Does the innovative 4R Cancer Care Delivery Model improve patient self-management in safety net and non-safety net centers?

224 Background: Under the “NCI ASCO Teams” Project, we proposed a 4R Model of teamwork and patient self-management (pSM) (Trosman JOP ’16). 4R is Right Info / Care / Patient / Time. It enables patient (pt) and care team to manage interdependent care along the care continuum with an innovative multimodality personalized 4R Care Project Plan. We piloted 4R at 3 centers (academic, community, safety net) and assessed its impact on pSM. Methods: 4R Plans were administered to breast cancer pts stage 0-III Sep ’16 – Aug ’17 (4R cohort). We surveyed the 4R cohort and a comparable historical cohort of pts who received care pre-4R, Jun ’15 – May ’16 (control). We used simple frequencies and Fisher’s exact test in analyses. Results: Survey response rates: 68%, 185/271 (4R cohort); 47%, 241/410 (control). 75% of 4R respondents reported 4R Plans very useful / useful in overall understanding and organizing their care; 68% found 4R’s novel “project” component, very useful / useful in managing timing & sequencing of interdependent care. Care complexity impacted 4R usefulness: 67% of pts who received > 6 care services found 4R very useful / useful vs. 47% of pts who received < = 6 services, p = .01. Pts with lower care complexity suggested how to make 4R more useful to them, eg focus on endocrine therapy. Table compares pSM metrics in the 4R and control cohort. Care complexity was a significant factor of feeling overwhelmed for pts in the control cohort (51% of pts receiving > 6 care services felt overwhelmed vs. 31% of pts receiving < = 6 services, p = .02), but not a significant factor for pts in the 4R cohort (30% vs. 28%, p = .9). Conclusions: The 4R model significantly improved pt self-management in early breast cancer and reduced the impact of care complexity on pts, but provider factors of pSM need improvement. A 4R pilot at additional 12 cancer centers across the U.S. is in progress.[Table: see text]

Introduction: Immune-related adverse events (irAE) occur in approximately 33.5% patients (pts) with early TNBC and 26.5% of pts with advanced TNBC treated with pembrolizumab plus chemotherapy. Severe irAE (grade 3+) occur in approximately 5.3-12.9% of pts, which often lead to serious symptoms resulting in hospitalization, treatment discontinuation, organ dysfunction, and/or death. Bone-modifying agents (BMAs) are frequently used in early breast cancer to treat osteoporosis and to decrease disease recurrence in postmenopausal women, while advanced breast cancer pts with bone metastases are treated with BMAs to reduce skeletal-related events. Preclinical studies demonstrate that anti-RANKL therapy can have immunomodulatory effects through dysregulation of T cell negative selection and disruption of Treg function. We recently showed that pre-treatment with anti-RANKL therapy prior to receiving an immune checkpoint inhibitor (ICI) significantly increased the rate of endocrine irAE in a mouse model. Here, we report the incidence of severe irAE in a cohort of breast cancer pts treated with pembrolizumab in combination with BMAs. Methods: We identified female pts with breast cancer who started treatment with pembrolizumab between December 2017 to January 2024. Pts were categorized according to BMA received: zoledronic acid (ZA), denosumab (Dmab), or none (no BMA). BMA therapy was considered received within a dose interval prior to ICI (12 months for ZA; 6 months for Dmab), during ICI therapy, or within 1 month of last ICI cycle. Pts who received both ZA and Dmab were excluded. Severe irAE data according to CTCAE v5.0 were collected. Clinical characteristics and outcomes were compared using chi-square or Kruskal-Wallis tests among pts who received ZA, Dmab, and none. Results: Our cohort consisted of 430 female breast cancer pts treated with pembrolizumab with 56 (13%) pts who received Dmab, 31 (7.2%) who received ZA, and 343 (79.8%) who received no BMA. A total of 148 (34.4%) pts had early-stage breast cancer, while 282 (65.6%) had late-stage disease. The median number of pembrolizumab cycles received was 8 (IQR 4-15), and the median duration of ICI therapy was 6.9 months (IQR 2.8-12.2). After a median follow-up of 19.4 months (95% confidence interval, 17.5-20.8), the incidence of severe irAE was 54/430 (12.6%) overall. Severe irAE occurred in 12/56 (21.4%) pts who received Dmab plus pembrolizumab, compared to 3/31 (9.7%) pts who received ZA plus pembrolizumab and 39/343 (11.4%) pts who received pembrolizumab alone. The median time from pembrolizumab initiation to onset of irAE was 2.3 months (IQR 1.1-6.9), which was not significantly different among the three groups (p=0.8). Of the 54 pts who developed severe irAE, the most common irAE included hepatitis (24%), pneumonitis (16.7%), colitis (13.0%), rash (13.0%), and hypophysitis (7.5%). Conclusion: In breast cancer pts treated with pembrolizumab, Dmab had the highest rates of severe irAE compared to those who received ZA and those who received neither BMA. This study is consistent with higher rates of irAE seen in melanoma and lung cancer pts and in preclinical studies that combined ICI and anti-RANKL therapy. Given the expanding indication of ICIs in breast cancer treatment, further studies are needed to validate these results and to identify mechanisms to optimize the antitumor response while mitigating irAE. Citation Format: Alexis LeVee, Esther Peluso, Melissa Lechner, Nora Ruel, Joanne Mortimer, Irene Kang, Karen Tsai. Anti-RANKL bone resorptive therapy increases immune-related adverse events (irAE) in breast cancer patients (pts) treated with pembrolizumab [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS5-04.

