A Phase I Single-Arm Study of Biweekly NHS-IL12 in Patients With Metastatic Solid Tumors.

BACKGROUND: NHS-IL12 is a first-in-class, recombinant fusion protein composed of the human monoclonal antibody NHS76 (binds exposed DNA/histones at sites of intratumoral necrosis) fused to 2 IL-12 heterodimers. The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NHS-IL12 monotherapy given subcutaneously (SC) every 4 weeks was previously reported. The study was expanded to include a high-exposure cohort with NHS-IL12 SC every 2 weeks (q2w). METHODS: This single-arm, phase I trial evaluated NHS-IL12 12 µg/kg SC q2w or 16.8µg/kg SC q2w in patients with metastatic solid tumors. The primary endpoint was safety. RESULTS: Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. There was 1 DLT (Grade 3 aspartate transaminase/alanine transaminase [AST/ALT] elevation). Other grade 3 toxicities included: flu-like symptoms 1/13 (8%), decreased absolute lymphocyte count (ALC) 1/13 (8%), decreased white blood cell count (WBC) 1/13 (8%), but most adverse events reported were low grade and self-limiting grade. Fifty percent of evaluable patients (6/12) experienced stable disease (SD) with 42% (5/12) developing progressive disease (PD) at the first restaging. CONCLUSION: Biweekly NHS-IL12 was well tolerated in this small phase I study. Additional studies incorporating NHS-IL12 with other immunomodulating agents are underway. (ClinicalTrials.gov Identifier: NCT01417546).

A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma.

BACKGROUND: ONC201 is a small molecule that can cause nonapoptotic cell death through loss of mitochondrial function. Results from the phase I/II trials of ONC201 in patients with refractory solid tumors demonstrated tumor responses and prolonged stable disease in some patients. METHODS: This single-arm, open-label, phase II clinical trial evaluated the efficacy of ONC201 at the recommended phase II dose (RP2D) in patients with recurrent or refractory metastatic breast or endometrial cancer. Fresh tissue biopsies and blood were collected at baseline and at cycle 2 day 2 for correlative studies. RESULTS: Twenty-two patients were enrolled; 10 patients with endometrial cancer, 7 patients with hormone receptor-positive breast cancer, and 5 patients with triple-negative breast cancer. The overall response rate was 0%, and the clinical benefit rate, defined by complete response (CR) + partial response (PR) + stable disease (SD), was 27% (n = 3/11). All patients experienced an adverse event (AE), which was primarily low grade. Grade 3 AEs occurred in 4 patients; no grade 4 AEs occurred. Tumor biopsies did not show that ONC201 consistently induced mitochondrial damage or alterations in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the TRAIL death receptors. ONC201 treatment caused alterations in peripheral immune cell subsets. CONCLUSION: ONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027).

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.

Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses' health study.

BACKGROUND: Breast tumor immune infiltration is clearly associated with improved treatment response and outcomes in breast cancer. However, modifiable patient factors associated with breast cancer immune infiltrates are poorly understood. The Nurses' Health Study (NHS) offers a unique cohort to study immune gene expression in tumor and adjacent normal breast tissue, immune cell-specific immunohistochemistry (IHC), and patient exposures. We evaluated the association of body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score, all implicated in systemic inflammation, with immune cell-specific expression scores. METHODS: This population-based, prospective observational study evaluated 882 NHS and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor IHC for four classic immune cell markers (CD8, CD4, CD20, and CD163). Four immune cell-specific scores were derived via lasso regression using 105 published immune expression signatures' association with IHC. In the remaining 620 patient evaluation cohort, we evaluated association of each immune cell-specific score as outcomes, with BMI change since age 18, physical activity, and EDIP score as predictors, using multivariable-adjusted linear regression. RESULTS: Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC. BMI change since age 18 was positively associated with CD4+ (ß = 0.16; p = 0.009), and CD163 novel immune scores (ß = 0.14; p = 0.04) in multivariable analyses. In other words, for each 10 unit (kg/m2) increase in BMI, the percentage of cells positive for CD4 and CD163 increased 1.6% and 1.4%, respectively. Neither physical activity nor EDIP was significantly associated with any immune cell-specific expression score in multivariable analyses. CONCLUSIONS: BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.

