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Background: The benefit of pathologic complete response (pCR) in early breast cancer (eBC) is not well described in the real-world setting. This study used the nationwide Flatiron Health electronic health record-derived deidentified database to describe treatment patterns and survival outcomes by pCR status after neoadjuvant therapy (NAT) in women with triple-negative or HR+/HER2- eBC. Materials & methods: Observational cohort study analyzing women with eBC who started NAT between 2011 and 2018. Results: 496 women were included in the study; of those, 16.1% achieved pCR, of which 35.7% were triple-negative and 6.1% were HR+/HER2- eBC. More women with triple-negative eBC (95.2%) were exclusively treated with chemotherapy-based NAT versus HR+/HER2- eBC (56.1%). In multivariate analyses from NAT start, not achieving pCR was associated with increased risk of death and progression. Conclusion: pCR status may be a reliable prognostic indicator for survival in these eBC subtypes in the real-world setting.

This study examined the real-world use of nivolumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). This was a multinational retrospective study (VOLUME) assessing treatment effectiveness and safety outcomes and a prospective study (VOLUME-PRO) assessing HRQoL and patient-reported symptoms. There were 447 and 51 patients in VOLUME and VOLUME-PRO, respectively. Across both studies, the median age was 64.0 years, 80.9% were male, and 52.6% were former smokers. Clinical outcomes of interest included real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). The median rwOS was 9.2 months. Among patients with at least one assessment, 21.7% reported their best response as ‘partial response’, with 3.9% reporting ‘complete response’. The median duration of response (DoR) and median rwPFS were 11.0 months and 3.9 months, respectively. At baseline, VOLUME-PRO patients reported difficulties relating to fatigue, physical and sexual functioning, dyspnea, nausea, sticky saliva, dry mouth, pain/discomfort, mobility, and financial difficulties. There were improvements in social functioning and financial difficulties throughout the study; however, no other clinically meaningful changes were noted. No new safety concerns were identified. This real-world, multinational, multicenter, retrospective and prospective study supports the effectiveness and safety of nivolumab for R/M SCCHN patients.

Absorption, distribution, metabolism, and excretion (ADME) are the key biologic processes for determination of a drug's pharmacokinetic parameters, which have direct impacts on efficacy and adverse drug reactions (ADRs). The chemical structures, dosage forms, and sites and routes of administration are the principal determinants of ADME profiles and consequent impacts on their efficacy and ADRs. Newly developed large molecule biologic antisense oligonucleotide (ASO) drugs have completely unique ADME that is not fully defined. ASO-based drugs are single-stranded synthetic antisense nucleic acids with diverse modes of drug actions from induction of mRNA degradation, exon skipping and restoration, and interactions with proteins. ASO drugs have a great potential to treat certain human diseases that have remained untreatable with small molecule-based drugs. The ADME of ASO drugs contributes to their unique set of ADRs and toxicity. In this review, to better understand their ADME, the 10 US Food and Drug Administration (FDA)-approved ASO drugs were selected: fomivirsen, pegaptanib, mipomersen, nusinersen, inotersen, defibrotide, eteplirsen, golodirsen, viltolarsen, and casimersen. A meta-analysis was conducted on their formulation, dosage, sites of administration, local and systematic distribution, metabolism, degradation, and excretion. Membrane permeabilization through endocytosis and nucleolytic degradation by endonucleases and exonucleases are major ADME features of the ASO drugs that differ from small-molecule drugs. The information summarized here provides comprehensive ADME characteristics of FDA-approved ASO drugs, leading to a better understanding of their therapeutic efficacy and their potential ADRs and toxicity. Numerous knowledge gaps, particularly on cellular uptake and subcellular trafficking and distribution, are identified, and future perspectives and directions are discussed. SIGNIFICANCE STATEMENT: Through a systematic analysis of the existing information of absorption, distribution, metabolism, and excretion (ADME) parameters for 10 US Food and Drug Administration (FDA)-approved antisense oligonucleotide (ASO) drugs, this review provides an overall view of the unique ADME characteristics of ASO drugs, which are distinct from small chemical drug ADME. This knowledge is useful for discovery and development of new ASO drugs as well as clinical use of current FDA-approved ASO drugs.

