAST04 trial (Modi et al, NEJM 2022) showed progression-free and overall survival efficacy of HER2-directed therapy using the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in HER2-low disease, suggesting a need to identify this population for selected therapy. This study evaluated a real-world population of metastatic breast cancer (MBC) patients treated according to traditional breast cancer subtypes to determine the frequency of HER2-low histology, with a focus on selection of first-line therapy. Methods: This retrospective audit identified patients being treated for MBC at a single tertiary hospital (Austin Health in Melbourne, Australia) over a 3.5 year period. Patients were identified from an electronic database, with a date of last follow-up as August 2022. Medical records were interrogated for clinicopathological information including review of pathology reports for breast cancer subtypes. Traditional breast cancer subtypes were defined as (i) ER positive and HER2-negative (HER2 0 or 1+, or 2+ and non-amplified); (ii) HER2-positive (HER2 3+ and/or amplified) and (iii) TNBC (negative for ER and PgR, and HER2 0 or 1+, or 2+ and non-amplified). Selection and duration of first-line treatment for MBC was also recorded. Results: Between March 2018 and August 2022, 202 MBC patients were identified. Based on traditional subtypes, 126 (62%) were ER positive and HER2-negative, 46 (23%) were HER2-positive, 26 (13%) were TNBC and 4 (2%) were unknown. In the total population, 87 (43%) were classified as having HER2-low disease based on retrospective pathology reports. HER2-low represented 61% of ER positive, HER2-non amplified patients and 45% of TNBC patients. Metastatic specimen data was known for 172 cases and of these, 95 patients (55%) were re-biopsied on metastatic progression. This occurred more commonly with HER2-positive (81%) and ER positive HER2-negative (78%) primaries. The most common change in subtype was loss of ER, which occurred in 7 patients (3%). Changes in HER2 status occurred in 29 (14%) of patients, most commonly as either an increase from 1+ to 2+ or decrease from 1+ to 0. HER2-low status remained consistent for 67% of patients who underwent biopsy on recurrence. For patients with ER positive HER2-negative MBC, first-line combination therapy with a CDK4/6 inhibitor + AI was preferred (51%), followed by single agent endocrine therapy (30%) and chemotherapy (17%). The majority (84%) of HER2-positive patients received first-line dual HER2 therapy (trastuzumab and pertuzumab) with taxane chemotherapy. Half of TNBC patients received upfront chemotherapy, with physician preference being capecitabine (45%). There was no significant difference in PFS between the HER2-low vs. HER2-0 cohorts, for either ER positive or TNBC subtypes. No patients in this series were treated based on HER2-low definition due to no funded access to such therapies at the time. Conclusion: HER2-low has emerged as an identifier for patients who may respond to HER2-directed therapies using ADCs such as T-DXd. However, its clinical significance as a discrete clinical subtype remains uncertain. In this retrospective audit, HER2-low patients were identified in both ER positive and TNBC subtypes. Dynamic changes in HER2 staining occurred infrequently. Further evaluation is needed to address whether HER2-low expression provides any prognostic value and whether prospective reporting of HER2-low status may alter how these new HER2-directed therapies are used in future. Citation Format: Michelle Li, Belinda Yeo. Characterising HER2-low status in metastatic breast cancer: a real-world retrospective study of patients at a metropolitan cancer centre in Australia [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 PO2-16-10.

Abstract PO1-05-01: Cyclin-dependent Kinase 4/6 Inhibitors Combined with Radiotherapy in the Management of Brain Metastases in HR-positive/HER2-negative Breast Cancer Patients

Abstract Purpose: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy demonstrated overall survival benefits in advanced breast cancer patients (ABC), hormone receptor-positive, HER2-negative (HR+/HER2-) and remains the mainstay in the first and second-line treatment. Brain metastases are rare at the beginning of treatment in this group of patients and are found more often during subsequent lines of treatment and other subtypes of breast cancer. However, there is a paucity of data on the safety and efficacy of multimodality CDK4/6i and radiotherapy treatment in the management of brain metastases. Thus, we performed a retrospective analysis of ABC patients (pts) treated at our institution with radiation therapy to the brain and CDK4/6i. Pts who received radiotherapy before CDK4/6i initiation or concurrently with CDK4/6i (group 1) were compared to the patients who progressed in the brain during CDK4/6i treatment and then received radiotherapy (group 2). The primary endpoint was progression-free survival (PFS) in group 1 vs. group 2; the secondary endpoints were local control (LC) within the brain in group 1 vs. group 2 and severe toxicity. Materials/Methods: Among 379 pts who received CDK4/6i, 26 pts (6.9%) received radiotherapy to the brain. 17 pts received radiotherapy before or concurrent with CDK4/6i and were included in group 1. Nine pts received radiotherapy after CDK4/6i discontinuation due to disease progression and comprised group 2. Results: The median age was 51.5 years (IQR range 41-62). Six pts had de novo metastatic disease. The majority of patients were treated in the first-line setting (15 pts, 58%). 17 pts received ribociclib, 7 palbociclib, and 2 abemaciclib. 15 pts received letrozole as an endocrine compound and 11 pts fulvestrant. 19 pts (73%) received previous chemotherapy. Six pts had an ECOG performance status of 0, 15 pts ECOG 1, and 5 pts ECOG 2. The most common local treatment was whole-brain radiotherapy with a total dose of 20 Gy delivered in 5 fractions (fr) (11 pts: 4 pts VMAT, 2 pts IMRT, 3 pts 3D, and 2 pts 2D). Eight pts received stereotactic radiation therapy (6 pts with Linac: 2 pts 24 Gy/2 fr, 2 pts 24 Gy/3 fr, 2 pts 25 Gy/5 fr; 1 pt GammKnife 20 Gy/1 fr, 1 pt Cyberknife 15 Gy/3 fr). Six- and 12-month PFS in group 1 was 88.2% (95% CI74.1-100) and 58.8% (95% CI: 37.7- 91.8), respectively, whereas in group 2, six- and 12-month PFS was 55.6% (95%CI: 31- 99.7) and 44.4% (95% CI: 21- 92.2), respectively. Six- and 12-month LC in group 1 was 92.3% (95%CI: 78.9-100) and 83.9% (65.7-100), respectively. LC in group 2 was poor: 3-month LC was only 66.7 (30-100). At a median follow-up of 8.8 months, no unanticipated toxicity was reported. Conclusion: Multimodality treatment with CDK4/6i and radiotherapy to the brain is safe and effective. Patients who developed metastases during CDK4/6i treatment tend to have a worse prognosis in comparison to those who received prior radiotherapy. CDK4/6i following radiotherapy seems to be an effective and valuable treatment option in this particular metastatic breast cancer population. Citation Format: Marcin Kubeczko, Dorota Gabryś, Anna Polakiewicz-Gilowska, Aleksandra Krzywon, Donata Gräupner, Barbara Łanoszka, Marta Mianowska-Malec, Aleksandra Leśniak, Katarzyna Świderska, Konstanty Chomik, Barbara Grandys, Michał Jarząb. Cyclin-dependent Kinase 4/6 Inhibitors Combined with Radiotherapy in the Management of Brain Metastases in HR-positive/HER2-negative Breast Cancer Patients [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 PO1-05-01.

