Real-world treatment patterns of adjuvant endocrine therapy and ovarian suppression in premenopausal HR+/HER2+ breast cancer.

BACKGROUND: The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real-world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC. METHODS: This retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti-HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use. RESULTS: Out of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients <35 years were more likely to receive OS compared with those ≥35 years (odds ratio 2.33, p < 0.001). CONCLUSIONS: This is the first real-world study evaluating ET treatment patterns in HR+/HER2+ premenopausal BC. OS use was uncommon and the majority received tamoxifen as the preferred ET regardless of most clinicopathologic risk factors. Additional research is needed to optimize ET decisions in young women with this distinct BC subtype.

The survival benefit of adjuvant trastuzumab with or without chemotherapy in the management of small (T1mic, T1a, T1b, T1c), node negative HER2+ breast cancer.

There is limited data regarding the added benefit of adjuvant systemic therapy in the management of small, node-negative, HER2+ breast cancer. In a multi-institutional retrospective analysis using the American Society of Clinical Oncology CancerLinQ database, we compared survival outcomes among T1a-c N0 HER2+ patients diagnosed between 2010 to 2021 who received locoregional therapy alone or in combination with adjuvant trastuzumab (+/- chemotherapy). Primary outcomes were invasive disease-free survival (iDFS) and overall survival (OS). Of the 1,184 patients, 436 received locoregional therapy alone. We found a statistically significant improvement in iDFS (HR 0.73, P = 0.003) and OS (HR 0.63, P = 0.023) on univariate analysis with adjuvant trastuzumab with or without chemotherapy which remained statistically significant on multivariate analysis. Three-arm univariate analysis found that iDFS was significantly improved with trastuzumab monotherapy (P = 0.003) and combination therapy (P = 0.027) compared to observation. Subgroup data suggests that T1b/c tumors derive the greatest benefit.

An Open-Label Study of Subcutaneous CpG Oligodeoxynucleotide (PF03512676) in Combination with Trastuzumab in Patients with Metastatic HER2+ Breast Cancer.

OBJECTIVES: CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in utilizing CpG ODN as an adjuvant to improve clinical efficacy of current treatments and immunogenicity of breast cancers not traditionally responsive to active immunotherapy, such as those that are human epidermal growth factor receptor 2 (HER2)-positive. This study aimed to study the efficacy and safety of combination CpG ODN plus anti-HER2 antibody trastuzumab treatment in patients with advanced/metastatic breast cancer. METHODS: This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response. RESULTS: Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment. CONCLUSIONS: CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored.

Why was the study done? Breast cancer that has metastasized (moved outside of the breast and local lymph nodes) is currently considered incurable and can be difficult to treat. Treatments that can stimulate the immune system to recognize cancer cells have been found to be useful for many types of cancers, including some types of breast cancers. This study tested a new immune stimulator (CpG ODN) in combination with a currently on-the-market antibody treatment for breast cancer (trastuzumab). What did the researchers do? The research team enrolled patients who had metastatic breast cancer and treated them all with a combination of trastuzumab and CpG ODN for 12 weeks. These patients were monitored for any side effects/toxicity, monitored for how long their breast cancer responded to this treatment, and monitored for how long they lived after beginning this treatment. Patients also had their blood drawn at different time points to observe how their immune cells and immune proteins (e.g. cytokines) changed on treatment. What did the researchers find? The research team enrolled six patients and found that the treatment was safe and that 50% of the patients treated did not have any breast cancer growth when given CpG ODN plus trastuzumab. Looking at the immune cells in the patient blood samples, some cells that are known to decrease the immune response to cancers (myeloid-derived suppressor cells) did increase towards the end of treatment. What do the findings mean? Overall, CpG ODN and trastuzumab treatment was found to be safe and potentially effective in preventing breast cancer growth.

Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study.

BACKGROUND: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein. METHODS: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032. FINDINGS: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event. INTERPRETATION: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile. FUNDING: Pfizer and Celcuity.

Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase.