80 Background: Breaking news in breast cancer (BC) pts often has to be supported by psychological help. It remains unclear which and how many BC pts need supportive psycho-oncological care, since pts may react in different ways. Some pts show high risk profiles for anxious reactions or depressions after breaking bad news and should be detected for interventions. Need for pychological intervention was screened with a simple 14-point item test (HADS). A scoring of <15 points was assumed to be at low risk for anxiousness and depression, a scoring of 15-21 points was considered medium risk while a score of >21 was assumed to describe high-risk pts. Pts considered to be at low risk, did not receive further intervention. Pts detected to be at medium or high risk received further psychological intervention. The aim was to evaluate efficacy of psychological support in pts with newly diagnosed BC or relapse of cancer >1 yr after a curative approach. Methods: Psycho-oncological screenings and interventions were analyzed in a tertiary cancer within a two-year period. Results: Out of a total of 611 cancer pts, 202 pts had BC. 63 pts had a newly diagnosis of cancer or a relapse of >1 year since primary diagnosis or therapy and signed informed consent. Pts assumed to be at low risk had a mean score of 6,97 (SD 3.71) prior and 7,03 (SD4.97) after the end of cancer therapy. In this group of low risk pts there was no further psychological intervention. In pts detected with a medium risk (15-21) mean HADS score prior therapy was 16.63 (SD 1.38) and fell down during cancer treatment and supportive psychotherapeutically intervention to 13.58 post therapy (SD 6.16). Pts with the highest risk at diagnosis had a mean of 28.25 (SD 4.41) and decreased to a mean HADS of 16.83 (SD 4.84) at the end of cancer therapy while being under supportive psychotherapeutically care. Mean number of psychotherapeutic sessions was 3.86/patient with a mean duration of intervention time of 1.38 h. Conclusions: BC pts with a HADS <15 should not be considered to be candidates for routine psychotherapeutically supportive care. Pts being at high-risk gained most benefit. A simplified scoring system for anxiousness and depression is recommended to detect pts with a need for further therapeutic treatment.