Abstract PO4-27-06: Design of Active Phase 3 ENABLAR-2 Study Evaluating Enobosarm +/- Abemaciclib in Patients with AR+ER+HER2- 2nd-Line Metastatic Breast Cancer Following Tumor Progression on an Estrogen Blocking Agent Plus Palbociclib or Ribociclib

Abstract Background: Targeting the androgen receptor (AR) with an oral selective agonist, enobosarm, is a novel approach to overcome ER and CDK4/6 resistance to suppress metastatic breast cancer (mBC). Preclinical studies in CDK4/6 inhibitor and estrogen blocking agent resistant PDX mBC models demonstrated that enobosarm alone or in combination with another CDK 4/6 inhibitor suppressed PDX mBC growth. In a subgroup analysis from a Phase 2 study, enobosarm demonstrated efficacy in the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who had tumor progression on estrogen blocking agent and a CDK 4/6 inhibitor with a best overall response rate of 30% (2CRs and 1 PR). A Phase 3 ENABLAR-2 multi-center, open label, study evaluating enobosarm +/- abemaciclib is open and active for the treatment of HR+HER2- mBC. Methods: The two-staged Phase 3 ENABLAR-2, open-label, randomized, multicenter study is being conducted in AR+ER+ HER2- 2nd-line mBC who have progressed on estrogen blocking agent plus palbociclib or ribociclib. In the Stage 1 of the study (160 patients), five treatment arms will be assessed with the primary efficacy endpoint of ORR: enobosarm 9 mg QD, enobosarm 1 mg QD + abemaciclib, enobosarm 3 mg QD + abemaciclib, enobosarm 9 mg QD + abemaciclib, and an estrogen blocking agent, active control (a nonsteroidal AI, exemestane +/- everolimus, or SERD). Secondary efficacy endpoints include progression-free survival (PFS). In Stage 2 of the study, patients will be randomized to receive enobosarm +/- abemaciclib (based on outcome of ORR in Stage 1) or estrogen blocking agent, active control, with the primary endpoint of PFS and secondary efficacy endpoints including, ORR, CBR, OS, as well as changes in quality-of-life measurements (SPPB, EORTC-QLQ, body composition measured by DEXA). Randomization will be stratified by AR% nuclei staining and by line of treatment for metastatic disease. Subjects will receive study drug until disease progression is observed. Preliminary Results: To date, 3 patients have been treated with enobosarm 9 mg in combination with abemaciclib. The combination therapy was well tolerated with no new safety findings. There were no drug-drug interactions between enobosarm and abemaciclib. Two patients have achieved BOR of a partial response with up to 79% and 56% reduction in their target lesion recorded by local reads on day 224 post-treatment initiation (PTI). The third patient has achieved a stable disease and continues to receive treatment (on study 10+ months). Conclusions: Preliminary data of efficacy and safety of enobosarm in combination with abemaciclib are encouraging. The Phase 3 ENABLAR-2 study is underway to further evaluate enobosarm monotherapy or in abemaciclib combination therapy in 2nd-line metastatic breast cancer population. Clinical trial information: NCT05065411. Research Sponsor: Veru Inc Citation Format: Kristine Rinn, Hannah Linden, Lee Schwartzberg, Gary Barnette, Domingo Rodriguez, Itay Shalev, Mitchell Steiner, Adam Brufsky, Joyce O'Shaughnessy. Design of Active Phase 3 ENABLAR-2 Study Evaluating Enobosarm +/- Abemaciclib in Patients with AR+ER+HER2- 2nd-Line Metastatic Breast Cancer Following Tumor Progression on an Estrogen Blocking Agent Plus Palbociclib or 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 PO4-27-06.

Abstract PO3-04-13: SUMIT-ELA: Phase 1b/2 combination of cyclin-dependent kinase 7 inhibitor (CDK7i) samuraciclib and selective estrogen receptor degrader (SERD) elacestrant in advanced hormone receptor positive (HR+) breast cancer after CDK4/6i