Myeloid-derived suppressor cell (MDSC) levels are elevated in patients with cancer and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton's tyrosine kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the antitumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of fluorescence-activated cell sorting-enriched MDSC from patients with different cancer types [breast, melanoma, head and neck squamous cell cancer (HNSCC)]. Melanoma patient MDSC were treated in vitro for 4 hours with 5 µmol/L ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10× Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from patients with breast, melanoma, and HNSCC cancer revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from patients with melanoma resulted in significant changes in gene expression. GBP1, IL-1ß, and CXCL8 were among the top downregulated genes whereas RGS2 and ABHD5 were among the top upregulated genes (P < 0.001). Double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes compared with early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL-6 signaling (P < 0.004). IMPLICATIONS: scRNA-seq revealed characteristic gene expression patterns for MDSC from different patients with cancer and BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration.

PRT543, a protein arginine methyltransferase 5 inhibitor, in patients with advanced adenoid cystic carcinoma: An open-label, phase I dose-expansion study.

OBJECTIVES: Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC. MATERIALS AND METHODS: This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1-5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy. RESULTS: Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8-8.3). The clinical benefit rate was 57% (95% CI: 43-70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease. CONCLUSION: In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC.

Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer.

Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

Phase 1b study of HSP90 inhibitor called onalespib in combination with paclitaxel in patients with advanced triple-negative breast cancer This Phase 1b study demonstrated that treatment with a combination of onalespib and paclitaxel was reasonably well tolerated by most patients. Onalespib at 260 mg/m² given intravenously on days 1, 8 and 15 on 28-day cycles in combination with standard dose and schedule of paclitaxel was established as the recommended phase 2 dose for further clinical development. Despite minor drug-drug interactions between these 2 agents, onalespib did not alter paclitaxel exposure and paclitaxel did not affect exposure to onalespib. While onalespib with paclitaxel combination therapy did not yield durable objective responses or prolonged progression-free survival, there were several patients with long-lasting benefit from this combination including patients who previously experienced progression on taxane therapy.

Retrospective cohort study of CDK4/6-inhibitor-induced alopecia in breast cancer patients.

PURPOSE: Dermatologic adverse events commonly result in the interruption of oncologic treatment, and targeted therapies are the most frequently interrupted class of anticancer agents. Alopecia is a common cutaneous adverse event reported with CK4/6i therapy. Though the clinical characteristics and therapeutic response of EIA have been well documented, few studies have characterized alopecia in patients treated with CDK4/6i. METHODS: This study analyzed a retrospective cohort of 28 breast cancer patients diagnosed with endocrine-induced alopecia (EIA) or CDKiA. Comparative analysis of the clinical characteristics of alopecia and therapeutic response to minoxidil was conducted. Therapeutic response to minoxidil (LDOM or topical [5%] solution or foam) was assessed by both Dean Scale and qualitative clinical improvement by comparison of pretreatment and posttreatment clinical images by single-blinded, board-certified academic dermatologists (ST and BD). RESULTS: CDKiA was clinically similar to androgenetic alopecia and specific vertex involvement was more common in patients treated with CDK4/6i + ET than endocrine monotherapy (n = 7 [70.0%] vs n = 4 [36.4%]; p = 0.04), respectively. After 4-6 months of minoxidil, there was a moderate to significant qualitative alopecia improvement in 80% of CDKiA patients versus 94.4% of EIA patients. Additionally, superior improvement of mean Dean Score grade was observed in EIA (with change from pre- to posttreatment - 0.44; p = 0.0002). CONCLUSION: Compared to endocrine monotherapy, patients on combination CDK4/6i + ET had greater extent of vertex involvement and were more recalcitrant to minoxidil. The preferential vertex involvement observed in CDKiA suggests that combination therapy with minoxidil and topical antiandrogens with poor systemic absorption should be studied in this setting.

First-in-human phase I/Ib study of NIZ985, a recombinant heterodimer of IL-15 and IL-15Rα, as a single agent and in combination with spartalizumab in patients with advanced and metastatic solid tumors.