e14039 Background: We previously proposed a 4R care delivery model that facilitates teamwork and patient self-management (pSM) in cancer care (NCI ASCO Teams Project, Trosman JOP 2016). 4R (Right Info / Care / Patient / Time) enables patient and care team to manage complex care with an innovative 4R Care Sequence. We tested 4R at 10 US sites in a stepwise mode 2016-2019. Methods: Step 1 included 1 academic and 2 nonacademic sites; step 2 included 3 academic and 4 nonacademic sites. Patients with stage 0-III breast cancer received 4R Sequences (4R Cohort). We surveyed 4R and historical control cohorts of patients treated at the same sites pre-4R. We assessed the impact of implementation metrics on usefulness of 4R to the 4R cohort and on improvement of pSM in 4R cohort vs historical control cohort. Results: Survey response rates: 63%, 422/670 (4R cohort); 47%, 466/992 (control cohort). Three of the five implementation metrics significantly impacted patient usefulness of 4R (Table). Patients at step 2 sites; sites with a systematic care process; and sites with small practices reported significantly higher 4R usefulness than patients in the comparison subgroup within respective metrics. 4R usefulness was not affected by practice setting or availability of patient navigators. pSM was significantly improved between control and 4R cohorts along all implementation metrics (p < .001), but the magnitude of incremental improvement between comparison subgroups varied across metrics (Table), with the largest increment associated with the program step metric. Conclusions: 4R is useful to patients across settings, with or without patient navigators. Stepwise design is effective in increasing 4R impact overtime. Future 4R Program will investigate an expanded array of implementation metrics and their influence on 4R outcomes. [Table: see text]

Background: Young breast cancer patients (pts) carrying a germline BRCA mutation (mBRCA) have similar outcomes as non-carriers. However, there is currently lack of evidence regarding the impact of mBRCA type and hormone receptor status on clinical behavior and outcomes of mBRCA breast cancer. We aim to address these questions in the largest dataset to date of young mBRCA breast cancer pts. Methods: This was an international, multicenter, hospital-based, retrospective cohort study. Women harboring deleterious germline mBRCA1 or mBRCA2 that received a diagnosis of stage I-III invasive early breast cancer at age ≤40 years between January 2000 and December 2012 were included. Baseline pts, tumor, and treatment characteristics, pattern and risk over time of disease-free survival (DFS) events, and survival outcomes (DFS, distant recurrence-free interval [DRFI] and overall survival [OS]) were compared between mBRCA1 and mBRCA2 pts overall and by hormone receptor status. Multivariate Cox proportional hazard models were used to compare hazard rates (HRs). Results: 1,236 young mBRCA breast cancer pts were included. Among 808 and 428 pts with mBRCA1 or mBRCA2, respectively, 191 (23.6%) and 356 (83.2%) had hormone receptor-positive tumors while 617 (76.4%) and 72 (16.8%) hormone receptor-negative disease (p<0.001). Compared to mBRCA2 breast cancer pts, those with mBRCA1 were younger, more likely to have reported Jewish ancestry, had more grade 3 tumors, less nodal involvement, lobular histology and HER2 positivity, and received more frequently chemotherapy (all p<0.001). More mBRCA1 pts with hormone receptor-positive tumors did not receive adjuvant endocrine therapy (14.7% vs. 4.2%, p<0.001). No difference between mBRCA1 and mBRCA2 pts was observed in risk-reducing mastectomy (43.9% vs. 46.0%; p=0.371) or salpingo-oophorectomy (48.3% vs. 48.8%; p=1.0). Median follow-up was 7.9 years (range 5.6-10.6 years). Second primary breast cancers (17.0% vs. 12.2%, p=0.025) and non-breast primary malignancies (4.3% vs. 1.9%, p=0.033) were more frequent among mBRCA1 pts compared to mBRCA2 pts, while distant recurrences were less frequent (10.4% vs. 15.4%, p=0.013). 8-year DFS was 62.8% and 65.9% for mBRCA1 and mBRCA2 pts, respectively (adjusted HR 0.76; 95% CI 0.60-0.96). The worse DFS in mBRCA1 was observed regardless of hormone receptor status (pinteraction=0.848): hormone receptor-positive (adjusted HR 0.77; 95% CI 0.58-1.03) and hormone receptor-negative (adjusted HR 0.73; 95% CI 0.48-1.13). No differences in DRFI and OS were observed between mBRCA1 and mBRCA2 pts. Compared to pts with hormone receptor-negative disease, those with hormone receptor-positive breast cancer had higher chances of developing distant (± loco-regional) recurrences (16.1% vs. 9.0%; p<0.001) and less frequent second primary malignancies (BC: 12.1% vs. 17.9%, p=0.005; non-BC: 2.8% vs. 4.0%, p=0.216). No differences in DFS and OS were observed between pts with hormone receptor-positive or negative breast cancer. However, there was a trend towards worse DRFI in women with hormone receptor-positive breast cancer as compared to those with hormone receptor-negative disease (8-year DRFI: 83.4% vs. 90.1%; adjusted HR 1.39; 95% CI 0.94-2.05). Conclusions: In this large unique dataset, young mBRCA1 breast cancer pts had worse DFS than those with mBRCA2 mostly due to higher rates of second primary malignancies. Hormone receptor positivity had no positive prognostic value in young mBRCA breast cancer pts