Background: BC remains the most commonly diagnosed cancer for women. TNBC is an aggressive form with a poorer prognosis compared with other subtypes. Neoadjuvant therapy (NAT) is the standard-of-care approach to shrink tumors in the breast and axilla and to improve patient outcomes. Few RW studies exist of US patients with early BC (eBC); this study aimed to describe clinical parameters by receipt of systemic therapy and to assess overall survival (OS) and progression-free survival (PFS) after NAT and adjuvant therapy (AT) in women with early HR+/HER2− or TNBC using RW evidence in the US. Methods: This retrospective observational study used the Flatiron Health nationwide electronic health record-derived de-identified database, including women ([pts], age ≥18 years) diagnosed with early HR+/HER2− BC or TNBC between 01/01/2011 and 05/31/2018. The primary outcome was to describe pt demographics, clinical characteristics, and treatment patterns. Secondary outcomes included OS and PFS. Results: Of the pts identified for inclusion (N = 5,299), 13.3% (n = 707) were diagnosed with early TNBC and 86.7% (n = 4,592) with HR+/HER2− eBC, of whom 34.7% (n = 245) and 10.9% (n = 502), respectively, did not receive systemic therapy (Table). Systemically treated pts with TNBC vs HR+/HER2− tended to be younger (59.0 years vs 64.0 years); were represented by a higher proportion of Black women (18.0% vs 7.2%); had a greater proportion presenting with invasive ductal carcinoma (IDC) (91.6% vs 78.2%); had a higher proportion with progression to metastasis (19.0% vs 5.7%) and presented with a more aggressive disease (Grade 3) at diagnosis (79.0% vs 18.4%). Most pts (98.4%) received surgery, predominantly breast-conserving surgery (BCS; unilateral lumpectomy: 62.8%); however, 17.8% received bilateral mastectomies. Overall, 9.1% of pts received NAT. More pts with TNBC vs HR+/HER2− received NAT (34.0% vs 7.9%) and achieved a pathologic complete response (pCR; 36.3% vs 6.2%). Consistent with treatment guidelines, pts with TNBC were treated with chemotherapy (CT)-doublet or single-agent regimens and pts with HR+/HER2− received hormone and CT-based regimens. Duration of NAT was similar for both subtypes (3.3 months) but was shorter for AT in pts with TNBC vs HR+/HER2− (3.4 vs 38.2 months). From initial diagnosis, the 36-month survival probability [standard error] was lower for systemically treated pts with TNBC vs HR+/HER2− (85.7% [1.8%] vs 95.6% [0.3%]) and from start of therapy by line setting (NAT: 80.6% [3.5%] vs 91.9% [1.7%]; AT: 84.7% [2.2%] vs 95.8% [0.4%]). Similarly, the 36-month PFS probability was lower for pts with TNBC vs HR+/HER2− from diagnosis (77.9% [2.1%] vs 93.3% [0.4%]) and from start of therapy by line setting (NAT: 68.7% [4.1%] vs 85.2% [2.1%]; AT: 79.5% [2.5%] vs 93.5% [0.4%]). Conclusion: This analysis of US RWE further confirms early TNBC to be a particularly aggressive form of BC, with poorer survival compared with pts with HR+/HER2− eBC. While these RW data indicate BCS is becoming more routine, almost one-fifth of pts still receive bilateral mastectomies. Overall, these data confirm there remains a high unmet need to reduce the