BACKGROUND: Preclinically, interleukin-15 (IL-15) monotherapy promotes antitumor immune responses, which are enhanced when IL-15 is used in combination with immune checkpoint inhibitors (ICIs). This first-in-human study investigated NIZ985, a recombinant heterodimer comprising physiologically active IL-15 and IL-15 receptor α, as monotherapy and in combination with spartalizumab, an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody, in patients with advanced solid tumors. METHODS: This phase I/Ib study had two dose-escalation arms: single-agent NIZ985 administered subcutaneously thrice weekly (TIW, 2 weeks on/2 weeks off) or once weekly (QW, 3 weeks on/1 week off), and NIZ985 TIW or QW administered subcutaneously plus spartalizumab (400 mg intravenously every 4 weeks (Q4W)). The dose-expansion phase investigated NIZ985 1 µg/kg TIW/spartalizumab 400 mg Q4W in patients with anti-PD-1-sensitive or anti-PD-1-resistant tumor types stratified according to approved indications. The primary objectives were the safety, tolerability, and the maximum tolerated doses (MTDs) and/or recommended dose for expansion (RDE) of NIZ985 for the dose-expansion phase. RESULTS: As of February 17, 2020, 83 patients (median age: 63 years; range: 28-85) were treated in dose escalation (N=47; single-agent NIZ985: n=27; NIZ985/spartalizumab n=20) and dose expansion (N=36). No dose-limiting toxicities occurred nor was the MTD identified. The most common treatment-related adverse event (TRAE) was injection site reaction (primarily grades 1-2; single-agent NIZ985: 85% (23/27)); NIZ985/spartalizumab: 89% [50/56]). The most common grade 3-4 TRAE was decreased lymphocyte count (single-agent NIZ985: 7% [2/27]; NIZ985/spartalizumab: 5% [3/56]). The best overall response was stable disease in the single-agent arm (30% (8/27)) and partial response in the NIZ985/spartalizumab arm (5% [3/56]; melanoma, pancreatic cancer, gastric cancer). In dose expansion, the disease control rate was 45% (5/11) in the anti-PD-1-sensitive and 20% (5/25) in the anti-PD-1-resistant tumor type cohorts. Pharmacokinetic parameters were similar across arms. The transient increase in CD8+ T cell and natural killer cell proliferation and induction of several cytokines occurred in response to the single-agent and combination treatments. CONCLUSIONS: NIZ985 was well tolerated in the single-agent and NIZ985/spartalizumab regimens. The RDE was established at 1 µg/kg TIW. Antitumor activity of the combination was observed against tumor types known to have a poor response to ICIs. TRIAL REGISTRATION NUMBER: NCT02452268.

Survival outcomes seen with neoadjuvant chemotherapy in the management of locally advanced inflammatory breast cancer (IBC) versus matched controls.

Inflammatory breast cancer (IBC) poses an ongoing challenge as rates of disease recurrence and mortality remain high compared to stage-matched controls. However, frontline therapy has evolved through the years, including the widespread use of neoadjuvant chemotherapy (NAC) given the prognostic importance of pathologic complete response (pCR). Due to these sweeping changes, we need new data to assess current recurrence and survival outcomes for locally advanced IBC in the context of matched non-inflammatory controls. We conducted a retrospective analysis of institutional IBC data from 2010 to 2016 with the primary objective of comparing overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS). We matched IBC patients to non-inflammatory controls based on age, receptor status, tumor grade, clinical stage, and receipt of prior NAC. Secondary objectives included assessing pCR rates and identifying prognostic factors. Among NAC recipients, we observed similar pCR rates (47.6 % vs. 49.4 %, p = 0.88) between IBC (n = 84) and matched non-IBC (n = 81) cohorts. However, we noted a significant worsening of OS (p = 0.0001), RFS (p = 0.0001), and DRFS (p = 0.001) in the IBC group. Specifically, 5-year OS in the IBC cohort was 58.9 % vs. 86.7 % for matched controls (p = 0.0003). Older age was a weak negative predictor for OS (HR 1.03, p = 0.001) and RFS (HR 1.02, p = 0.01). For DRFS, older age was also a weak negative predictor (HR 1.02, p = 0.02), whereas the use of NAC was a positive predictor (HR 0.47, p = 0.02). Despite no clear difference in pCR, survival outcomes remain poor for IBC compared to matched non-inflammatory controls.