with a trend towards worse DRFI in those with hormone receptor-negative disease. These results provide important information for counseling young mBRCA breast cancer pts regarding treatment, prevention and follow-up care strategies. Citation Format: Matteo Lambertini, Marcello Ceppi, Anne-Sophie Hamy, Olivier Caron, Philip D. Poorvu, Estela Carrasco, Albert Grinshpun, Kevin Punie, Christine Rousset-Jablonski, Alberta Ferrari, Shani Paluch-Shimon, Angela Toss, Claire Senechal, Fabio Puglisi, Katarzyna Pogoda, Jose Alejandro Pérez-Fidalgo, Laura De Marchis, Riccardo Ponzone, Luca Livraghi, Maria Del Pilar Estevez-Diz, Cynthia Villarreal-Garza, Maria Vittoria Dieci, Florian Clatot, Francois P. Duhoux, Rossella Graffeo, Luis Teixeira, Octavi Córdoba, Amir Sonnenblick, Arlindo R. Ferreira, Ann H. Partridge, Antonio Di Meglio, Claire Saule, Fedro A. Peccatori, Marco Bruzzone, Lucia Del Mastro, Lieveke Ameye, Judith Balmaña, Hatem A. Azim, Jr. Clinical behavior and outcomes of BRCA-mutated breast cancer in young patients according to type of BRCA mutation and hormone receptor status: Results from an international cohort study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-06.

6527 Background: Under the “NCI ASCO Teams” Project, we proposed a 4R Model of teamwork and patient self-management (pSM) (Trosman JOP ’16). 4R is Right Info / Care / Patient / Time. It enables patient (pt) and care team to manage interdependent care along the care continuum with an innovative multimodality personalized 4R Care Project Plan. We piloted 4R at 3 centers (academic, community, safety net) and assessed its impact on pSM. Methods: 4R Plans were administered to breast cancer pts stage 0-III Sep ’16 – Aug ’17 (4R cohort). We surveyed the 4R cohort and a comparable historical cohort of pts who received care pre-4R, Jun ’15 – May ’16 (control). We used simple frequencies and Fisher’s exact test in analyses. Results: Survey response rates: 68%, 185/271 (4R cohort); 47%, 241/410 (control). 75% of 4R respondents reported 4R Plans very useful / useful in overall understanding and organizing their care; 68% found 4R’s novel “project” component, very useful / useful in managing timing & sequencing of interdependent care. Care complexity impacted 4R usefulness: 67% of pts who received > 6 care services found 4R very useful / useful vs. 47% of pts who received < = 6 services, p = .01. Pts with lower care complexity suggested how to make 4R more useful to them, eg focus on endocrine therapy. Table compares pSM metrics in the 4R and control cohort. Care complexity was a significant factor of feeling overwhelmed for pts in the control cohort (51% of pts receiving > 6 care services felt overwhelmed vs. 31% of pts receiving < = 6 services, p = .02), but not a significant factor for pts in the 4R cohort (30% vs. 28%, p = .9). Conclusions: The 4R model significantly improved pt self-management in early breast cancer and reduced the impact of care complexity on pts, but provider factors of pSM need improvement. A 4R pilot at additional 12 cancer centers across the U.S. is in progress. Aspect of pSM %, 4R cohort, N = 185 %, Historical control cohort, N = 241 P value Know stage of your cancer 93 80 .0001 Care plan clear / very clear 84 67 .0001 Able to manage own care well / very well 78 69 .05 During care, seldom / never overwhelmed, not in control of your care 71 58 .008 Care coordination by providers to support the patient 72% 69% .5 Having a “go to” clinician to support the patient 76% 78% .7

Introduction Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality globally, and rural patients are at higher risk for poor COPD health outcomes. The United States National Institutes of Health (NIH) has issued a call for innovative care delivery models to address this gap in COPD care quality in rural communities. This paper explores the perspective of healthcare teams at two rural VA medical centers sustaining an innovative interprofessional COPD care delivery model, COPD Coordinated Access to Reduce Exacerbations (CARE). Methods This qualitative evaluation was conducted at two rural VA medical centers in the Southeast and Midwest regions of the US. Eleven semi-structured interviews with diverse clinical stakeholders were conducted including: facility leaders, hired pharmacists, clinical pharmacists, nurse care managers, primary care providers, and referral champions. The Practical Robust Implementation and Sustainability Model (PRISM) was applied to develop interview guides and informed data analysis. Interviews were transcribed and a mixed inductive-deductive approach was used for data analysis, involving iterative coding and consensus-building among five evaluators to identify emerging themes. Results Five overarching themes emerged as key facilitators of COPD CARE sustainment including (1) leadership support, (2) value alignment, (3) service institutionalization, (4) service adaptation, and (5) interprofessional collaboration. Notably, clinical pharmacists were described as filling care gaps in these under-resourced facilities. Conclusion This evaluation demonstrated the impact of clinical pharmacists serving as prescribers in improving COPD management in rural settings. The sustainment factors identified can be utilized to inform the expansion of similar, team-based healthcare programs across rural settings.