Abstract Background: CDK7 has 3 critical roles in cancer: enhanced transcription of oncogenes and upregulation of anti-apoptotic genes, acceleration of the cell cycle through phosphorylation of other CDKs and driving estrogen receptor (ER) resistance to hormonal therapy. Inhibition of CDK7 is therefore a potential novel anti-cancer therapeutic strategy. Samuraciclib (CT7001), a once daily oral CDK7 inhibitor has demonstrated a favorable safety profile and clinical activity in combination with fulvestrant (SERD) in patients with HR+/HER2- advanced breast cancer who have previously been treated with a CDK4/6 inhibitor [1]. Extended benefit was observed in patients with no TP53-mutation per circulating tumor DNA (ctDNA) analysis detectable at baseline. Limitations in the pharmacokinetic (PK) properties and route of administration (intramuscular only) of fulvestrant mean that oral alternatives are desirable. Recently, the EMERALD phase 3 study of the oral SERD elacestrant demonstrated a significant PFS benefit over standard of care endocrine treatment in the ER+/HER2- advanced or metastatic breast cancer population previously treated with a CDK4/6 inhibitor. [2]. Non-clinical data indicate that the underlying biology driving samuraciclib combination with endocrine therapy translates from fulvestrant to elacestrant, clinical evaluation is warranted [3]. This open-label Phase 1b dose escalation and Phase 2 dose expansion study will evaluate the safety, efficacy and pharmacokinetics of samuraciclib in combination with elacestrant. ctDNA analysis is informative for both elacestrant and samuraciclib, via ESR1-mutation status and TP53-mutation status respectively, and is an integral part of the study design. Trial Design: Eligible patients will provide written informed consent, be aged 18 years or older, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor in combination with a CDK4/6 inhibitor in either the adjuvant or advanced setting, be receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal and have RECIST v1.1 evaluable disease. Prior SERD, mammalian target of rapamycin inhibitor (mTORi) or chemotherapy for advanced breast cancer are not permitted. The study will enrol ~48 patients. All patients will undergo baseline Guardant360 ctDNA analysis to establish their ESR-1 and TP53-mutation status. Patients will undergo RECIST v1.1 evaluation at baseline every 8-weeks until week 48, followed by every 12-weeks thereafter. Initially both samuraciclib and elacestrant will be administered once daily in a dose escalation/de-escalation approach under supervision of the study Safety Review Committee. The primary endpoint in Phase 1b is the identification of tolerable combination dose levels for both samuraciclib and elacestrant and in Phase 2 expansion to quantify the progression free survival benefit of the combination. Secondary endpoints are tolerability, clinical benefit response at 24 weeks, overall response rate, duration of response, best percent change in tumor size, pharmacokinetics and correlations between ctDNA detectable ESR1 and TP53 mutations and efficacy/safety finding in this patient population. The study opened for recruitment in June 2023.

High expression of SULF1 is associated with adverse prognosis in breast cancer brain metastasis.

Breast cancer is the most common cancer in women, and in advanced stages, it often metastasizes to the brain. However, research on the biological mechanisms of breast cancer brain metastasis and potential therapeutic targets are limited. Differential gene expression analysis (DEGs) for the datasets GSE43837 and GSE125989 from the GEO database was performed using online analysis tools such as GEO2R and Sangerbox. Further investigation related to SULF1 was conducted using online databases such as Kaplan-Meier Plotter and cBioPortal. Thus, expression levels, variations, associations with HER2, biological processes, and pathways involving SULF1 could be analyzed using UALCAN, cBioPortal, GEPIA2, and LinkedOmics databases. Moreover, the sensitivity of SULF1 to existing drugs was explored using drug databases such as RNAactDrug and CADSP. High expression of SULF1 was associated with poor prognosis in advanced breast cancer brain metastasis and was positively correlated with the expression of HER2. In the metastatic breast cancer population, SULF1 ranked top among the 16 DEGs with the highest mutation rate, reaching 11%, primarily due to amplification. KEGG and GSEA analyses revealed that the genes co-expressed with SULF1 were positively enriched in the 'ECM-receptor interaction' gene set and negatively enriched in the 'Ribosome' gene set. Currently, docetaxel and vinorelbine can act as treatment options if the expression of SULF1 is high. This study, through bioinformatics analysis, unveiled SULF1 as a potential target for treating breast cancer brain metastasis (BM).

Abstract P3-07-14: A phase II study of CFI-400945 in patients with advanced/metastatic cancer: Canadian Cancer Trials Group (CCTG) IND.237

Abstract Background: CFI-400945 is a selective oral inhibitor of Polo-like Kinase 4 (PLK4), a controller of centriole duplication and mitotic progression identified by functional screening of genomically unstable breast cancer (BC). IND.237 (NCT01954316) is an open label, multicentre, phase 2 study in HER2 negative metastatic breast cancer (MBC) with 3 cohorts, 1 enriched for PTEN loss of function. Enrollment started in 2018 at 64mg based on a previously established recommended phase 2 dose (RP2D). The initial patients had higher than expected grade 3/4 neutropenia which led to a voluntary hold and dose de-escalation; the new RP2D was declared at 32mg as previously reported Here we report the results of the phase 2 study of CFI-400945 in advanced BC patients. Materials and Methods: 49 patients were enrolled across 3 cohorts: 1: triple negative; 2: ER+/HER2- PTEN low (by IHC); 3: ER+/HER2-, PTEN intact. The primary outcome is objective response rate (ORR); secondary outcomes included disease control rate (DCR) >16w, and safety. A Simon 2-stage design was used (9 – 25 pts planned for each cohort). CFI-400945 would be considered active if ≥3 responses were observed in any given cohort. Eligibility included ECOG 0-1, adequate organ function and receipt of at ≥1 prior line of cytotoxic chemotherapy in any setting including anthracycline taxane (unless contraindicated). Treatment was 32mg 7d on 7d off in cycle 1 (cycle length=28d), then continuously starting cycle 2. Safety assessments were performed each cycle and response (RECIST 1.1) every 2 cycles. Results: 60 patients have been screened, 49 enrolled: 10 were in initial dose ranging and were excluded from phase 2 response assessment. 10 patients were enrolled in cohort 1, 4 in cohort 2, and 25 in cohort 3. Table 1 presents patient characteristics and response results. 1 patient in cohort 3 has not had disease re-assessed at time of abstract submission. The most common adverse events have been cytopenias, nausea, fatigue, headache, constipation and vomiting. Less than 5% of patients experienced a non-hematologic AE > grade 3; 33% experienced ≥ grade 3 neutropenia. Conclusions: CFI-400945 32mg is well tolerated in this MBC population with moderate incidence of uncomplicated neutropenia. The TNBC cohort so this arm has been closed to further accrual for lack of responses. The PTEN loss group has been slow to accrue and remains open. Responses in the ER+/HER2- arm are encouraging – results from patients remaining on study are awaited and correlative studies to identify features associated with responses are underway. Acknowledgements: Sponsored by the Canadian Cancer Trials Group. Supported by Stand Up To Cancer Canada (scientific partner AACR) Canadian Cancer Society (CCS) Breast Cancer Dream Team Research Funding, Ontario Institute for Cancer Research (funding provided by the Government of Ontario) and grants from CCS to CCTG. Table 1. Table 1. Patient characteristics and response rates in each cohort treated with CFI-400945. Citation Format: David W. Cescon, John Hilton, Philippe Bedard, Phillip Blanchette, Rossanna C. Pezo, Ayesha Bashir, Vikaash Kumar, Terry L. Ng, Arif Awan, Anthony Lott, Jacques Antoun Raphael, Linda Hagerman, Mark Bray, Lindsay Muyot, Jesus Fuentes Antras, Lesley Seymour, Dongsheng Tu, Pierre-Olivier Gaudreau, Moira Rushton. A phase II study of CFI-400945 in patients with advanced/metastatic cancer: Canadian Cancer Trials Group (CCTG) IND.237 [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 P3-07-14.