Depression, Inflammation, and Intestinal Permeability: Associations with Subjective and Objective Cognitive Functioning throughout Breast Cancer Survivorship.

About one-in-three breast cancer survivors have lingering cognitive complaints and objective cognitive impairment. Chronic inflammation and intestinal permeability (i.e., leaky gut), two risk factors for cognitive decline, can also fuel depression-another vulnerability for cognitive decline. The current study tested whether depression accompanied by high levels of inflammation or intestinal permeability predicted lower subjective and objective cognitive function in breast cancer survivors. We combined data from four breast cancer survivor studies (n = 613); some had repeated measurements for a total of 1015 study visits. All participants had a blood draw to obtain baseline measures of lipopolysaccharide binding protein-a measure of intestinal permeability, as well as three inflammatory markers that were incorporated into an inflammatory index: C-reactive protein, interleukin-6, and tumor necrosis factor-α. They reported depressive symptoms on the Center for Epidemiological Studies depression scale (CES-D), and a binary variable indicated clinically significant depressive symptoms (CES-D ≥ 16). The Kohli (749 observations) and the Breast Cancer Prevention Trial (591 observations) scales assessed subjective cognitive function. Objective cognitive function tests included the trail-making test, Hopkins verbal learning test, Conners continuous performance test, n-back test, FAS test, and animal-naming test (239-246 observations). Adjusting for education, age, BMI, cancer treatment type, time since treatment, study visit, and fatigue, women who had clinically elevated depressive symptoms accompanied by heightened inflammation or intestinal permeability reported poorer focus and marginally poorer memory. However, poorer performance across objective cognitive measures was not specific to inflammation-associated depression. Rather, there was some evidence of lower verbal fluency; poorer attention, verbal learning and memory, and working memory; and difficulties with visuospatial search among depressed survivors, regardless of inflammation. By themselves, inflammation and intestinal permeability less consistently predicted subjective or objective cognitive function. Breast cancer survivors with clinically significant depressive symptoms accompanied by either elevated inflammation or intestinal permeability may perceive greater cognitive difficulty, even though depression-related objective cognitive deficits may not be specific to inflammation- or leaky-gut-associated depression.

Inflamed but not impulsive: Acute inflammatory cytokine response does not impact prepotent response inhibition.

BACKGROUND: Prior evidence has linked inflammation with impulsivity, but most of this evidence is cross-sectional. In this study, we provoked an acute inflammatory cytokine response to see whether it lowered prepotent response inhibition on three cognitive tasks. METHOD: This study features secondary analyses from a randomized crossover trial in which 171 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence at two separate visits at least one month apart. Participants completed the Stroop Color-Discrepant Task, the 2-back, and the Conners Continuous Performance Test (CPT) on the computer between 5 and 7 h after the injections. They had their blood drawn once before and repeatedly after the injection to measure interleukin-1 receptor antagonist and interleukin-6 responses. RESULTS: Women committed marginally fewer errors on the Stroop color-discrepant trials after the typhoid vaccine (M = 0.36, SE = 0.08), compared to placebo (M = 0.54, SE = 0.09, p = .076). Injection type did not predict 2-back accuracy (p = .80) or CPT commission errors (p = .47). Inflammatory cytokine responses were also unrelated to the outcomes of interest (ps>.16). CONCLUSION: We found no evidence that an acute inflammatory cytokine response provokes response disinhibition - an important facet of impulsivity. In fact, our only marginally non-significant result suggested that women were better able to inhibit their prepotent responses on the Stroop after receiving the typhoid vaccine, compared to placebo. Further experimental tests of the acute inflammatory cytokine response's effect on other aspects of impulsivity are warranted. LIMITATIONS: The sample was female, primarily White, highly educated cancer survivors, and recruitment was not premised on impulsive traits or diagnosis with an impulsive-related disorder. Also, there are many facets of impulsivity, and this study only measured response inhibition.

Missing Components of Receptor Status Among Women With Invasive Breast Cancer.