e19211 Background: We previously proposed a 4R model of teamwork and patient self-management (pSM) in cancer care (NCI ASCO Teams Project, Trosman JOP 2016). 4R (Right Info / Care / Patient / Time) enables patient and care team to manage complex care with an innovative 4R Care Sequence plan, including a novel visual feature describing timing and sequence of care. We report final results of a program which tested 4R at 5 safety net and 5 non safety net US centers from 2016 to 2019. Methods: Patients with stage 0-III breast cancer received 4R plans (4R Cohort). We surveyed 4R cohort and a historical control cohort of patients receiving care at same centers pre-4R. We assessed the usefulness of 4R to the 4R cohort and the impact on pSM in 4R cohort compared to historical cohort. Results: Survey response rates: 63%, 422/670 (4R cohort); 47%, 466/992 (control). 4R significantly increased the composite pSM score and 5 of 7 pSM metrics vs control (Table). The increase was not influenced by patient age, stage or whether treated at safety net site. pSM scores increased in 4R vs control cohort to a similar extent for patients &lt; 65 years old (74% vs 51%, p = .0001) as for patients ≥ 65 years old (78% vs 57%, p = .0002). pSM improved similarly for patients with stage 0 or I breast cancer (77% vs 56%, p = .0001) as for patients with stage II or III breast cancer (72% vs 54%, p = .0001). Safety net patients showed pSM increase (77% vs 51%, p = .0001) similar to non safety net patients (74% vs 58%, p = .0002). Within the 4R cohort, 80% found 4R useful for organizing care and 70% found the novel visual feature useful to manage care timing and sequence. Usefulness was similar for age groups and stages, but higher for safety net than non safety net patients (88% vs 74%, p = .0008). Conclusions: 4R markedly improved patient self-management in early breast cancer across age groups and cancer stages, but further enhancements are needed to benefit as many patients as possible. 4R benefits in safety net setting indicate that 4R may reduce disparities. [Table: see text]

1092 Background: ORIN1001 is a first-in-class small molecule targeting a novel enzyme with a unique mode of inhibition that selectively blocks the Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum. ORIN1001 is now undergoing Phase 1/2 clinical testing in advanced solid tumors. Methods: In a Phase 1 dose escalation trial (3+3 design), ORIN1001 was administered PO daily as a single agent in patients (pts) with advanced solid tumors and in combination with Abraxane in pts with relapsed, refractory breast cancer. Safety, tolerability, pharmacokinetics, and preliminary efficacy of ORIN1001 was evaluated and a RP2D determined. Results: As of Jan, 2023, 30 patients with advanced cancer have received ORIN1001 as a single agent at doses up to 650 mg per day in 21-day continuous cycles and 13 patients with breast cancer have received ORIN1001 at doses up to 400 mg in combination with Abraxane in 28-day continuous cycles. For single agent, DLTs consisting of thrombocytopenia were observed at 200 mg (2 pts) and 650 mg (2 pts) and, rash was observed at 200 mg (1 pt) and 500 mg (1 pt). For combination treatment, DLTs consisting of thrombocytopenia were observed at 300 mg (1 pt), fatigue/ rash at 400 mg (1 pt), febrile neutropenia/low WBC at 400/500 mg (1 pt at each dose). Common ( &gt; 15%) adverse events were predominantly nausea and/or vomiting (Grade 1-2 in severity). ORIN1001 exposure increased in a dose proportional manner with a mean T1/2 at steady state of approximately 20 hours. For single agent, best response per RECIST 1.1 was partial response (PR) in 2 of 30 pts. These PRs included a stage IV colon cancer pt exceeding 44 months on treatment at 100 mg, and stage IV ER-/PR-/HER2+ breast cancer pt with 5 months on treatment at 500 mg. Stable disease (SD) was observed in a total of 16 of 30 pts with breast, colorectal, mesothelioma, liver, prostate, kidney or ovarian cancer. For combination therapy with Abraxane, a PR was observed in one ER+/PR-/HER2- breast cancer pt at 300 mg ORIN1001 and SD was observed in 5 of 13 pts. SD included both triple negative and ER+/HER2- breast cancer pts at 300 or 400 mg with ongoing treatment exceeding 5 months. Of note, in a separate Phase 1 oncology basket trial in China, there were 2 PRs; 1 pt with stage IV NSCLC at 300 mg and 1 pt with metastatic castrate resistant prostate cancer at 100 mg exceeding 9 and 5 months of treatment with ORIN1001 in combination with Abraxane, respectively. Conclusions: Phase 1 clinical evaluation of ORIN1001 has demonstrated tolerability and dose proportional PK. The proposed RP2D is estimated to be 500 mg and 300 mg ORIN1001 for single agent and in combination with Abraxane, respectively. Early efficacy data with ORIN1001 demonstrate clinical responses (SD and PR) in multiple pts with heavily-pretreated advanced solid tumors as a single agent or in combination with Abraxane in breast cancer patients. Clinical trial information: NCT03950570 .