Abstract PD6-06: PD6-06 Racial and ethnic disparities with influenza vaccine use in long-term survivors of metastatic breast cancer

Abstract Background: Due to therapeutic advancements, people diagnosed with metastatic breast cancer (MBC) are living longer. This is particularly true for elderly patients who are often diagnosed with more indolent disease. However, elderly patients have higher rates of comorbidity and are vulnerable to other adverse health outcomes, but the primary care management of patients with advanced cancer may be sub-optimal. Every year influenza results in hundreds of thousands of hospitalizations and tens of thousands of deaths. Guidelines recommend the influenza vaccine annually for those over the age of 65 as well as those with cancer based on studies showing a 40-60% reduction in hospitalizations and death. Patterns of use in patients with MBC is unknown. Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data. Patients were included if they were diagnosed with stage IV MBC from 1/1/2008 – 12/31/2017, were ≥65 years of age, and had continuous Medicare enrollment for 12 months prior to diagnosis and at least three months after. Our primary outcome of interest was influenza vaccine use identified via CPT codes and defined as any use, use among patients surviving > 3-years, use among patients surviving >5-years, and repeated vaccine use. We then conducted bivariate analyses using demographic variables, including race, ethnicity, SES, age, and marital status, and clinical factors, including chemotherapy use, ER/PR positivity, and HER2 positivity. A multivariable logistic model was used to identify factors associated with influenza vaccine use in each cohort. Results: We identified 5182 patients with stage IV MBC during the study period that met our inclusion criteria. Overall, the median survival was 21 months and only 44% received at least one vaccination at any time after diagnosis. Within the cohort with the > 3-year survival (n=1864), only 1222 (66%) received an influenza vaccination at least one time and only 54% received the vaccine at least two times during 3 years of follow-up. Among patients with at least five-years of survival (n=763), 73% received at least one vaccination and only 65% received the vaccine at least two times during 5 years of follow-up. In a bivariate analysis in the 3-year survival cohort, we found that black race (47% vs 67%, p< 0.001) and Hispanic ethnicity (53% vs 66%, p=0.026), compared to white race and non-Hispanic ethnicity, respectively, were significantly associated with decreased vaccine use. The only factor associated with increased use was chemotherapy exposure. A multivariable model found lower odds of influenza vaccine receipt for black patients (OR=0.44, 95% CI 0.30-0.65, p< 0.001) and Hispanic patients (OR=0.58, 95% CI 0.36-.94, p=0.026). Similar findings were found in the 5-year survival cohort. Ongoing landmark analyses will be presented evaluating the impact of vaccination on survival. Conclusions: Over 50% of survivors with MBC do not receive the influenza vaccine after diagnosis. Importantly black and Hispanic patients with MBC are about half as likely to receive the influenza vaccine as white patients. Given the known impact of influenza vaccination in the elderly, improving access to vaccination could be an important strategy to reduce disparities in health outcomes. Our findings demonstrate primary care access disparities amongst the MBC population and indicate a need for educational and policy-based interventions. Citation Format: Sahil D. Doshi, David DeStephano, Melissa K. Accordino, Elena B. Elkin, Jason D. Wright, Dawn Hershman. PD6-06 Racial and ethnic disparities with influenza vaccine use in long-term survivors of metastatic 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 PD6-06.

Abstract P6-05-27: FEASIBILITY, SAFETY AND EFFICACY OF A COMBINED SUPERVISED PHYSICAL EXERCISE AND NUTRITIONAL PROGRAM IN A SELECTED POPULATION OF LUMINAL METASTATIC BREAST CANCER PATIENTS: ONCARE-01 PILOT STUDY

Abstract Background: Supervised exercise programs (SEP) have demonstrated an improvement in quality of life (QoL), cardiovascular health, treatment tolerance and disease outcomes in early breast cancer patients. In metastatic breast cancer (MBC), previous data suggest SEP are safe but no impact on QoL and a low adherence to programs were shown. These studies included a heterogenous population in terms of type of treatments received, numbers of previous lines or comorbidities. From our perspective, MBC profile that could benefit most from SEP needs to be explored. Thus, we conducted a pilot study to assess adherence, safety and impact on QoL of a combined SEP and nutritional program (NP) in a selected population of MBC of patients treated with cyclin-dependent kinase 4/6 inhibitors (iCDK 4/6). Methods: This is a prospective, single center, single arm pilot study. SEP consisted in a 12-week intervention with twice a week in-person resistance exercise session. Patients also completed weekly aerobic exercise goals in self-managed sessions monitored with activity trackers. SEP was conducted by registered Physical Activity and Sports Science instructors that followed American College of Sports Medicine guidelines. In addition, participants had an initial nutritional assessment and personalized counselling by a qualified nutritionist. Adherence to treatment, biological variables and QoL assessments (FACIT-Fatigue and QLQ-C30 questionnaires) were collected at baseline (B) and week-12 (w12). Primary endpoint was global adherence (≥70% of attended sessions relative to scheduled sessions). Secondary endpoints included safety, changes in biological variables and QoL. Paired samples t-tests (Wilcoxon) were used to assess biological changes and QoL. Results: Patients (n=26) were recruited from October 2020 to November 2021. Median age was 47,5 years (45-55); 84,6% of patients were ECOG 0. 42,3% of patients were receiving Abemaciclib; 34,6% Ribociclib and 23,1% Palbociclib in first (73,1%) or second (26,9%) line treatment. Patients had bone (69,2%); visceral metastasis (57,7%) or both (30,8%). 2 patients did not start the intervention and additional 7 patients discontinued the program prematurely, the majority of them due to COVID-related concerns. Considering all patients who at least attended one session, global adherence was 66% (39-77,5%) and 45,8% of patients achieved an adherence of ≥ 70%. Patients reported an improvement in QoL [B global QLQ-C30 66,6 (50-75), w12 75 (66,6-83,3); p 0,0121] and fatigue [B FACIT-Fatigue 37 (30-44), w12 42 (38-48); p 0,0017]. Sit-to-stand repetitions in 30-second period also improved [(B 15 (12-17), 19 (15-23); p 0,0002]. Same benefits were seen in patients with adherence ≥ 70%. No statistically significant changes were seen in body fat or muscular composition and handgrip scores. Importantly, no safety issues related to study intervention were reported. Conclusions: Even though the study was conducted during COVID-19 pandemic, global adherence was 66%. For the first time in MBC, SEP and NP combined program demonstrated to be safe and improved QoL in patients with first or second line MBC treated with iCDK4/6. Further research is needed to identify strategies that improve QoL in MBC. Citation Format: Alfonso Cortés, Alejandro Riquelme, Gemma Ferrero, Federico Longo, Manuel Garví, Lisandro Lamas, Ángela Morales, Lidia García, Patricia Cortez-Castedo, Maria Gión, Cristina Saavedra, Noelia Martínez-Jáñez, María Fernández-Abad. FEASIBILITY, SAFETY AND EFFICACY OF A COMBINED SUPERVISED PHYSICAL EXERCISE AND NUTRITIONAL PROGRAM IN A SELECTED POPULATION OF LUMINAL METASTATIC BREAST CANCER PATIENTS: ONCARE-01 PILOT STUDY [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 P6-05-27.

