TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS: We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS: Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION: In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02876302. Registered 23 August 2016.

Evaluation of alpelisib-induced hyperglycemia prophylaxis and associated risk factors in PIK3CA-mutated hormone-receptor positive, human epidermal growth factor-2 negative advanced breast cancer.

PURPOSE: SOLAR-1 investigated alpelisib-fulvestrant (ALP + FLV) in patients with HR + /HER2-, PIK3CA-mutated advanced breast cancer and demonstrated a clinically significant increase in all-grade and grade (G) 3-4 hyperglycemia (HG) compared to placebo-fulvestrant. Given high rates of HG, a preventative protocol and identification of associated risk factors was implemented. METHODS: This single-center, retrospective study included patients receiving ALP + FLV. One week before ALP initiation, patients started an insulin-sensitizer. Patients had fasting plasma glucose (FPG) levels drawn day 8, 15, 28, then monthly. Primary outcome was incidence of G2-4 HG by day 28. Risk factors assessed included age, BMI, FPG, and HbA1c. Number of risk factors were compared between patients with and without HG. RESULTS: Sixteen women were included with median age of 59 years. The cohort was 69% White, 25% Black, 75% with BMI ≥ 25 kg/m2, and 50% with history of diabetes. By day 28, 9 patients (56%) had G2-4 HG, with only 3 (19%) G3 and zero G4. Patients with G2-4 HG had a median of 2 risk factors compared to only 1 if no HG (p = 0.03). 5 patients (31%) required a temporary hold of ALP and 3 (19%) required dose reduction due to HG. 13 patients permanently discontinued ALP-9 due to disease progression and 4 from an adverse event (only 1 HG). CONCLUSION: Implementation of a HG prophylaxis protocol with ALP in a single-center study demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%). An increase in HG-associated risk factors correlated with a higher incidence of G2-4 HG.

Neoadjuvant Chemotherapy and Endocrine Therapy for Older Patients with Estrogen Receptor Positive Breast Cancer: Comparison of Approaches.

BACKGROUND: Benefits of a pathologic complete response (pCR) following neoadjuvant therapy are well established, yet outcomes for older women are understudied. We sought to examine the pCR and overall survival (OS) rates of women with estrogen receptor (ER) positive breast cancer across age groups. METHODS: Women diagnosed with cT1-4, N0-3, M0, ER+/HER2- breast cancer (2010-2018) who underwent neoadjuvant chemotherapy (NACT) or neoadjuvant endocrine therapy (NET) followed by surgery were selected from the National Cancer Database and categorized by age. Differences were tested, and Cox proportional hazards models were used to estimate the association of response with OS after adjustment for covariates. RESULTS: In the 43,009-patient cohort, 84.8% received NACT and 15.2% received NET. Of those aged ≥ 70 (N = 5623), 51.0% received NACT, and 49.0% received NET. Compared with younger women receiving NACT, older women were less likely to have a breast or nodal pCR [no pCR by age: 85.1% (≥ 70 years) vs 82.2% (50-69 years) vs 77.7% (< 50 years), p < 0.001]. Rates of pCR were similarly low for all women receiving NET [no pCR by age: 95.6% (≥ 70 years) vs 95% (50-69 years) vs 96% (< 50 years), p = 0.06]. After adjustment, pCR after NACT was not associated with OS for older patients, but better survival outcomes were noted for older patients achieving pCR after NET. CONCLUSION: For women with ER+/HER2- breast cancer, pCR rates after NACT are lower in older women compared with younger women, and are equally low after NET for all women. However, pCR after NET is associated with improved OS among older women, unlike pCR after NACT.

A Novel Staging System for De Novo Metastatic Breast Cancer Refines Prognostic Estimates.