1074 Background: There is an increasing proportion of metastatic breast cancer patients (pts) who have been exposed to anthracyclines and taxanes either during perioperative treatment or during intial therapy of metastatic disease. The efficacy of gemcitabine plus cisplatin has been consistently demonstrated in several trials. This study evaluates the combination of gemcitabine plus carboplatin as a treatment option for intensively pretreated breast cancer pts. Methods: Metastatic breast cancer pts were treated with gemcitabine (1,000 mg/m2 iv on days 1 and 8) and carboplatin (AUC 4 iv on day 1) in a 3-week regimen. The trial was performed as a 2-stage phase II study according to the optimal design described by Simon (p0 = 0.1, p1 = 0.3, a = 0.05, β = 0.1) with overall remission rate (according to RECIST) as the primary objective. Results: 39 pts were recruited, median age was 60 years (29–77 yrs): median Karnofsky performance status was 90% (range, 70–100%), 77% of pts were ER- and/or PR-positive, and 28% of pts presented with Her-2 overexpression (IHC 3+ or FISH-positive). 87% of pts had visceral metastasis and 79.5% had =2 sites of metastasis. All patients had received prior chemotherapy and 92% of pts had received prior anthracyclines (87%) and/or taxanes (67%). Prior endocrine therapy had been applied to 77% of patients. Median follow-up time was 13.2 months (1–27 months) during which 207 treatment cycles were documented with a median number of 5 cycles per pt (range 1–12). A CR was observed in 1 pt, a PR in 11 pts for an overall remission rate of 31% (95%-CI: 17–48%). Stable disease was documented in 12 pts (31%) resulting in a disease control rate of 61.5%. Median time to remission was 2.6 months (1.3–5.1 months), median time to progression was 4.9 months (95%CI, 2.6–6.7 months), and overall survival was 13,2 months (95% CI, 8.7–16.7 months). Grade 3–4 leucopenia (NCI-CTC) was observed in 64%, neutropenia in 51%, thrombocytopenia in 49%, and anemia in 10% of pts. Conclusion: Gemcitabine plus carboplatin is an effective and well tolerated treatment option in intensively pretreated breast cancer pts. No significant financial relationships to disclose.