Immune Checkpoint Inhibitors in the Treatment of Breast Cancer Brain Metastases.

The management of breast cancer brain metastases (BCBM) has historically involved local therapies. However, as novel systemic treatments have become more effective in controlling visceral disease, BCBM have also been better controlled. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in brain metastases in patients with lung cancer and melanoma and represent a promising option for patients with triple-negative BCBM, a group with limited systemic therapy options. In this review we summarize current data about the role of ICIs in the treatment BCBM. We identified 15 clinical trials that evaluated ICIs ± chemotherapy in patients with breast cancer. The studies were mostly focused on triple-negative breast cancer (TNBC). Of these trials, 4 excluded patients with BCBM, while 11 allowed patients with stable, treated or asymptomatic BCBM. In total, 2692 patients were enrolled in the identified clinical trials, but only 91 trial patients (3.3%) had BCBM. Furthermore, only 2 of these clinical trials reported BCBM-specific outcomes and none of the clinical trials reported BCBM-specific adverse events. Up to 45% of patients with TNBC will develop BCBM; however, only 3.3% of the patients included in the clinical trials that led to the U.S. Food and Drug Administration approvals for ICIs in advanced breast cancer had brain metastases. This review reinforces that efficacy data are greatly needed for patients with BCBM-this is an area of unmet need in oncology. More inclusive clinical trials and real-world data that evaluate the safety and efficacy of ICIs in patients with BCBM are greatly needed.

A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer.

BACKGROUND: FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine. METHODS: Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed. RESULTS: Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint. CONCLUSIONS: SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell-mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit.

Hormone receptor-positive breast cancer and black race: does sex matter?

PURPOSE: Black breast cancer patients have worse clinical outcomes than their White counterparts. There are few studies comparing clinical outcomes between Black male breast cancer (MBC) and female breast cancer (FBC) patients. The objective of this study is to examine differences in presentation, treatment, and mortality between Black MBC and FBC. METHODS: The National Cancer Database was queried for all Black MBC and FBC patients, ages 18-90, with hormone receptor-positive breast cancer diagnosed between 2010 and 2016. Hormone receptor positivity was defined as estrogen receptor-positive, progesterone-positive and HER 2-negative cancer. Sociodemographic and clinical variables were compared between MBC and FBC patients on bivariable analysis. After propensity score matching, overall survival was evaluated using the log-rank test and Cox proportional hazards. RESULTS: Compared to FBC patients, MBC patients had higher rates of metastatic disease (stage 4, MBC 4.4% vs. FBC 2.6%, p < 0.001), larger tumors (tumor size < 2 cm, MBC 32.1 vs. FBC 49.1%, p < 0.001) and a higher percentage of poorly differentiated tumors (grade 3, MBC 28.5% vs. FBC 21.4%, p < 0.001). MBC patients had lower rates of hormone therapy (MBC 66.4% vs. FBC 80.7%, p < 0.001) and neoadjuvant chemotherapy (MBC 5.8% vs. FBC 7.5%, p = 0.05) than FBC. On propensity score matched analysis, Black MBC patients had a higher overall mortality (p25 of 60 months vs. 74 months) compared to FBC patients (p = 0.0260). CONCLUSION: Among hormone receptor-positive Black MBC and FBC patients, there are sex-based disparities in stage, hormone therapy use and overall survival.

Patient preferences and adherence to adjuvant GnRH analogs among premenopausal women with hormone receptor positive breast cancer.