OBJECTIVE: We aim to identify prognostic groups within a de novo metastatic cohort, incorporating both anatomic and biologic factors. BACKGROUND: Staging for breast cancer now includes anatomic and biologic factors, although the guidelines for stage IV disease do not account for how these factors may influence outcomes. METHODS: Adults with de novo metastatic breast cancer were selected from the National Cancer DataBase (2010-2013). Recursive partitioning analysis was used to group patients with similar overall survival (OS) based on clinical T/N stage, tumor grade, ER, PR, HER2, number of metastatic sites, and presence of bone-only metastases. Categories were created by amalgamating homogeneous groups based on 3-year OS rates (stage IVA: >50%, stage IVB: 30%-50%, stage IVC: <30%). RESULTS: 16,187 patients were identified; median follow-up was 32 months. 65.2% had 1 site of distant metastasis, and 42.9% had bone-only metastases. Recursive partitioning analysis identified the number of metastatic sites (1 vs >1) as the first stratification point, and ER status as the second stratification point for both resulting groups. Additional divisions were made based on HER2 status, PR status, cT stage, tumor grade, and presence of bone-only metastases. After bootstrapping, significant differences in 3-year OS were noted between the 3 groups [stage IVB vs IVA: HR 1.58 (95% confidence interval 1.50-1.67), stage IVC vs IVA: HR 3.54 (95% confidence interval 3.33-3.77)]. CONCLUSIONS: Both anatomic and biologic factors yielded reliable and reproducible prognostic estimates among patients with metastatic disease. These findings support formal stratification of de novo stage IV breast cancer into 3 distinct prognosis groups.

Treatment Patterns and Outcomes of Women with Breast Cancer and Supraclavicular Nodal Metastases.

BACKGROUND: In 2002, breast cancer patients with supraclavicular nodal metastases (cN3c) were downstaged from AJCC stage IV to IIIc, prompting management with locoregional treatment. We sought to estimate the impact of multimodal therapy on overall survival (OS) in a contemporary cohort of cN3c patients. METHODS: Women ≥ 18 years with cT1-T4c/cN3c invasive breast cancer who underwent systemic therapy were identified from the 2004-2016 National Cancer Database. We compared three patient cohorts: (a) cN3c + multimodal therapy (systemic therapy, surgery, and radiation); (b) cN3c + non-standard therapy; and, (c) cM1. Logistic regression identified factors associated with receipt of multimodal therapy and Kaplan-Meier was used to estimate unadjusted OS. The Cox proportional hazards model estimated effects of diagnosis and treatment on OS after adjustment. RESULTS: Overall, 1827 (3.7%) patients with cN3c disease and 46,919 (96.3%) cM1 patients were identified. Of cN3c patients, 74.5% (n = 1362) received multimodal therapy and 25.5% (n = 465) received non-standard therapy; receipt of multimodal therapy was associated with improved 5-year OS (multimodal: 59% vs. M1: 28% vs. non-standard: 28%, log-rank p < 0.001). Adjusting for covariates, non-standard therapy was associated with an increased risk of death compared with receipt of multimodal therapy (HR 2.20, 95% CI 1.71-2.83, p < 0.001). Private insurance was the only patient characteristic associated with a greater likelihood of receiving multimodal therapy (OR 2.81; 95% CI, 1.64-4.82; p < 0.001). CONCLUSION: Women with cN3c breast cancer who received multimodal therapy demonstrated improved overall survival when compared with patients undergoing non-standard therapy and those with metastatic (M1) disease. Although selection bias may contribute to worse overall survival among cN3c patients undergoing non-standard therapy, national guidelines should encourage locoregional treatment in carefully selected patients.

Biomarkers of Immune Checkpoint Blockade Response in Triple-Negative Breast Cancer.

OPINION STATEMENT: Immune checkpoint blockade (ICB) has revolutionized the treatment landscape across multiple solid tumor types. In triple-negative breast cancer (TNBC), clinical benefit for the addition of ICB to chemotherapy has been shown in both the metastatic and early stage disease settings. A minority of patients with TNBC will truly benefit from ICB, with many tumors unlikely to respond, and ICB can cause additional toxicities for patients to incur. In clinical practice, ICB-based regimens are emerging as standard-of-care treatment options in TNBC subpopulations. Atezolizumab in combination with nab-paclitaxel is recommended as first-line treatment for patients with PD-L1-positive metastatic TNBC. Clinical trials are needed to confirm this benefit and evaluate if additional biomarkers may allow for improved patient selection. Trials investigating ICB in early-stage breast cancer show promise for the benefit of combination ICB with neoadjuvant chemotherapy. However, longer follow-up is required before ICB can be considered as standard-of-care treatment in the early stage setting. In both metastatic and early stage TNBC, novel biomarkers to improve patient selection are now under investigation. These include multiplex IHC to profile immune cell subtypes (such as tumor infiltrating lymphocytes) or RNA gene expression profiling to detect signatures suggestive of a T-cell-inflamed microenvironment. Detecting somatic mutations through tumor next-generation DNA sequencing may predict resistance mechanisms or suggest sensitivity to ICB monotherapy or in combination with other forms of systemic therapy. These biomarker platforms may allow for a more granular analysis of immune activity and should be further investigated in prospective studies with the aim of personalizing ICB-focused therapies in TNBC.