Background: Some breast cancer patients (pts) refused treatment despite their providers’ recommendations. Treatment refusals can be detrimental to these pts’ short- and long-term health outcomes. Limited research has investigated the national trends in treatment refusals and their impacts on the survival of breast cancer pts. Methods: We analyzed data collected from breast cancer pts in the 2004-2020 National Cancer Database (NCDB). Four treatment modalities were assessed: chemotherapy (CT), hormone therapy (HT), radiotherapy (RT), and surgery. The CT cohort included stage I-IV pts. The HT cohort included stage I-IV, hormone receptor-positive pts. The RT or surgery cohort was limited to only stage I-III pts. Refusal status was categorized as “yes/no,” and its correlates were assessed using multivariable logistic regression. Estimated rates of overall survival (OS) were calculated using the Kaplan-Meier method. The association between refusal status and OS was examined using log-rank tests, followed by multivariable Cox regression models. Results: In the CT cohort, 9.6% of 1,296,488 pts who were offered the treatment refused. In the RT cohort, 6.1% of 1,635,916 pts refused. In the HT cohort, 5.0% of 1,893,339 pts refused. In the surgery cohort, only 0.6% of 2,590,963 pts refused. Significant increasing trends in treatment refusals from 2004-2020 across the four treatment modalities were observed (all p-trends &amp;lt; .001). We found significant differences in age, race, AJCC stage group, molecular subtype, tumor grade, and care access indicators (e.g., insurance, median household income, facility type, and rural/urban area) by refusal status. Black pts were more likely than White pts to refuse surgery (adjusted odds ratio [AOR] 2.01, 95% CI: 1.89-2.14). Asian or Pacific Islander pts were also more likely to refuse surgery (AOR 1.29, 95% CI: 1.15-1.44) and CT (AOR 1.21, 95% CI: 1.16-1.27). Uninsured pts were more likely than privately insured pts to refuse surgery (AOR 4.83, 95% CI: 4.22-5.51), RT (AOR 1.97, 95% CI: 1.83-2.12), CT (AOR 1.61, 95% CI: 1.51-1.72), and HT (AOR 1.61, 95% CI: 1.49-1.73). Compared with pts who did not refuse treatment, those who refused had lower rates of 5-year OS in the cohorts of HT (81.4% vs. 88.4%), CT (74.9% vs. 84.4%), RT (74.4% vs. 90.8%), and surgery (42.0% vs. 88.1%). When stratified by stage, similar patterns of 5-year OS rates were observed across all cohorts. After adjusting for sociodemographic and clinicopathologic factors, pts who refused surgeries had a higher mortality risk than those who did not (aHR 2.91, 95% CI: 2.82-3.01). Pts who refused RT had a higher risk of dying than those who did not (aHR 1.97, 95% CI: 1.93-2.01). Pts who refused CT had a greater risk of dying than those who did not (aHR 1.86, 95% CI: 1.83-1.90). Pts who refused HT had a greater risk of death than those who did not (aHR 1.56, 95% CI: 1.53-1.59). Black pts had higher mortality risk than their White counterparts across all cohorts (HT: aHR 1.15, 95% CI: 1.13-1.17; CT: aHR 1.14, 95% CI: 1.12-1.16; RT: aHR 1.11, 95% CI: 1.1.09-1.14; surgery: aHR 1.10, 95% CI: 1.08-1.11). Conclusions: In this sample of breast cancer pts, the rate of treatment refusal was highest for CT and lowest for surgery, and there were significantly increased trends in refusals over time. Age, race, stage, molecular subtype, tumor grade, and care access measures were independently associated with treatment refusals, suggesting that differential refusals not only are affected by biological factors but also may reflect disparities in socioeconomic status. Furthermore, pts who refused treatment experienced worse OS, regardless of treatment modality. These findings suggest that stressing the importance of recommended treatment and interventions tailored for this patient population may be needed to improve their survival outcomes. Citation Format: Jincong Freeman, James Li, Susan Fisher, Katharine Yao, Sean David, Dezheng Huo. Prevalence of Refusal of Recommended Cancer Treatments and Survival Differences in Breast Cancer Patients: Analysis of the National Cancer Database [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 PS18-02.