need for aggressive treatments while further improving outcomes in pts with early TNBC and HR+/HER2− BC. Table: Patient demographics, clinical characteristics, OS and PFSPatient selection criteriaNumber of patients, n (%)SubgroupsEarly HR+/HER2− BC4,592 (86.7)Patients who received systemic therapy4,090 (89.1)Early TNBC707 (13.3)Patients who received systemic therapy462 (65.3)All patients [1] (N = 5,299), n (%)Systemically treated patients with early HR+/HER2− BC (n = 4,090), n (%)Systemically treated patients with early TNBC (n = 462), n (%)Patient demographicsMedian age (years)64.064.059.0RaceBlack or African American449 (8.5)294 (7.2)83 (18.0)White3,602 (68.0)2,835 (69.3)283 (61.3)Asian139 (2.6)111 (2.7)9 (1.9)Hispanic or Latino15 (0.3)12 (0.3)1 (0.2)Clinical characteristicsHistology at initial diagnosisIDC4,222 (79.7)3,197 (78.2)423 (91.6)ILC684 (12.9)612 (15.0)7 (1.5)Infiltrating ductal mixed and infiltrating lobular mixed132 (2.5)108 (2.6)3 (0.6)Mucinous adenocarcinoma97 (1.8)88 (2.2)0 (0.0)Other [2]122 (2.3)63 (1.5)26 (5.6)Unknown/ND42 (0.8)22 (0.5)3 (0.6)Tumor grade at initial diagnosisGrade 11,350 (25.5)1,161 (28.4)5 (1.1)Grade 22,462 (46.5)2,098 (51.3)88 (19.0)Grade 31,374 (25.9)752 (18.4)365 (79.0)Unknown/ND113 (2.1)79 (1.9)4 (0.9)Surgery at initial diagnosisYes5,215 (98.4)4,032 (98.6)450 (97.4)Surgery type [3]Unilateral lumpectomy3,277 (62.8)2,568 (63.7)241 (53.6)Unilateral mastectomy1,168 (22.4)883 (21.9)128 (28.4)Bilateral lumpectomy75 (1.4)61 (1.5)5 (1.1)Bilateral mastectomy927 (17.8)713 (17.7)89 (19.8)Treatment line settingNumber of patients who received NAT481 (9.1)324 (7.9)157 (34.0)Number of patients who received AT4,263 (80.4)3,949 (96.6)314 (68.0)pCR to NATAchieved pCR77 (16.0)20 (6.2)57 (36.3)OSFrom initial diagnosis: survival probability at Month 36, % (SE)94.0 (0.4)95.6 (0.3)85.7 (1.8)From NAT: survival probability at Month 36, % (SE)88.3 (1.6)91.9 (1.7)80.6 (3.5)From AT: survival probability at Month 36, % (SE)94.9 (0.4)95.8 (0.4)84.7 (2.2)PFSFrom initial diagnosis: progression-free probability at Month 36, % (SE)91.3 (0.4)93.3 (0.4)77.9 (2.1)From NAT: progression-free probability at Month 36, % (SE)79.9 (2.0)85.2 (2.1)68.7 (4.1)From AT: progression-free probability at Month 36, % (SE)92.5 (0.4)93.5 (0.4)79.5 (2.5)Duration of treatment, Months (n)Median duration of NAT3.3 (481)3.3 (324)3.3 (157)Median duration of AT35.3 (4263)38.2 (3,949)3.4 (314)[1] All patients includes both patients systemically treated and systemically untreated. [2] Other includes Inflammatory, Papillary, Metaplastic, Medullary and Tubular histologies. [3] Patient may have received more than one surgery. AT, adjuvant therapy; IDC, invasive ductal carcinoma; NAT, neoadjuvant therapy; ND, not documented; SE, standard error. Citation Format: Anagha Gogate, Amanda Crosbie, Trong Kim Le, Ying Zhang, Rolee Das, Catherine Davis. Clinical characteristics, treatment patterns, and survival outcomes in women with early triple-negative (TN) or hormone receptor-positive/human epidermal growth factor receptor-2 negative (HR+/HER2−) breast cancer (BC) in the real-world (RW) setting [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 P3-12-15.