Importance: There are well-known differences in patient outcomes and effective therapeutic options across subtypes of breast cancer (BC), defined by the status of estrogen receptor, progesterone receptor, and erb-B2 receptor tyrosine kinase 2 (ERBB2 [formerly HER2]) expression, making testing for these receptors part of the routine workup for all patients with a diagnosis of invasive BC. Despite its importance, this information is missing in some BC cases. Objective: To identify female patients with BC without record of testing for estrogen receptor, progesterone receptor, or ERBB2 status, defined as missing components of receptor status (MCRS). Design, Setting, and Participants: This cross-sectional study used data from National Cancer Institute's Surveillance, Epidemiology and End Results Program of 18 population-based registries from women with a diagnosis of invasive BC (excluding death certificate-only and autopsy cases) from January 2012 to December 2016. The final analyses were completed in February 2022. Main Outcome and Measure: The primary outcome was MCRS. Those with MCRS were summarized by age, race, stage at diagnosis, reporting source, primary payer, and geography. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) for MCRS. Results: Overall, 321 913 patients with invasive BC were included (1928 [1%] American Indian or Alaska Native, 28 173 [9%] Asian or Pacific Islander, 36 357 [11%] Black, and 252 447 [78%] White individuals); of these, 15 250 (4.7%) had MCRS. The multivariable model showed that the odds of MCRS were higher in women 80 years or older compared with those younger than 49 years (aOR, 1.75; 95% CI, 1.65-1.88), Black compared with White women (aOR, 1.09; 95% CI, 1.00-1.16), and those with distant stage or unknown/unstaged cancer at diagnosis compared with a local stage at diagnosis (aOR, 3.33; 95% CI, 3.17-3.50; and aOR, 19.39; 95% CI, 18.15-20.72; respectively). With hospital inpatient/outpatient or clinic as the reference group, cases reported by laboratory only, nursing/convalescent home/hospice, and a physician's office were more likely to have MCRS (aOR, 1.42; 95% CI; 1.28-1.60; aOR, 9.37; 95% CI, 6.03-14.53; and aOR, 2.32; 95% CI, 2.06-2.62; respectively). Adjusted odds of MCRS were higher for the categories of insured/no specifics and insurance status unknown compared with those who were insured. The adjusted odds of MCRS were higher in rural compared with urban areas (aOR, 1.08; 95% CI, 1.03-1.15). Conclusions and Relevance: The results of this cross-sectional study of women with a diagnosis of invasive BC suggest that despite a standard of care recommended by all expert guidelines, there needs to be greater focus on hormone receptor and ERBB2 testing in all women with invasive BC. The results of this study may help clinicians, public health practitioners, and policymakers target affected populations to minimize or eliminate this critical health disparity and help save more lives.

Worry and Mindfulness Differentially Impact Symptom Burden Following Treatment Among Breast Cancer Survivors: Findings From a Randomized Crossover Trial.

BACKGROUND: Breast cancer survivors often experience many somatic and cognitive side effects resulting from their cancer diagnosis and treatment, including higher rates of pain, fatigue, and memory/concentration problems. Emotion regulation offers opportunities to either enhance or dampen physical health. PURPOSE: In a secondary analysis of a double-blind randomized controlled trial (RCT) using a typhoid vaccine to assess factors associated with breast cancer survivors' inflammatory responses, we assessed how two specific aspects of emotion regulation, mindfulness, and worry, corresponded to acute changes in focus problems, memory problems, and fatigue along with performance on pain sensitivity and cognitive tasks across two visits among breast cancer survivors. METHODS: Breast cancer survivors (N = 149) completed two 8.5-hr visits at a clinical research center. Survivors were randomized to either the vaccine/saline placebo or a placebo/vaccine sequence. Worry and mindfulness questionnaires provided data on trait-level emotion regulation abilities. Fatigue, memory problems, and focus difficulties were assessed via Likert scales six times-once before the injections and then every 90 min for 7.5 hr thereafter. Women also completed a pain sensitivity task and several cognitive tasks at each visit. RESULTS: Findings from this study showed that breast cancer survivors who worried more and were less mindful experienced subjective memory problems, focus problems, and cold pain sensitivity across two visits and irrespective of injection type. Lower mindfulness also corresponded to higher subjective fatigue and hot pain sensitivity and objective ratings. Emotion regulation skills did not predict objective pain sensitivity or cognitive problems. CONCLUSION: Results from this study highlight the benefits of adaptive emotion regulation in helping mitigate symptoms associated with breast cancer survivorship.