PURPOSE: Adjuvant ovarian function suppression (OFS) in premenopausal hormone receptor (HR) positive breast cancer (BC) improves survival. Adherence to adjuvant gonadotropin-releasing hormone analogs (GnRHa) remains a challenge and is associated with toxicities and inconvenient parenteral administration. The goal of this study was to describe real-world adherence patterns and patient preferences surrounding adjuvant GnRHa. METHODS: We analyzed the medical records of premenopausal women with non-metastatic HR positive BC from January 2000 to December 2017; participants received adjuvant monthly goserelin or leuprolide at The Ohio State University. Data collected included demographics, clinicopathologic characteristics, and OFS adherence/side effects. We defined non-adherence as discontinuation of GnRHa within 3 years for a reason other than switching to an alternate OFS, delay > 7 days from a dose, or a missed dose. Chi-square tests assessed associations between clinical characteristics and outcomes. RESULTS: A total of 325 patients met eligibility. Of these, 119 (37%) patients were non-adherent to GnRHa; 137 (42%) underwent elective bilateral salpingo-oophorectomy after initial GnRHa. Those opting for surgery reported significantly more hot flashes (74% vs 48%, p < 0.001), arthralgias (46% vs 30%, p = 0.003), and vaginal dryness (37% vs 21%, p = 0.001) compared with patients remaining on GnRHa. CONCLUSION: Non-adherence to adjuvant GnRHa occurred in over a third of patients and almost half the patients initiating GnRHa underwent subsequent surgical ablation. These high frequencies highlight real-world patterns of OFS. Additionally, treatment toxicities may impact personal preference of OFS modality. Personalized practices to target predictors of adjuvant GnRHa non-adherence are critical to optimize symptoms, adherence, and survivorship.

Improving Breast Cancer Responses to Immunotherapy-a Search for the Achilles Heel of the Tumor Microenvironment.

PURPOSE OF REVIEW: To explore the role of the tumor microenvironment (TME) in breast cancer, identify the changes that occur in the TME during breast cancer progression, and explore the possibility of modifying the TME to improve immune checkpoint inhibitor responses. RECENT FINDINGS: Emerging evidence shows the TME may be shaped by internal and external factors. Preclinical data suggests it may be possible to shift the TME to allow for better immune infiltration. In this review, we summarize emerging evidence of changes in the TME and how it can affect prognosis and responses to therapy. We also examine pre-clinical and clinical research aiming at modulating TME to increase proportion of patients who benefit from immune checkpoint inhibitors. The composition of the TME in breast cancer is likely dynamic and may be altered. These changes may lead to more or less responses to immunotherapy.

A Phase II Single Arm Pilot Study of the CHK1 Inhibitor Prexasertib (LY2606368) in BRCA Wild-Type, Advanced Triple-Negative Breast Cancer.

LESSONS LEARNED: Monotherapy with prexasertib demonstrated modest activity in BRCA wild-type, recurrent triple-negative breast cancer, highlighting the unmet need for combination treatment strategies. Neutropenia, anemia, and thrombocytopenia are common with the use of prexasertib but are manageable with supportive care measures. Prophylactic use of granulocyte colony stimulating factor should be considered to avoid dose reductions or treatment delays. Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells. BACKGROUND: Cell cycle checkpoint kinase 1 (CHK1) is a major G2/M cell cycle regulator in tumors with p53 dysfunction, such as triple-negative breast cancer (TNBC). We hypothesized the second-generation CHK1 inhibitor, prexasertib, would yield clinical activity in sporadic TNBC. METHODS: This single arm, phase II trial evaluated prexasertib at 105 mg/m2 IV every 2 weeks in patients with metastatic/recurrent TNBC. The primary endpoint was overall response rate (ORR). RESULTS: All nine patients enrolled were germline BRCA wild-type (BRCAwt) and had at least one prior treatment. One partial response (PR) was observed (ORR of 11.1%). Four patients experienced stable disease. The median progression-free survival (PFS) was 86 days (range 17 to 159 days). Grade 3/4 treatment-related adverse events included afebrile neutropenia (n = 8; 88.9%), anemia (n = 3; 33.3%), and thrombocytopenia (n = 1; 11.1%). Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells and demonstrated a decrease in activated/reinvigorated CD8 T cells; however, the one patient with a PR showed evidence of T-cell recovery. CONCLUSION: Prexasertib monotherapy had modest clinical efficacy in BRCAwt TNBC. Further studies of prexasertib in combination with other agents are needed.

A Phase I Trial Using a Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury)-Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer.