Background OS, the “gold standard” endpoint in oncology studies, is challenging to measure in earlier stages of BC because of considerably long survival. Further, during extended patient follow-up, treatment effect on OS can become impacted by multiple factors such as non-malignant causes of death, treatment cross-over, and post-progression treatments, making it difficult to isolate the true treatment effect. As an alternative, surrogate endpoints (SE) such as DFS, EFS, and pCR can be used to ascertain meaningful benefit in true endpoint (TE). While studies have previously explored the association of such SEs with OS in different BC populations, there is a dearth in literature of studies reporting on correlation in the NAdj/Adj settings in the HR+/HER2- BC population. The aim of this study is to conduct a correlation analysis between various SE-TE pairs (DFS/EFS vs OS, pCR vs OS and pCR vs DFS/EFS) in this population, from data reported in studies identified from a systematic literature review (SLR). For each pair of endpoints, both absolute and relative treatment effects were evaluated. Methods An SLR was conducted in NAdj/Adj setting for HR+/HER2- BC to identify studies that reported any two of pCR, DFS/EFS and OS. The search was carried out using MEDLINE, Embase, Cochrane Library databases (2000 onward), four BC-related conference proceedings (2018-2020) and clinical trial registries. Relative treatment effect sizes were quantified in terms of HRs for DFS/EFS and OS, and odds ratios (ORs) for pCR. Absolute treatment effects were analyzed in terms of survival probability of EFS/DFS and OS at landmark time points and pCR rates. A weighted least squares regression analysis was carried out to determine the strength of association between the various TE-SE pairs. The regression analysis was carried out on log scale for relative treatment effects and on linear scale for absolute treatment effects. Pearson correlation coefficient (r) was used to quantify the strength of association; coefficient of determination (R2) was also reported to evaluate goodness-of-fit. Sensitivity analyses were performed by considering linear scale (for relative outcomes only), using inverse of variance as weights, and by removing outliers. Results A total of 135 publications were identified in the SLR. Regression analysis showed that there is a statistically significant positive association (r= 0.91; 95%CI, 0.83-0.96, p Correlation analysis for HR(DFS/EFS) vs. HR(OS) and OR(pCR) vs. HR(DFS/EFS)Model# studies# observationsPearson coefficient, r (95% CI)p-valueCoefficient of determination, R2 (95% CI)Slope (95% CI)P-valueHRDFS/EFS vs. HROS24320.91 (0.83-0.96) Citation Format: Anagha Gogate, Inkyu Kim, Sandip Ranjan, Amit Kumar, Eros Papademetriou, Hitesh Bhandari, Ravi Potluri. Correlation between pathologic complete response (pCR), event-free survival (EFS)/disease-free survival (DFS) and overall survival (OS) in neoadjuvant and/or adjuvant (NAdj/Adj) hormone receptor positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer (BC) [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 P2-12-09.

PURPOSE Treatments for endocrine-refractory or triple-negative metastatic breast cancer (mBC) are modestly effective at prolonging life and improving quality of life but can be extremely expensive. Given these tradeoffs in quality of life and cost, the optimal choice of treatment sequencing is unclear. Cost-effectiveness analysis can explicitly quantify such tradeoffs, enabling more informed decision making. Our objective was to estimate the societal cost-effectiveness of different therapeutic alternatives in the first- to third-line sequences of single-agent chemotherapy regimens among patients with endocrine-refractory or triple-negative mBC. METHODS Using three dynamic microsimulation models of 10,000 patients each, three cohorts were simulated, based upon prior chemotherapy exposure: (1) unexposed to either taxane or anthracycline, (2) taxane- and anthracycline-exposed, and (3) taxane-exposed/anthracycline-naive. We focused on the following single-agent chemotherapy regimens as reasonable and commonly used options in the first three lines of therapy for each cohort, based upon feedback from oncologists treating endocrine-refractory or triple-negative mBC: (1) for taxane- and anthracycline-unexposed patients, paclitaxel, capecitabine (CAPE), or pegylated liposomal doxorubicin; (2) for taxane- and anthracycline-exposed patients, Eribulin, CAPE, or carboplatin; and (3) for taxane-exposed/anthracycline-naive patients, pegylated liposomal doxorubicin, CAPE, or Eribulin. RESULTS In each cohort, accumulated quality-adjusted life-years were similar between regimens, but total societal costs varied considerably. Sequences beginning first-line treatment with paclitaxel, carboplatin, and CAPE, respectively, for cohorts 1, 2, and 3, had lower costs and similar or slightly better outcomes compared with alternative options. CONCLUSION In this setting where multiple single-agent chemotherapy options are recommended by clinical guidelines and share similar survival and adverse event trajectories, treatment sequencing approaches that minimize costs early may improve the value of care.