Breast cancer survivors experience side effects resulting from their cancer diagnosis and treatment, including higher rates of pain, fatigue, and memory/concentration problems. Emotion regulation offers the possibility to either better or worse physical health. This study assessed how two emotion regulation strategies, mindfulness and worry, corresponded to changes in focus problems, memory problems, and fatigue along with performance on pain sensitivity and cognitive tasks across two visits among breast cancer survivors. A total of 149 survivors completed 2 day-long visits in the laboratory where they rated their fatigue and memory problems six times across the day, completed cognitive tests, and a pain sensitivity test. Findings from this study showed that breast cancer survivors who worried more and were less mindful experienced subjective memory problems, focus problems, and cold pain sensitivity across two visits. Emotion regulation skills did not predict objective pain sensitivity or cognitive problems. Results from this study highlight the benefits of adaptive emotion regulation skills like mindfulness in helping improve the cognitive and physical symptoms commonly experienced by breast cancer survivorship.

The Immunomodulatory Effects of Dexamethasone on Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer.

INTRODUCTION: The immunomodulatory impact of corticosteroids and concurrent chemotherapy is poorly understood within triple-negative breast cancer (TNBC). On a biochemical level, steroids have been linked to the signaling of chemotherapy-resistant pathways. However, on a clinical level, steroids play an essential role in chemotherapy tolerance through the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions. Given these conflicting roles, we wanted to evaluate this interplay more rigorously in the context of early-stage TNBC. METHODS: We performed a retrospective analysis of patients with operable TNBC who received neoadjuvant chemotherapy (NAC) between January 2012 and November 2018, with the primary goal of examining the dose-dependent relationship between pathological complete response (pCR) rates and corticosteroid use. Secondary endpoints included the impact of steroid dosing on overall survival (OS) and recurrence-free survival (RFS), along with a breakdown in pCR rates based on steroid doses provided during each chemotherapy phase. Further adjusted analyses were performed based on patient age, diabetic status, and anatomical stage. Finally, we explored the relationship between tumor-infiltrating lymphocytes (TILs) seen on tissue samples at baseline and dexamethasone doses in terms of pCR rates. RESULTS: In total, of the 174 patients screened within this study period, 116 met full eligibility criteria. Of these eligible patients, all were female, with a median age of 51.5 years (27.0 to 74.0) and a mean body mass index (BMI) of 29.7 [standard deviation (SD) 7.04]. The majority were nondiabetic (80.2%). For cancer stage, 69.8% (n = 81) had stage 2 breast cancer. We found no statistically significant association between pCR rates and dexamethasone use, both in terms of the total dose (p = 0.55) and mean dose per NAC cycle (p = 0.74). Similarly, no difference was noted when adjusting for diabetic status, metformin use, or age at diagnosis, regardless of the total steroid dose provided (p = 0.72) or mean dose per cycle (p = 0.49). No meaningful changes to pCR rate were seen with higher mean or higher total steroid doses during the paclitaxel (T) phase (adjusted p = 0.16 and p = 0.76, respectively) or doxorubicin and cyclophosphamide (AC) phase (adjusted p = 0.83 and p = 0.77, respectively). Furthermore, we found no clinically significant association between dexamethasone dose and either RFS (p = 0.45) or OS (p = 0.89). Of the 56 patients who had available pre-treatment biopsy tissue samples, 27 achieved pCR, with higher TILs at baseline being associated with higher pCR rates, regardless of the mean dexamethasone dose used. CONCLUSION: Our findings demonstrate that dexamethasone has no clinically significant impact on pCR, RFS, or OS when given concurrently with NAC in patients with curative TNBC, regardless of diabetic status.

Phase 1 dose-escalation study evaluating the safety, pharmacokinetics, and clinical activity of OBI-3424 in patients with advanced or metastatic solid tumors.