Extent of axillary surgery in inflammatory breast cancer: a survival analysis of 3500 patients.

PURPOSE: Inflammatory breast cancer (IBC) is an aggressive variant for which axillary lymph node (LN) dissection following neoadjuvant chemotherapy (NACT) remains standard of care. But with increasingly effective systemic therapy, it is unclear whether more limited axillary surgery may be appropriate in some IBC patients. We sought to examine whether extent of axillary LN surgery was associated with overall survival (OS) for IBC. METHODS: Female breast cancer patients with non-metastatic IBC (cT4d) diagnosed 2010-2014 were identified in the National Cancer Data Base. Cox proportional hazards modeling was used to estimate the association between extent of axillary surgery (≤ 9 vs ≥ 10 LNs removed) and OS after adjusting for covariates, including post-NACT nodal status (ypN0 vs ypN1-3) and radiotherapy receipt (yes/no). RESULTS: 3471 patients were included: 597 (17.2%) had cN0 disease, 1833 (52.8%) had cN1 disease, and 1041 (30%) had cN2-3 disease. 49.9% of cN0 patients were confirmed to be ypN0 on post-NACT surgical pathology. Being ypN0 (vs ypN1-3) was associated with improved adjusted OS for all patients. Radiotherapy was associated with improved adjusted OS for cN1 and cN2-3 patients but not for cN0 patients. Regardless of ypN status, there was a trend towards improved adjusted OS with having ≥ 10 (vs ≤ 9) LNs removed for cN2-3 patients (HR 0.78, 95% CI 0.60-1.01, p = 0.06) but not for cN0 patients (p = 0.83). CONCLUSIONS: A majority of IBC patients in our study presented with node-positive disease, and for those presenting with cN2-3 disease, more extensive axillary surgery is potentially associated with improved survival. For cN0 patients, however, more extensive axillary surgery was not associated with a survival benefit, suggesting an opportunity for more personalized care.

Surgery for Men with Breast Cancer: Do the Same Data Still Apply?

BACKGROUND: Men represent a small proportion of breast cancer diagnoses, and they are often excluded from clinical trials. Current treatments are largely extrapolated from evidence in women. We compare practice patterns between men and women with breast cancer following the publication of several landmark clinical trials in surgery. PATIENTS AND METHODS: Patients with invasive breast cancer (2004-2015) from the National Cancer Data Base were identified; subcohorts were created based on eligibility for NSABP-B06, CALGB 9343, and ACOSOG Z0011. Practice patterns were stratified by gender and compared. Cox proportional hazards regression analyses were utilized to estimate the association between OS and gender. RESULTS: Of the 1,664,746 patients identified, 99% were women and 1% were men. Among NSABP-B06 eligible men, mastectomy rates did not change (consistently ~ 80%), and their adjusted OS was minimally worse compared with women (HR 1.19, 95% CI 1.11-1.28). Following publication of CALGB 9343, omission of radiation after lumpectomy was less likely in men and lagged behind that of women, despite similar OS (male HR 0.92, 95% CI 0.59-1.44). Application of ACOSOG Z0011 findings resulted in deescalation of axillary surgery for men and women with comparable OS (male HR 0.69, 95% CI 0.33-1.45). CONCLUSIONS: Uptake of clinical trial results for men with breast cancer often mirrors that for women, despite exclusion from these studies. Furthermore, when study findings were applied to eligible patients, men and women demonstrated similar survival. Observational studies can help inform the potential application of study findings to this unique population and improve patient enrollment in clinical trials.

Checkpoint Blockade Strategies in the Treatment of Breast Cancer: Where We Are and Where We Are Heading.