Abstract P4-03-22: Linking Internal Medicine Care to Metastatic Breast Cancer Patients for Success: LIMBS

Abstract Background: The Advanced Breast Cancer (ABC) program at The University of Texas MD Anderson Cancer Center was created by metastatic breast cancer (MBC) patients for MBC patients. The ABC Program seeks to improve quantity and quality of life for patients living with MBC. MD Anderson actively treats 2,076 patients living with MBC. ABC program patient advocates voiced the need to increase MBC patients’ access to internal medicine services coordinated with oncology care. Significance: Previous literature suggests patients living with MBC have difficulty receiving oncology coordinated internal medicine services due to their terminal diagnosis and indefinite prescription of anti-cancer treatment. Comorbidities in this setting are known to be associated with inferior outcomes. ABC Program patient advocates reported various challenges seeking care from community based medical professionals including, timely awareness of their local provider on the status of their cancer. Other challenges included the lack of familiarity of some providers with novel MBC cancer treatment, side effects, and interactions of their cancer treatment with non-cancer conditions and treatment. Therefore, with the increasing life expectancy of MBC patients, there is a growing realization of the importance of managing the medical comorbidities in coordination with the MBC patient’s cancer treatment. Purpose: To increase access and coordinate internal medicine services for MBC patients with medical comorbidities. Interventions: In partnership with ABC Program patient advocates, the Linking Internal Medicine and Metastatic Breast cancer for Success (LIMBS) clinic was created in February 2021. The LIMBS clinic aimed to bridge the gap in lack of oncology coordinated internal medicine service for MBC patients. Evaluation: Breast Medical Oncology providers requested LIMBS clinic consults for 108 patients for comorbidity management since the clinic inception. This is a 44% increase in internal medicine consultations prior to LIMBS clinic creation (60 vs 108). The LIMBS clinic consults resulted in 474 follow up visits. Compared to MBC patients at MD Anderson, LIMBS patients were more likely to be African American (20% vs 13%) and were more likely to be older (59 years vs 57 years). Gender, marital status, and clinical trial enrollment did not differ between LIMBS patients and MBC patients. LIMBS patients had significantly higher rates of hypertension (46% vs 19%), Type II DM (19% vs 6%), hyperlipidemia (13% vs 10%), and hypothyroidism (13% vs 6%) compared to MBC patients in general. LIMBS patients had lower rates of anxiety (8% vs 11%) and depression (2% vs 7%) when compared to the MBC patients in general. The top 10 comorbidities for all MBC patients versus LIMBS patients are listed in Table 1. Discussion: It is feasible to build and integrate internal medicine with breast medical oncology services for patients with metastatic breast cancer. Future research should focus on exploring, describing, and meeting the internal medicine needs of MBC patients. Future initiatives are needed to bridge the gap in care for oncology coordinated internal medicine services between community and tertiary care centers. Table 1. Top 10 Comorbidities of all MBC patients versus LIMBS clinic patients Note. This table demonstrates the top 10 comorbidities for MBC population and the LIMBS population. Citation Format: Abbey Kaler, Akshara Singareeka Raghavendra, Ginny T. Kirklin, Dawn Cunningham, Ellen Manzullo, Debu Tripathy, Zayd Razouki. Linking Internal Medicine Care to Metastatic Breast Cancer Patients for Success: LIMBS [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 P4-03-22.

Abstract P5-03-12: DNA repair genes are more frequently mutated in non-white populations of metastatic breast cancer (MBC) patients