BACKGROUND: Report of a Phase 1 dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). METHODS: A classic 3 + 3 design was used to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of OBI-3424 administered intravenously, as a single agent, at doses of 1, 2, 4, 6, 8, or 12 mg/m2 (days 1 and 8 of a 21-day cycle, Schedule A) or 8, 10, 12, or 14 mg/m2 (day 1 of a 21-day cycle, Schedule B). RESULTS: Dose-limiting hematologic toxicities at 12 mg/m2 in Schedule A led to dose and schedule modifications (Schedule B). In Schedule B, maximum tolerated dose was not reached at the maximum dose tested (14 mg/m2). Grade ≥3 anemia was noted in 3/6 patients treated at 14 mg/m2; the RP2D was 12 mg/m2 (Schedule B). Grade ≥3 treatment-emergent adverse events were experienced by 19/39 (49%) and included anemia (41%) and thrombocytopenia (26%); three patients experienced serious treatment-emergent adverse events (grade ≥3 anemia and thrombocytopenia). One patient had a partial response and 21/33 (64%) had stable disease. CONCLUSIONS: The RP2D is 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated; dose-dependent, noncumulative thrombocytopenia and anemia were dose-limiting.

BCR-Net: A deep learning framework to predict breast cancer recurrence from histopathology images.

Breast cancer is the most common malignancy in women, with over 40,000 deaths annually in the United States alone. Clinicians often rely on the breast cancer recurrence score, Oncotype DX (ODX), for risk stratification of breast cancer patients, by using ODX as a guide for personalized therapy. However, ODX and similar gene assays are expensive, time-consuming, and tissue destructive. Therefore, developing an AI-based ODX prediction model that identifies patients who will benefit from chemotherapy in the same way that ODX does would give a low-cost alternative to the genomic test. To overcome this problem, we developed a deep learning framework, Breast Cancer Recurrence Network (BCR-Net), which automatically predicts ODX recurrence risk from histopathology slides. Our proposed framework has two steps. First, it intelligently samples discriminative features from whole-slide histopathology images of breast cancer patients. Then, it automatically weights all features through a multiple instance learning model to predict the recurrence score at the slide level. On a dataset of H&E and Ki67 breast cancer resection whole slides images (WSIs) from 99 anonymized patients, the proposed framework achieved an overall AUC of 0.775 (68.9% and 71.1% accuracies for low and high risk) on H&E WSIs and overall AUC of 0.811 (80.8% and 79.2% accuracies for low and high risk) on Ki67 WSIs of breast cancer patients. Our findings provide strong evidence for automatically risk-stratify patients with a high degree of confidence. Our experiments reveal that the BCR-Net outperforms the state-of-the-art WSI classification models. Moreover, BCR-Net is highly efficient with low computational needs, making it practical to deploy in limited computational settings.

Conflicts hurt: social stress predicts elevated pain and sadness after mild inflammatory increases.

ABSTRACT: Individuals respond differently to inflammation. Pain, sadness, and fatigue are common correlates of inflammation among breast cancer survivors. Stress may predict response intensity. This study tested whether breast cancer survivors with greater exposure to acute or chronic social or nonsocial stress had larger increases in pain, sadness, and fatigue during an acute inflammatory response. In total, 156 postmenopausal breast cancer survivors (ages 36-78 years, stage I-IIIA, 1-9 years posttreatment) were randomized to either a typhoid vaccine/saline placebo or the placebo/vaccine sequence, which they received at 2 separate visits at least 1 month apart. Survivors had their blood drawn every 90 minutes for the next 8 hours postinjection to assess levels of interleukin-6 and interleukin-1 receptor antagonist (IL-1Ra). Shortly after each blood draw, they rated their current levels of pain, sadness, and fatigue. Women also completed the Test of Negative Social Exchange to assess chronic social stress and the Trier Inventory of Chronic Stressors screen to index chronic general stress. At each visit, a trained experimenter administered the Daily Inventory of Stressful Events to assess social and nonsocial stress exposure within the past 24 hours. After statistical adjustment for relevant demographic and behavioral covariates, the most consistent results were that survivors who reported more chronic social stress reported more pain and sadness in response to IL-1Ra increases. Frequent and ongoing social stress may sensitize the nervous system to the effects of inflammation, with potential implications for chronic pain and depression risk among breast cancer survivors.