Aim: Investigate real-world outcomes and healthcare utilization of patients with glioblastoma multiforme (GBM) related to O6-methylguanine DNA methyltransferase (MGMT) promoter testing and methylation. Patients & methods: US Oncology Network data were analyzed for patients receiving first-line (1L) treatment for GBM. Results: Most patients received 1L radiation with temozolomide. Unadjusted median overall survival (OS) was higher in tested versus untested (median:18.1 vs 11.8 months) and in methylated versus unmethylated (median: 25.5 vs 12.4 months). Untested status, unmethylated MGMT and older age were associated with reduced OS and longer 1L treatment with increased OS. Similar findings were observed for progression-free survival. Utilization was similar between cohorts. Conclusion: In community oncology practices, MGMT methylation and testing were predictive of better survival in GBM., Lay abstract We studied the characteristics and survival of patients with newly diagnosed glioblastoma multiforme (GBM) in community-based oncology practices. These patients had received temozolomide and radiotherapy with surgery, which is the standard of care for GBM. We were interested in how patient survival was related to methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter. The study showed that patients with methylated versus unmethylated MGMT GBM survived longer. However, patients who were tested for methylation, whether MGMT was methylated or not, also survived longer. This may be because patients who get tested also get better care in general., Graphical abstract Kaplan–Meier analysis showed that patients with methylated MGMT GBM had better overall survival compared with unmethylated MGMT (median: 25.5 vs 12.4 months). However, so did patients who were tested for MGMT methylation compared with those untested for MGMT methylation (median: 18.1 vs 11.8 months).

Background This study projected the number of metastatic breast cancer (mBC) cases and costs (medical and productivity) attributable to mBC through 2030 among 3 age groups: younger (aged 18-44 years), midlife (aged 45-64 years), and older women (aged 65 years and older). Methods We developed a stock/flow model in which women enter the mBC population at initial diagnosis (de novo stage IV) or through progression of an earlier-stage cancer. Women exit the mBC population through death. Input parameters by age and phase of treatment came from the US Census, Surveillance, Epidemiology, and End Results and peer-reviewed literature. Results In 2030, we estimated there would be 246 194 prevalent cases of mBC, an increase of 54.8% from the 2015 estimate of 158 997. We estimated total costs (medical and productivity) of mBC across all age groups and phases of care were $63.4 billion (95% sensitivity range = $59.4-$67.4 billion) in 2015 and would increase to $152.4 billion (95% sensitivity range = $111.6-$220.4 billion) in 2030, an increase of 140%. Trends in estimated costs were higher for younger and midlife women than for older women. Conclusions The cost of mBC could increase substantially in the coming decade, especially among younger and midlife women. Although accounting for trends in incidence, progression, and survival, our model did not attempt to forecast structural changes such as technological innovations in breast cancer treatment and health-care delivery reforms. These findings can motivate early detection activities, direct value-driven mBC treatment, and provide a useful baseline against which to measure the effect of prevention and treatment efforts.