Abstract Background: Although improvements in detection, therapeutic development and molecular profiling have decreased MBC mortality over the last twenty years, clinical outcomes are not being equally realized among all patients. Representation and enrollment into clinical trials are often not reflective of the general MBC population in terms of race and ethnicity, with Black and Hispanic patients being largely and often underrepresented. Not only does this imbalance translate into overall access to novel agents, but the lack of understanding of therapeutic efficacy in minority populations and tumor-based molecular differences reduce the use of truly personalized treatments for these groups. There is an opportunity to improve clinical outcomes for all patients with MBC, starting with a better understanding of the degree of any potential differences in underlying tumor molecular biology between racial groups. Methods: We utilized data from two cohorts of patients whose tumors underwent molecular profiling to examine differences in the frequency of genetic mutations across racial groups with MBC. The first cohort included 856 MBCs whose genomic profiles were retrieved from the AACR Genomics Evidence Neoplasia Information Exchange (GENIE) publicly available database. The second cohort included a separate set of 91 patients with MBC from an ongoing precision medicine program sponsored by the Side-Out Foundation (SOF). While the GENIE data were collected at 19 large academic cancer centers, the SOF data are derived from patients treated in the community setting. We compared the relative distributions of age and reported ethnicity between datasets, and compared the 20 most frequently mutated genes in each racial group across datasets. The analysis across races included 73 genes that were examined for differences in mutation frequency using Fisher’s Exact test and Pearson Chi-Square test (p< 0.05 uncorrected). Results: Although the GENIE set was significantly larger, race distribution was not statistically significant across the two populations. The combined populations included 831 white patients (88.4%), 43 Black patients (4.6%), 30 Asian patients (3.2%), and 35 Hispanic patients (3.7%). The age of initial (59.61) and metastatic (61.19) diagnosis was older in the SOF population compared to the GENIE population (48.81, 53.14; p < 0.001). Hispanic patients (46.92) were diagnosed with MBC at a younger age compared to White patients (53.78; p < 0.001). Of the 73 genes analyzed, 11 genes were found less frequently mutated in whites compared to non-whites including, NTRK1, SDHA, MSH6, TCF3, FANCC, GNAS, COP1, RECQL4, WRN, BCL6, and U2AF1. When the same 73 genes were examined for differences across racial groups, alterations of 22 genes reached statistical significance. The gene(s) with the largest difference compared to white patients were RECQL4 in black patients (13.95% vs 5.29%; p = 0.019), WRN in Asian patients (16.63% vs 2.53%; p < 0.001), and RECQL4 and ERBB2 in Hispanic patients (16.13% vs 5.29%; p = 0.019, p = 0.020). Of the 22 genes that were more frequently altered in the non-white population, 6 have roles in DNA repair including RECQL4, WRN, ERCC2, BLM, MSH6, FANCC. 4/22 are receptor tyrosine kinases (RTKs), including NTRK2, RET, ERBB3, and ERBB2, and 3/22 have roles in immune function, including BCL6, CIITA, and TLR4. Conclusion: Analysis of genomic alterations derived from 2 independent real-world molecular profiling-based cohorts identified in non-whites MBC patients a set of candidate “actionable” genes involved in DNA damage repair, RTK expression, and immune function. Although these results require further validation, considering the relatively small samples sizes of the non-white populations, these findings may provide actionable targets for non-white patients with MBC that could be utilized in future trials. Citation Format: Sydney Hilley, Rick Dunetz, Edik Blais, Mariaelena Pierobon, Emanuel F. Petricoin, Elisa Baldelli. DNA repair genes are more frequently mutated in non-white populations of metastatic breast cancer (MBC) patients [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 P5-03-12.

Abstract P6-03-03: Persistence and compliance of the French metastatic breast cancer population

Abstract Keywords Metastatic breast cancer, Endocrine therapy, Targeted therapy, Oral chemotherapy, French population Context Oral anti-cancer treatments have been shown to be effective when followed carefully. Tamoxifen, for example, reduces the risk of relapse by half within 10 years of the diagnosis [1]. However, these treatments are frequently poorly adhered to. To determine the categories of patients at risk and the appropriate moment to contact them, we developed predictive models trained on anonymised reimbursement data extracted from the French Health Insurance database. Objective The primary objective is to model a metastatic breast cancer patient’s persistence and compliance to the treatment. We aim at detecting unwanted episodes (non persistence and non compliance) six months before they happen. The oncologist may then follow the patient more closely. Methods Patients data is extracted from the SNDS database, one of the largest structured databases of health data in the world. It contains reimbursement data of the French Health System, covering 98% of the French population (66 million persons). Useful data are, for example, hospitalisations, drug purchases or the patient’s age and city of residence. From this database, patients were selected on the basis of a diagnosis of metastatic breast cancer (if hospital stay) or on the basis of specific treatments for metastatic breast cancer. Men and patients under 18 are excluded from the study. We consider that a patient has a non persistent event if she has no treatment stock for 2 months (during a phase of targeted therapy or oral chemotherapy) or 3 months (during a phase of endocrine therapy) and if no change in treatment, palliative care entry or death is observed. The compliance is labelled through the MPR (Medical Possession Ratio): a patient is considered non-compliant if the MPR of her 3 nexts purchases is below 80%. The proposed models are trained to detect non-persistence and non-compliance events in the next 180 days. We created several groups of features describing the patient and her healthcare pathway. Results 250 000 patients were spotted with a breast cancer in the SNDS database. Amongst these, around 40 000 were spotted for a metastatic breast cancer between 2013 and 2018. 14% of the patients had at least one non persistence episode and 46% had at least one non compliance episode. For the persistence study, we used a logistic regression with a feature selection. This model has a Gini coefficient of 0.35. For the compliance study, we used a deep learning model based on a GRU model. This model has a Gini coefficient of 0.37. A multivariate analysis shows that the following features had a significative impact on both predicted risks (persistence and compliance) : age, previous compliance, type of oral treatment(s) currently followed (endocrine therapy, targeted therapy, or oral chemoterapy), number of different oral treatments followed in the past year. In both models, if the patient’s age is between 50 and 70 years it does not correlate with an increased risk. On the other hand, the more they deviate from this interval, the more likely they are to be non-compliant. Conclusion Both studies have models with quite the same interpretation. Patients younger than 50 or older than 70 are more likely to be non-persistent and non-prevalent. The past compliance is highly correlated to the future events. The consumption of oral chemotherapy in comparison to oral endocrine and targeted therapy is linked to an increased risk in both studies. Bibliographie [1]: E. Ekinci, S. Nathoo, T. Korattyil et al. (2018) Interventions to improve endocrine therapy adherence in breast cancer survivors: what is the evidence? J Cancer Surviv 12:348-356 Citation Format: Pierre Rinder, Théo Marcille, Paul Sinel–Boucher, Pierre Hornus, Pierre E. Heudel, Chantal Bernard-Marty, Christelle Levy, Luis Teixeira, Dorra Kanoun. Persistence and compliance of the French metastatic breast cancer population [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 P6-03-03.