A troubled heart: Mood disorder history longitudinally predicts faster cardiopulmonary aging in breast cancer survivorship.

OBJECTIVE: Breast cancer survivors live longer due to more advanced cancer treatments; however, cardiovascular disease (CVD) is the leading non-cancer cause of death in breast cancer survivors. Previous studies have shown that depression is associated with an increased risk of CVD development. This study investigated whether depressive symptoms or mood disorder history, either independently or in combination with cardiotoxic treatments, predicted older cardiopulmonary age using a novel index-the Age Based on Exercise Stress Test (ABEST)-among breast cancer survivors. METHODS: Breast cancer survivors (N = 80, ages 26-72, stage I-IIIA) were assessed an average of 53 days (SD = 26) post-surgery, but before adjuvant treatment, and again an average of 32 (SD = 6) months thereafter. At both visits, they reported depressive symptoms on the Center for Epidemiologic Studies Depression Scale (CES-D), completed the Structured Clinical Interview for DSM-V, and engaged in an exercise stress test to obtain ABEST scores. RESULTS: Controlling for treatment type, age, education, trunk fat, antidepressant use, and time between visits, longitudinal analyses showed that breast cancer survivors with a mood disorder history had worsening ABEST scores over time, compared to their peers without this history (p = .046). Change in physical activity between Visits 1 and 2 did not mediate this relationship (95% CI: -0.16-0.51). Ancillary analyses provided some additional support for the primary finding, such that those with a mood disorder history trended toward greater decreases in Vo2max, although results were marginally non-significant (p = .095). There were no cross-sectional relationships between depressive symptoms or mood disorder history and ABEST scores (ps>.20). Treatment type did not modulate observed relationships (ps>.22). CONCLUSIONS: Breast cancer survivors with a mood disorder history may experience faster cardiopulmonary aging compared to their peers without such a history, raising risk for CVD.

Incidence, Clinicopathologic Features, HER2 Fluorescence In Situ Hybridization Profile, and Oncotype DX Results of Human Epidermal Growth Factor Receptor 2-Low Breast Cancers: Experience From a Single Academic Center.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer, defined by an immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization, is emerging as a predictive marker for the use of the antibody-drug conjugate. To understand how this category differs from HER2-zero cases, we investigated clinicopathological characteristics and HER2 fluorescence in situ hybridization results in a large cohort of 1309 continuous HER2-negative invasive breast carcinomas from 2018 to 2021 evaluated by the Food and Drug Administration-approved HER2 IHC test. Additionally, we compared Oncotype DX recurrence scores and HER2 mRNA expression between HER-low and HER2-zero cases in a separate cohort of 438 estrogen receptor-positive (ER+) early-stage breast carcinoma cases from 2014 to 2016. Based on the cohort from 2018 to 2021, the incidence of HER2-low breast cancers was approximately 54%. HER2-low cases had less frequent grade 3 morphology, less frequent triple-negative results, ER and progesterone receptor negativity, and a higher mean HER2 copy number and HER2/CEP17 ratio than HER2-zero cases (P < .0001). Among ER+ cases, HER2-low cases showed significantly less frequent Nottingham grade 3 tumors. In the cohort from 2014 to 2016, HER2-low cases showed significantly higher ER+ percentages, fewer progesterone receptor-negative cases, lower Oncotype DX recurrence scores, and higher HER2 mRNA expression scores than HER2-zero cases. In summary, this is the first study, to our knowledge, using a large cohort of continuous cases evaluated by the Food and Drug Administration-approved HER2 IHC companion diagnostic test for HER2-low expression and HER2 fluorescence in situ hybridization profile in a real-world setting. Although HER2-low cases showed a higher HER2 copy number, ratio, and mRNA level than HER2-zero cases statistically, such small differences are unlikely to be biologically or clinically meaningful. However, our study suggests that HER2-low/ER+ early-stage breast carcinoma may represent a less aggressive group of breast carcinoma, given its association with a lower Nottingham grade and Oncotype DX recurrence score.