OPINION STATEMENT: Immunotherapy has become one of the greatest advances in medical oncology over the last century; however, the optimal application for the treatment of breast cancer remains an active area of investigation. Modern immunotherapy strategies augment the immune system and ideally, permit durable tumor-specific immune memory. In fact, several monoclonal antibodies that mediate the immune checkpoint receptors have provided the most clinically meaningful improvement for breast cancer patients to date, particularly for the triple negative subtype. Checkpoint blockade as monotherapy has demonstrated some encouraging results, although some combination strategies appear to augment those responses and may be particularly effective when administered earlier in the course of disease. For example, the combination of atezolizumab and nab-paclitaxel as first-line therapy for metastatic triple negative breast cancer demonstrated significant improvements in progression-free survival when compared with chemotherapy alone. Herein, we review the data for immune therapy in breast cancer and highlight promising future directions.

The Clinical Significance of Breast-only and Node-only Pathologic Complete Response (pCR) After Neoadjuvant Chemotherapy (NACT): A Review of 20,000 Breast Cancer Patients in the National Cancer Data Base (NCDB).

OBJECTIVE: To determine whether the association between overall survival (OS) and response to neoadjuvant chemotherapy (NACT) in breast cancer patients varies with tumor subtype and anatomic extent of pathologic complete response (pCR). BACKGROUND: pCR after NACT predicts improved OS in breast cancer, but it is unclear whether pCR limited to the breast or axilla is also associated with OS. METHODS: Women with cT1-3/cN0-1 breast cancer diagnosed in 2010 to 2014 who underwent surgery following NACT were identified in the NCDB and divided into 4 subtypes based on reported hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Kaplan-Meier curves and Cox proportional hazards models were used to estimate OS. Multivariate logistic regression was used to identify factors associated with post-NACT response, defined as upstage (yp stage>clinical stage); no change (clinical stage = yp stage); overall (breast+axilla, ypT0N0), breast-only (ypT0N1/N1mic), or node-only (ypT1-3N0) pCR. RESULTS: Of 33,162 identified patients, 20,265 experienced overall pCR (n = 6370, 19.2%), breast-only pCR (n = 494, 1.5%), node-only pCR (n = 1133, 3.4%), no stage change (n = 9641, 29.1%), or upstage (n = 2627, 7.9%). Compared with no stage change, breast-only pCR was associated with improved OS in triple-negative disease [hazard ratio = 0.58, 95% confidence interval (95% CI) = 0.37-0.89], and node-only pCR was associated with improved OS in both triple-negative (hazard ratio = 0.55,95% CI = 0.39-0.76) and HR+/HER2- disease (hazard ratio = 0.54, 95% CI = 0.33-0.89). For patients achieving overall (breast+axilla) pCR, unadjusted 5-year OS was 0.94 (95% CI = 0.93-0.95), with no difference between patients who were cN0 (hazard ratio = 0.95, 95% CI = 0.93-0.96) or cN1 (hazard ratio = 0.94, 95% CI = 0.92-0.96) at diagnosis. CONCLUSIONS: In node-positive patients, pCR limited to either the breast or axilla predicts survival for select receptor subtypes. In patients achieving pCR in both the breast and axilla, survival is driven by response to NACT rather than presenting cN stage.

Metaplastic Breast Cancer Treatment and Outcomes in 2500 Patients: A Retrospective Analysis of a National Oncology Database.

BACKGROUND: Metaplastic breast cancer (MBC) is characterized by chemoresistance and hematogenous spread. We sought to identify factors associated with improved MBC outcomes and increased likelihood of MBC diagnosis. METHODS: Women ≥ 18 years of age with stage I-III MBC and non-MBC diagnosed between 2010 and 2014 were identified in the National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional hazards models were used to estimate associations with overall survival (OS). Multivariate logistic regression identified factors associated with MBC diagnosis. RESULTS: Overall, 2451 MBC and 568,057 non-MBC patients were included; 70.3% of MBC vs. 11.3% of non-MBC patients were triple negative (p < 0.001). Five-year OS was reduced among MBC vs. non-MBC patients for the entire cohort (72.7 vs. 87.5%) and among triple-negative patients (71.1 vs. 77.8%; both p < 0.001). In MBC, triple-negative (vs. luminal) subtype was not associated with worse OS (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.88-1.54, p = 0.28). Compared with non-MBC patients, MBC patients were more likely to receive mastectomy (59.0 vs. 44.9%), chemotherapy (74.1 vs. 43.1%), and axillary lymph node dissection (ALND; 35.2 vs. 32.2%, all p ≤ 0.001). MBC patients more frequently had negative ALND (pN0) than non-MBC patients (20.0 vs. 10.6%, p < 0.001). Among MBC patients, chemotherapy (HR 0.69, 95% CI 0.53-0.89, p = 0.004) and radiotherapy (HR 0.52, 95% CI 0.39-0.69, p < 0.001) were associated with improved survival, while ALND was associated with decreased survival (HR 1.37, 95% CI 1.06-1.77, p = 0.02). CONCLUSIONS: MBC patients had worse survival than non-MBC patients, independent of receptor status, suggesting that MBC may confer an additional survival disadvantage. Multimodal therapy was associated with improved outcomes, but ALND was not and may be overutilized in MBC.