Capecitabine efficacy after cycline-dependent-kinase 4/6 inhibitor plus endocrine therapy in metastatic hormone receptor-positive breast cancer

BackgroundThe combination of endocrine treatment with cycline-dependent-kinase 4/6 inhibitor is the new standard of treatment in hormone receptor-positive HER2 negative metastatic breast cancer. The optimal subsequent treatment after CDK4/6 inhibitor remain unclear. As recommended by standard guidelines, capecitabine, an oral chemotherapy is a therapeutic option in endocrine resistant metastatic breast cancer.The objective of this study was to evaluate capecitabine efficacy after disease progression under combination of ET and CDK4/6 inhibitor in a hormone receptor positive metastatic breast cancer population. Patients and MethodsPatients progressing under CDK 4/6 inhibitor plus ET and treated with capecitabine, between January 2016 and December 2020, were retrospectively included. Primary endpoint was time to treatment failure (TTF) on capecitabine. Logistic regression were used to identify predictive factors: exclusive bone versus visceral metastases, first-line versus ≥ 2 lines of combination therapy, aromatase inhibitor (AI) versus fulvestrant. ResultsFifty-six patients with a 62-year median age (IC95% 42–81) were analyzed. The CDK 4/6 inhibitor and ET combination was prescribed in first-line setting in 26 patients (46%). Twenty-five patients (44%) had exclusive bone metastasis.Median TTF was 6.1 months. Six patients discontinued capecitabine due to toxicity. Outcomes were not significantly different regardless of metastases localization, ET, and treatment line of the combination of CDK 4/6 inhibitor and ET. Median PFS was 7.1 months. Median OS was 41.3 months. ConclusionCompared to other data of capecitabine prescribed in patients with hormonal resistant MBC, this retrospective study suggests that capecitabine remains effective after CDK 4/6 inhibitor plus ET progression, regardless of therapeutic-line setting and metastases localization. Micro AbstractCycline dependant kinase 4/6 inhibitor plus endocrine therapy have become the standard of care in metastatic hormone receptor positive (HR+) breast cancer (BC). Few data reported the optimal subsequent therapy after progression under the combination. Capecitabine is a therapeutic option in endocrine resistant HR+/HER2- metastatic breast cancer. Data evaluating efficacy of capecitabine after disease progression on endocrine therapy plus cycline-dependant kinase 4/6 inhibitor are poor. This study showed a 6.1-month median time to treatment failure on capecitabine. Capecitabine remained effective regardless of therapeutic-line setting and metastases localization.

A propensity score–weighted study comparing a two- versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer

A 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly regimen. This study aimed to compare the efficacy and safety of these two schedules. Data from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules. Among the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries. PLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.

Palliative care utilization and trends among patients with metastatic breast cancer: A SEER-Medicare analysis.

75 Background: Receiving palliative care (PC) is associated with improving quality of life in patients with cancer. Despite its clinical benefits, limited data is available regarding PC utilization among the metastatic breast cancer population. Examining the trends and current patterns of PC provide an opportunity for improved effective implementation of PC in management of patients with breast cancer. Methods: SEER-Medicare linked data was queried to identify patients with metastatic breast cancer aged > 65 years between 2006 and 2017. PC utilization since diagnosis was identified using ICD-9 code V66.7 or ICD-10 Z51.5. Descriptive statistics were used to summarize patient characteristics by the receipt of PC. Multivariable logistic regression was estimated to identify predictors of PC use. Trends in PC utilization were then compared by patient race/ethnicity, residential region, and census poverty rate. Results: Of 11,245 patients with metastatic breast cancer diagnosed between 2006 and 2017 (median survival, 17.9 months), 1,756 (15.6%) received PC (median time from diagnosis to PC, 18.5 months). During the study period, PC use increased significantly from 2.5% in 2006-2007 to 28.1% in 2016-2017 (P trend <.001). Patients with metastatic breast cancer who received PC were more likely to be younger (20.6% among 65-69 years old vs. 11.9% among 80+), living in the West census region (17.2% vs. 14.1% in South), urban areas (16.8% vs. 8.2% in rural), and low poverty rate (16.1% with < 5% poverty level vs. 12.9% with > 20%) (P all <.05). There was no significant difference observed by race or ethnicity (P >.05). Conclusions: There was a significant increase in PC utilization among patients with metastatic breast cancer aged > 65 years between 2006 and 2017. However, its utilization rate remains suboptimal, with geographic, age and income disparities in PC use.

Overall survival of patients with metastatic breast cancer in Sweden: a nationwide study

BackgroundBreast cancer is the most common cancer among women in Sweden. Whereas survival for the overall breast cancer population is well-documented, survival of patients with metastatic breast cancer (MBC) is harder to quantify due to the lack of reliable data on disease recurrence in national cancer registers.MethodsThis study used machine learning to classify the total MBC population in Sweden diagnosed between 2009 and 2016 using national registers, with the aim to estimate overall survival (OS).ResultsThe total population consisted of 13,832 patients—2528 (18.3%) had de novo MBC whereas 11,304 (81.7%) were classed as having a recurrent MBC. Median OS for patients with MBC was found to be 29.8 months 95% confidence interval (CI) [28.9, 30.6]. Hormone-receptor (HR)-positive MBC had a median OS of 37.0 months 95% CI [35.9, 38.3] compared to 9.9 months 95% CI [9.1, 11.0] for patients with HR-negative MBC.ConclusionThis study covered the entire MBC population in Sweden during the study time and may serve as a baseline for assessing the effect of new treatment strategies in MBC introduced after the study period.

Long term outcome data from the EORTC 75111-10114 ETF/BCG randomized phase II study: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer, followed by T-DM1 after progression

IntroductionOlder patients are at higher risk of chemotherapy-induced toxicity, raising interest in less toxic anti-HER2 regimens for older persons with HER2-positive (HER2+) metastatic breast cancer (MBC). Patients and methodsThis phase II study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide (M) + Trastuzumab (T) and Pertuzumab (P) or TP alone. T-DM1 was offered in case of progression. ResultsIn total, 39 and 41 patients were randomized to TP and TPM arm respectively. Median follow-up is 54.0 months. 24-month PFS was 18.7% (95% CI 8.2–32.4) and 28.7% (95% CI 15.8–43.0), respectively. A total of 49 (61.3%) patients died of whom 37 (75.5%) from disease progression; number of deaths per arm was 27 (69.2%) for TP and 22 (53.7%) for TPM. There was no significant difference in OS between the two arms (median OS TP vs TPM: 32.1 vs 37.5 months, p 0.25). Among the 40 patients who have started T-DM1 after disease progression on TP/TPM, PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7–58.5) and grade 3 or higher AE occurred in 18 pts (45%). ConclusionsMetronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and relatively well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years. Nevertheless, the majority of this older/frail population died from breast cancer, highlighting the need for well tolerated and efficacious treatments in these patients.