The goal of this systematic review is to provide an update to the review by Pouwels et al. by conducting a systematic review and an assessment of the reporting quality of the economic analyses conducted since 2014. This systematic review identified published articles focused on metastatic breast cancer treatment using the Medline/PubMed and Scopus databases and the following search criteria: (((cost effectiveness[MeSH Terms]) OR (cost effectiveness) OR (cost-effectiveness) OR (cost utility) OR (cost–utility) OR (economic evaluation)) AND ((“metastatic breast cancer”) OR (“advanced breast cancer”))). The reporting quality of the included articles was evaluated using the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Of the 256 identified articles, 67 of the articles were published after October 2014 when the prior systematic review stopped its assessment (Pouwels et al. in Breast Cancer Res Treat 165:485–498, 2017). From the 67 articles, we narrowed down to include 17 original health economic analyses specific to metastatic or advanced breast cancer. These articles were diverse with respect to methods employed and interventions included. Although each of the articles contributed their own analytic strengths and limitations, the overall quality of the studies was moderate. The review demonstrated that the vast majority of the reported incremental cost-effectiveness ratios exceeded the typically employed willingness to pay thresholds used in each country of analysis. Only three of the reviewed articles studied chemotherapies rather than treatments targeting either HER2 or hormone receptors, demonstrating a gap in the literature.

BACKGROUND: This study estimated average medical costs due to metastatic breast cancer (mBC) in three different life stages -- younger (aged 18-44), midlife (aged 45-64), and older women (aged 65 and older)—and by phase of care: initial, continuing, and terminal. METHODS: We used 2003-2014 North Carolina cancer registry data linked with administrative claims from public and private payers. In addition to women with mBC at diagnosis, we developed a claims-based algorithm to identify breast cancer patients who progressed to metastatic disease. We matched breast cancer patients (mBC and earlier stage) to non-cancer patients on age group, county of residence, and insurance plan. Outcomes were average monthly medical expenditures and expected medical expenditures by phase. We used generalized estimating equation regression models to estimate excess costs attributed to mBC as the difference in mean payments between patients with mBC and patients with each earlier stage breast cancer (stage 1, stage 2, stage 3 and unknown stage) and non-cancer controls by treatment phase and age group. Regressions adjusted for age, insurance, months enrolled, Klabunde Comorbidity Index and year. RESULTS: We analyzed 4,805 women with mBC, 21,772 women with earlier stage breast cancer, and 109,631 matched non-cancer controls. Adjusted monthly costs for women with mBC were significantly higher than for women with earlier stage breast cancer and non-cancer controls for all age groups and treatment phases except the initial treatment among women with stage 3 breast cancer at diagnosis. Across all age groups, cancer stages and treatment phases, the largest expected total costs were for women aged 18-44 with mBC during the continuing phase ($209,961 95% Confidence Interval $165,736 – 254,186). CONCLUSIONS: We found substantial excess costs for mBC among younger women and during the continuing and terminal phases of survivorship. It is important to ensure this care is high value for these women.

Objectives Neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) for advanced epithelial ovarian cancer (AEOC) remains controversial in the United States. Generalizability of existing trial results has been criticized because of less aggressive debulking procedures than commonly used in the United States. As a result, economic evaluations using input data from these trials may not accurately reflect costs and outcomes associated with more aggressive primary surgery. Using data from an ongoing trial performing aggressive debulking, we investigated the cost-effectiveness and cost-utility of NACT versus PDS for AEOC. Methods A decision tree model was constructed to estimate differences in short-term outcomes and costs for a hypothetical cohort of 15,000 AEOC patients (US annual incidence of AEOC) treated with NACT versus PDS over a 1-year time horizon from a Medicare payer perspective. Outcomes included costs per cancer-related death averted, life-years and quality-adjusted life-years (QALYs) gained. Base-case probabilities, costs, and utilities were based on the Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasms trial. Base-case analyses assumed equivalent survival; threshold analysis estimated the maximum survival difference that would result in NACT being cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds. Probabilistic sensitivity analysis was used to characterize model uncertainty. Results Compared with PDS, NACT was associated with $142 million in cost savings, 1098 fewer cancer-related deaths, and 1355 life-years and 1715 QALYs gained, making it the dominant treatment strategy for all outcomes. In sensitivity analysis, NACT remained dominant in 99.3% of simulations. Neoadjuvant chemotherapy remained cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds if survival differences were less than 2.7 and 1.4 months, respectively. Conclusions In the short term, NACT is cost-saving with improved outcomes. However, if PDS provides a longer-term survival advantage, it may be cost-effective. Research is needed on the role of patient preferences in tradeoffs between survival and quality of life.