Cost-Effectiveness Analysis of the Oncotype DX Breast Recurrence Score® Test from a US Societal Perspective.

Background and Objectives: The 21-gene assay (the Oncotype DX Breast Recurrence Score® test) estimates the 10-year risk of distant recurrence in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) early-stage breast cancer to inform adjuvant chemotherapy decisions. The cost-effectiveness of the 21-gene assay compared against standard clinical-pathological risk tools alone for HR+/HER2- early-stage breast cancer was assessed using an economic model informed by evidence from randomized controlled trials. Materials and Methods: A cost-effectiveness model consisted of a decision-tree to stratify patients according to their Recurrence Score (RS) results and the use of adjuvant chemotherapy, followed by a Markov component to estimate the long-term costs and outcomes of the chosen treatment. Distributions of patients and distant recurrence probabilities were derived from the TAILORx (N0) and RxPONDER (N1) trials. The model was evaluated from a healthcare payer and societal perspective. Endocrine therapy and chemotherapy use were informed using clinical expert opinion to reflect US clinical practice and were combined with Medicare drug costs (2021) to estimate the cost of treatment. Societal costs included lost productivity and patient out-of-pocket costs obtained from literature. Results: The Oncotype DX test generated more quality-adjusted life-years (QALYs) (N0: 0.25; N1: 0.08) at a lower cost (N0: -$13,395; N1: -$2526) compared to clinical-pathological risk alone from a societal cost perspective. The overall conclusions from the model did not change when considering a payer perspective. The main cost drivers were avoidance of distant recurrence for N0 (-$12,578), and the cost of adjuvant chemotherapy for N1 (-$2133). Lost productivity had a major impact in the societal perspective analysis (N0: -$4607; N1: -$1586). Conclusion: Adjuvant chemotherapy decisions based on the RS result led to more life year gains and lower healthcare costs (dominant) compared to using clinical-pathological risk factors alone among patients with HR+/HER2- N0 and N1 early-stage breast cancer.

A Phase I Trial of Alpelisib Combined With Capecitabine in Patients With HER2-Negative Metastatic Breast Cancer.

BACKGROUND: Alpelisib is an oral α-specific class I PI3K inhibitor approved in combination with fulvestrant for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. The tolerability of this drug with the oral chemotherapy capecitabine is unknown. PATIENTS AND METHODS: This phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of alpelisib (250 mg or 300 mg daily for 3-weeks) with capecitabine (1000 mg/m2 twice daily for 2-weeks followed by a 1-week rest period) in patients with metastatic HER2-negative breast cancer, regardless of PIK3CA mutation status. RESULTS: Eighteen patients were treated with alpelisib-capecitabine. Half of the patients had HR+ breast cancer, and 16 had prior systemic therapy for metastatic disease. The MTD of alpelisib was 250 mg daily in combination with capecitabine 1000 mg/m2 twice daily. DLTs included hyperglycemia, QTc prolongation, fatigue, and chest pain. The most common grade 3 adverse event (AE) was hyperglycemia (28%). No grade 4 AEs were observed. Three patients discontinued therapy due to an AE. One-third of patients required dose reduction of both alpelisib and capecitabine. Four patients experienced a partial response and 8 patients experienced stable disease. The median progression-free survival was 9.7 months (95% CI 2.8-13.5 months) and median overall survival was 18.2 months (95% CI 7.2-35.2 months). Twelve patients had PIK3CA mutation testing completed, of these 2 had known or likely deleterious PIK3CA mutation. CONCLUSION: This study provides safety data for an oral combination therapy of alpelisib-capecitabine and defines tolerable doses for further study.

Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors.

ROS1 is the largest receptor tyrosine kinase in the human genome. Rearrangements of the ROS1 gene result in oncogenic ROS1 kinase fusion proteins that are currently the only validated biomarkers for targeted therapy with ROS1 TKIs in patients. While numerous somatic missense mutations in ROS1 exist in the cancer genome, their impact on catalytic activity and pathogenic potential is unknown. We interrogated the AACR Genie database and identified 34 missense mutations in the ROS1 tyrosine kinase domain for further analysis. Our experiments revealed that these mutations have varying effects on ROS1 kinase function, ranging from complete loss to significantly increased catalytic activity. Notably, Asn and Gly substitutions at Asp2113 in the ROS1 kinase domain were found to be TKI-sensitive oncogenic variants in cell-based model systems. In vivo experiments showed that ROS1 D2113N induced tumor formation that was sensitive to crizotinib and lorlatinib, FDA-approved ROS1-TKIs. Collectively, these findings highlight the tumorigenic potential of specific point mutations within the ROS1 kinase domain and their potential as therapeutic targets with FDA-approved ROS1-TKIs.

The budget impact of utilizing the Oncotype DX Breast Recurrence Score test from a US healthcare payer perspective.

BACKGROUND AND OBJECTIVES: The Oncotype DX Breast Recurrence Score test is used to estimate distant recurrence risk of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) early-stage breast cancer and inform decisions on the use of adjuvant chemotherapy. A model-based budget impact analysis compared the Oncotype DX test in combination with clinical-pathological risk against using clinical-pathological risk alone for HR+/HER2- node-negative (N0) and node-positive (N1; 1-3 axillary lymph nodes) early-stage breast cancer patients. MATERIALS AND METHODS: Test and medical costs associated with treatment of breast cancer were assessed through a US healthcare payer perspective. Distributions of patients by Recurrence Score result and distant recurrence probabilities with chemo-endocrine and endocrine therapy were derived from the TAILORx (N0) and RxPONDER (N1) trials. Changes in budget impact were evaluated over a 5-year horizon for a 1,000,000-member hypothetical health plan. RESULTS: With the Oncotype DX test, there was an incremental budget impact of $261,067 (per member per month (PMPM): $0.004), in the N0 population, and $56,143 (PMPM: $0.001) in the N1 population over the 5-year period. The largest budget impact reduction in the N0 population was attributed to reduced breast cancer recurrence costs (incremental: -$633,457, PMPM: -$0.011), while chemotherapy sparing reduced costs in the N1 population (incremental: -$94,884, PMPM: -$0.002). CONCLUSION: The clinical benefit of using the Oncotype DX test to inform adjuvant chemotherapy decisions has been shown in multiple randomized controlled trials. This analysis demonstrated that while using the Oncotype DX test to inform adjuvant chemotherapy decisions may slightly increase US healthcare costs over an initial 5-year time horizon (driven by a cost increase in the first year with cost savings reflected in remaining 4 years), there is significant scope for cost savings when assessing beyond this period due to avoided downstream costs of distant recurrence and long-term chemotherapy adverse events. PMPM costs also remain low across all populations examined, demonstrating a close-to-neutral budget impact.

Clinical trials of self-replicating RNA-based cancer vaccines.

Therapeutic cancer vaccines, designed to activate immune effectors against tumor antigens, utilize a number of different platforms for antigen delivery. Among these are messenger RNAs (mRNA), successfully deployed in some prophylactic SARS-CoV2 vaccines. To enhance the immunogenicity of mRNA-delivered epitopes, self-replicating RNAs (srRNA) that markedly increase epitope expression have been developed. These vectors are derived from positive-strand RNA viruses in which the structural protein genes have been replaced with heterologous genes of interest, and the structural proteins are provided in trans to create single cycle viral replicon particles (VRPs). Clinical stage srRNA vectors have been derived from alphaviruses, including Venezuelan Equine Encephalitis (VEE), Sindbis, and Semliki Forest virus (SFV) and have encoded the tumor antigens carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), prostate specific membrane antigen (PSMA), and human papilloma virus (HPV) antigens E6 and E7. Adverse events have mainly been grade 1 toxicities and minimal injection site reactions. We review here the clinical experience with these vaccines and our recent safety data from a study combining a VRP encoding HER2 plus an anti-PD1 monoclonal antibody (pembrolizumab). This experience with VRP-based srRNA supports recent development of fully synthetic srRNA technologies, where the viral structural proteins are replaced with protective lipid nanoparticles (LNP), cationic nanoemulsions or polymers.

Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

Purpose: To examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAT). Patients and Methods: We identified responders (RCB-0/1) and matched non-responders (RCB-2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel vs. cisplatin in TNBC. We collected plasma samples at baseline, three weeks, and twelve weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. Results: Of 139 patients, 68 had complete samples and no additional NAT. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3, and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10 -4 (range: 7.9 × 10 -7 to 4.9 × 10 -1 ). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10/11 patients with RCB-0, 3/8 with RCB-1, 4/15 with RCB-2, and 0/4 with RCB-3. Among 6 patients with known recurrence five had persistent ctDNA at week 12. Conclusion: NAT for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine if ctDNA-guided approaches can improve outcomes.

APOBEC Mutagenesis Inhibits Breast Cancer Growth through Induction of T cell-Mediated Antitumor Immune Responses.

The APOBEC family of cytidine deaminases is one of the most common endogenous sources of mutations in human cancer. Genomic studies of tumors have found that APOBEC mutational signatures are enriched in the HER2 subtype of breast cancer and are associated with immunotherapy response in diverse cancer types. However, the direct consequences of APOBEC mutagenesis on the tumor immune microenvironment have not been thoroughly investigated. To address this, we developed syngeneic murine mammary tumor models with inducible expression of APOBEC3B. We found that APOBEC activity induced antitumor adaptive immune responses and CD4+ T cell-mediated, antigen-specific tumor growth inhibition. Although polyclonal APOBEC tumors had a moderate growth defect, clonal APOBEC tumors were almost completely rejected, suggesting that APOBEC-mediated genetic heterogeneity limits antitumor adaptive immune responses. Consistent with the observed immune infiltration in APOBEC tumors, APOBEC activity sensitized HER2-driven breast tumors to anti-CTLA-4 checkpoint inhibition and led to a complete response to combination anti-CTLA-4 and anti-HER2 therapy. In human breast cancers, the relationship between APOBEC mutagenesis and immunogenicity varied by breast cancer subtype and the frequency of subclonal mutations. This work provides a mechanistic basis for the sensitivity of APOBEC tumors to checkpoint inhibitors and suggests a rationale for using APOBEC mutational signatures and clonality as biomarkers predicting immunotherapy response in HER2-positive (HER2+) breast cancers.

A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel with or without atezolizumab in triple negative breast cancer (TNBC) - NCI 10013.

Atezolizumab with chemotherapy has shown improved progression-free and overall survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Atezolizumab with anthracycline- and taxane-based neoadjuvant chemotherapy has also shown increased pathological complete response (pCR) rates in early TNBC. This trial evaluated neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with clinical stages II-III TNBC. The co-primary objectives were to evaluate if chemotherapy and atezolizumab increase pCR rate and tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in the mITT population. Sixty-seven patients (ages 25-78 years; median, 52 years) were randomly assigned - 22 patients to Arm A, and 45 to Arm B. Median follow up was 6.6 months. In the modified intent to treat population (all patients evaluable for the primary endpoints who received at least one dose of combination therapy), the pCR rate was 18.8% (95% CI 4.0-45.6%) in Arm A, and 55.6% (95% CI 40.0-70.4%) in Arm B (estimated treatment difference: 36.8%, 95% CI 8.5-56.6%; p = 0.018). Grade 3 or higher treatment-related adverse events occurred in 62.5% of patients in Arm A, and 57.8% of patients in Arm B. One patient in Arm B died from recurrent disease during the follow-up period. TIL percentage increased slightly from baseline to cycle 1 in both Arm A (mean ± SD: 0.6% ± 21.0%) and Arm B (5.7% ± 15.8%) (p = 0.36). Patients with pCR had higher median TIL percentages (24.8%) than those with non-pCR (14.2%) (p = 0.02). Although subgroup analyses were limited by the small sample size, PD-L1-positive patients treated with chemotherapy and atezolizumab had a pCR rate of 75% (12/16). The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in a statistically significant and clinically relevant increased pCR rate in patients with clinical stages II and III TNBC. (Funded by National Cancer Institute).