Locoregional tumor burden and risk of mortality in metastatic breast cancer

The role of lymph node involvement and tumor size in metastatic disease including breast cancer is unclear. Here, nodal metastasis and T stage on the risk of mortality were investigated in de novo metastatic breast cancer population (35812 patients) in the Surveillance, Epidemiology, and End Results (SEER) Program database in the United States. We found an association between all-cause mortality and regional node involvement (adjusted hazard ratio [HR] = 1.45, 95% confidence interval [CI] 1.36–1.55, p < 0.0001) or T stage (HR = 1.20, 95% CI 1.14–1.25, p < 0.0001), independent of known clinicopathologic measurements. Number of positive nodes, and size and chest wall involvement of the breast tumors exhibited similar significance for breast cancer-specific mortality in the population (p < 0.0001 each), and all-cause mortality in hormone receptor (HR)-positive/HER2-negative (HR+/HER2–), HR+/HER2+, HR–/HER2+ and triple-negative metastatic breast cancer subtypes. Thus, nodal involvement and T stage are independent risk factors for mortality in the population of de novo metastatic breast cancer.

808 Metastatic Breast Cancer to the Spine: Outcomes After the Introduction of Small Molecule Inhibitors

INTRODUCTION: Over the past decade, with the development of small molecule inhibitors and immunotherapies, expanded attention is being paid to the somatic mutations expressed within a patient’s individual breast tumor, especially in the case of advanced or metastatic disease. A number of mutations have been found to occur most commonly in patients with metastatic breast cancer, including TP53, PI3K, CDH1, and MAP3K. Specifically, with regards to patients with metastases to bone, PIK3 mutations have been found to increase in frequency. METHODS: This is a retrospective study of patients who underwent treatment (surgery/radiation) at a tertiary care center for their diagnosis of breast cancer metastatic to the spine between 2010 and 2020. Review of peripheral sample gene sequencing reports was conducted to calculate the prevalence of different somatic gene mutations within our population. The use of small molecule inhibitors in the post-treatment period was determined and patient post-treatment mortality was calculated in order to elucidate the effect of systemic therapy on overall survival. RESULTS: 77 patients were included in our final analysis. Within our population of spine metastases patients, 44 (57%) were found to have a PI3K mutation, followed by 20 (26%) with a TP53 mutation. Furthermore, those patients given targeted molecular therapies in the post-treatment period were found to have a median overall survival of 1356 days. In comparison, those who did not receive targeted molecular therapies were found to have a median overall survival of 503 days (p&lt;0.001). CONCLUSIONS: The results of the present study demonstrate that not only is there an increased prevalence of PI3K mutations within spine metastases in comparison to the general metastatic breast cancer population, there is also a significant mortality benefit with adding targeted molecular therapies to the patient’s post-operative treatment plan.

Abstract P1-18-06: Long term outcome data from the EORTC 75111-10114 ETF/BCG randomized phase II study: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer, followed by T-DM1 after progression

Abstract Introduction: Pertuzumab (P) is approved as first line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC) combined with trastuzumab (T) and docetaxel. However older patients are at high risk of chemotherapy-induced toxicity ,raising interest in less toxic anti-HER2 therapy regimens.Patients and Methods: This phase II selection study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide 50 mg/day + TP (TPM) or TP alone. Prior endocrine therapy and up to 1 line of anti-HER2 therapy (without chemotherapy) for MBC were allowed. T-DM1 was offered in case of progression. Randomization was stratified according to hormonal receptors, previous anti-HER2 treatment and geriatric assessment. Primary endpoint was progression-free survival (PFS) rate at 6months, already reported (Lancet Oncol 2018, Wildiers et al). We now present data on long term outcome (including cause of death), and on response and tolerance of T-DM1 given after progression on TP(M).Results: Between July 2013 and May 2016, 39 and 41 patients were randomized to TP and TPM arm respectively: median age 76.7 years, hormone receptor positivity 69%, prior (neo)adjuvant T 11%, prior metastatic T (with endocrine therapy) 3%, visceral involvement 93.7%, potential frailty profile according to geriatric screening G8 (≤14) 70% and/or to short physical performance battery (&amp;lt;10) 81%, Charlson comorbidity score &amp;gt; 0 in 41%. With 54.0 months of median follow-up, 6-month PFS was 43.1% (95% CI 27.1-58.1) versus 73.0% (95% CI 55.8-84.3) for TP and TPM, respectively. 12-month PFS was 33.7% and 51.9%, and 24-month PFS 18.7% and 28.7%, respectively. A total of 49 (61.3%) patients died, 27 (69.2%) in the TP arm and 22 (53.7%) in the TPM arm. There was no significant difference in OS between the two arms (TPM vs TP: HR=0.72, 95% CI 0.41-1.26) with median OS 32.1 months for TP, and 37.5 months for TPM. The causes of death were progressive disease (N=37, 75.5%), toxicity (cardiac failure, N=1, 2.0%), and other causes not due to PD/toxicity (N=9, 22.5%). Among the 40 patients who have started T-DM1 (22 in TPM arm and 18 in TP arm), median follow-up was 33.7 months from T-DM1 start. PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7-58.5). Grade 3 or higher AE occurred in 18 pts (45%). Most relevant reported grade III or higher toxicities on T-DM1 were fatigue (N=3), anorexia (N=2), anemia (N=1), febrile neutropenia (N=1), diarrhoea (N=1), hepatic failure (N=1), lung infection (N=1), increased GGT (N=1), thrombocytopenia (N=1), weight loss (N=1), hypophosphatemia (N=1), dyspnoea (N=1), epistaxis (N=1), hematoma (N=1). Two patients (5%) experienced grade 5 toxicity: one death was considered as related to cachexia and tumor progression; the other death was considered to be related to acute pneumonia and renal failure. The prognostic impact of geriatric assessment on PFS and OS, and frailty evolution during therapy will be presented at the meeting.Conclusions: Metronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years despite the associated frailty in the majority of the study population. T-DM1 provides a PFS rate at 6 months of 43.6% (95% CI: 27.7-58.5) with a wide range of possibly related toxicities in this generally frail population. Citation Format: Hans Wildiers, Sandrine Marreaud, Lissandra Dal Lago, Peter Vuylsteke, Giuseppe Curigliano, Simon Waters, Barbara Brouwers, Bart Meulemans, Berta Sousa, Coralie Poncet, Etienne Brain. Long term outcome data from the EORTC 75111-10114 ETF/BCG randomized phase II study: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer, followed by T-DM1 after progression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-06.