Background: The recommended cut-off of &amp;lt; 1% positive cells to define estrogen receptor (ER) negative status in breast cancer (BC) is highly debated. Few data exist on transcriptomic features of ER-low BC, suggesting no major differences vs ER-neg. Among HER2-negative BCs, we compared gene-expression profiling (including PAM50 intrinsic subtyping) according to ER status (ER-neg: 0% vs. ER-low: 1-9%) and assessed its impact on Tumor-infiltrating lymphocytes (TILs) levels. Methods: Across two cancer centers, stage I-III HER2-negative BCs FFPE samples were reviewed for ER status. All ER-low (ER 1-9%) samples were identified and a cohort of ER-neg BC samples, matched for age and stage, was also retrieved. A small cohort of pts with intermediate ER expression (ER-int: 10-50%) was included as a control cohort. Expression of 776 BC–related genes was evaluated by nCounter® (Breast Cancer 360TM Panel) and intrinsic molecular subtyping was determined using the PAM50 subtype predictor. A False Discovery Rate (FDR) corrected unpaired two-class SAM was used to identify genes differentially expressed in different subgroups. TILs were evaluated on archival H&amp;E slides following guidelines. Results: Of 116 stage I-III HER2-neg BC pts included, 39 had ER-neg BC, 65 had ER-low BC, and 12 had ER-int disease. PAM50 intrinsic subtype distribution was similar in ER-neg and ER-low BCs, (with an enrichment in basal-like tumors), while both subgroups differed significantly from ER-int samples (Table). As compared to ER-neg tumors, ER-low BCs showed significantly higher expression of GATA3 gene and lower expression of EDN1 and PROM1 genes by SAM analysis (FDR&amp;lt; 5%); however, when the analysis was limited to PAM50 basal-like tumors (N=77) we only identified two genes that were downregulated in ER-low BCs (EDN1, PROM1) as compared to ER-neg BCs. On the contrary, significant differences in transcriptomic regulation were observed between ER-low and ER-int BCs, with ER-low BCs showing significantly higher expression of 53 genes and lower expression of 398 genes, as compared to ER-int (SAM analysis FDR&amp;lt; 5%). We previously reported similar TIL levels in ER-low and ER-neg tumors. In both ER-low and ER-int BCs, PAM50 basal-like subtype was associated with significantly higher TILs: median TIL levels 20 (range 0-80) and 6 (range 1-40) for PAM50 Basal-like BCs versus other PAM50 subtypes respectively in ER-low samples (p&amp;lt; 0.001); median TIL levels 53 (range 25-80) and 5 (range 0-10) for PAM50 Basal-like BCs versus other PAM50 subtypes respectively in ER-int samples (p=0.036). No significant difference in TIL levels according to PAM50 subtyping were observed in ER-neg tumors. No significant difference in mRNA levels for PD-1 (PDCD1) and PD-L1 (CD274) genes was observed between ER-low and ER-neg tumors. Conclusions: Among patients with HER2-neg BC, gene-expression profiling is similar in ER-neg (i.e., &amp;lt; 1%) vs. ER-low tumors with a high prevalence of PAM50 Basal-like tumors and few differentially expressed genes. In both ER-low and ER-int HER2-neg BCs, PAM50 Basal-like subtype is also associated with higher TIL levels. Our results strongly indicate that HER2-neg/ER-low BCs and HER2-neg/ER-neg BCs are similar biological entities, thus further supporting the use of similar treatments in patients with early-stage ER-low and triple-negative BC, including immune checkpoint inhibitors. PAM50 intrinsic subtype distribution according to ER levels Citation Format: Gaia Griguolo, Claudio Vernieri, Davide Massa, Lorenzo Nicolè, Claudia Pinato, Federica Miglietta, Andrea Vingiani, Silvia Brich, Riccardo Lobefaro, Francesca Schiavi, Matteo Fassan, Giancarlo Pruneri, Valentina Guarneri, Maria Vittoria Dieci. Transcriptomic profiling of ER-negative and ER-low, HER2-negative breast cancer and its implications on immune regulation [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-09.

Tumor-associated immune suppression is known to be an important contributor to cancer progression. One such mechanism is the abnormal accumulation of ImC in the peripheral blood. Although both tumor burden and CTX-induced accumulation of ImC are well described in animal studies, human studies have been limited. Thus, the goal of our study was to determine whether levels of ImC in whole blood correlate with clinical cancer stage in cancer patients (pts). Flow cytometry analyses were performed on whole peripheral blood from newly diagnosed solid tumor pts. ImC population was defined as lineage−CD33+HLA-DR−CD11b+. Peripheral blood specimens from 14 normal healthy controls and 35 cancer pts (stages: I, n=3; II, n=9; III, n=9; IV, n=14), revealed greater ImC in cancer pts vs. normal (3.21% vs. 1.47%; p=.002). Stage IV pts had the highest percentage of ImC (4.39%). Initial results from stage II-III breast cancer pts (n=10) treated with preoperative chemotherapy showed that CTX treatment was associated with significant increases in circulating ImC compared with baseline (2.91% vs. 10.57%; p=0.001), and also when compared to taxane chemotherapy independent of G-CSF (10.57% vs. 3.25%; p=0.00025). In conclusion, overall ImC levels correlate with clinical cancer stage and CTX treatment leads to transient increases in ImC in breast cancer pts.

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