LESSONS LEARNED: Concurrent ETBX-011, ETBX-051, and ETBX-061 can be safely administered to patients with advanced cancer. All patients developed CD4+ and/or CD8+ T-cell responses after vaccination to at least one tumor-associated antigen (TAA) encoded by the vaccine; 5/6 patients (83%) developed MUC1-specific T cells, 4/6 (67%) developed CEA-specific T cells, and 3/6 (50%) developed brachyury-specific T cells. The presence of adenovirus 5-neutralizing antibodies did not prevent the generation of TAA-specific T cells. BACKGROUND: A novel adenovirus-based vaccine targeting three human tumor-associated antigens-CEA, MUC1, and brachyury-has demonstrated antitumor cytolytic T-cell responses in preclinical animal models of cancer. METHODS: This open-label, phase I trial evaluated concurrent administration of three therapeutic vaccines (ETBX-011 = CEA, ETBX-061 = MUC1 and ETBX-051 = brachyury). All three vaccines used the same modified adenovirus 5 (Ad5) vector backbone and were administered at a single dose level (DL) of 5 × 1011 viral particles (VP) per vector. The vaccine regimen consisting of all three vaccines was given every 3 weeks for three doses then every 8 weeks for up to 1 year. Clinical and immune responses were evaluated. RESULTS: Ten patients enrolled on trial (DL1 = 6 with 4 in the DL1 expansion cohort). All treatment-related adverse events were temporary, self-limiting, grade 1/2 and included injection site reactions and flu-like symptoms. Antigen-specific T cells to MUC1, CEA, and/or brachyury were generated in all patients. There was no evidence of antigenic competition. The administration of the vaccine regimen produced stable disease as the best clinical response. CONCLUSION: Concurrent ETBX-011, ETBX-051, and ETBX-061 can be safely administered to patients with advanced cancer. Further studies of the vaccine regimen in combination with other agents, including immune checkpoint blockade, are planned.

Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors.

LESSONS LEARNED: Modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury followed by fowlpox virus-BN-Brachyury was well tolerated upon administration to patients with advanced cancer. Sixty-three percent of patients developed CD4+ and/or CD8+ T-cell responses to brachyury after vaccination. BN-Brachyury vaccine also induced T-cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines. BACKGROUND: Brachyury, a transcription factor, plays an integral role in the epithelial-mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)-Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules. METHODS: Patients with metastatic solid tumors were treated with two monthly doses of MVA-brachyury s.c., 8 × 108 infectious units (IU), followed by FPV-brachyury s.c., 1 × 109 IU, for six monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability. RESULTS: Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose-limiting toxicities were observed. The most common treatment-related adverse event was grade 1/2 injection-site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6-month progression-free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients. CONCLUSION: BN-Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit.

Analysis of breast cancer in young women in the Department of Defense (DOD) database.

PURPOSE: Breast tumors from young women under the age of 40 account for approximately 7% of cases and have a poor prognosis independent of established prognostic factors. We evaluated the patient population served by the Military Health System, where a disproportionate number of breast cancer cases in young women are seen and treated in a single universal coverage healthcare system. METHODS: The Military Health System Repository and the DoD Central Registration databases were used to identify female breast cancer patients diagnosed or treated at military treatment facilities from 1998 to 2007. RESULTS: 10,066 women were diagnosed with invasive breast cancer at DoD facilities from 1998 to 2007, of which 11.3% (1139), 23.4% (2355) and 65.2% (6572) were < 40, 40-49 and > 50 years old (yo), respectively, at diagnosis. 53% in the < 40 yo cohort were white, 25% were African American (AA) and 8% were Hispanic, with 14% undisclosed. Breast cancer in women diagnosed < 40 yo was more high grade (p < 0.0001), Stage II (p < 0.0001) and ER negative (p < 0.0001). There was a higher rate of bilateral mastectomies among the women < 40 compared to those 40-49 and > 50 (18.4% vs. 9.1% and 5.0%, respectively). Independent of disease stage, chemotherapy was given more frequently to < 40 yo (90.43%) and 40-49 yo (81.44%) than ≥ 50 yo (53.71%). The 10-year overall survival of younger women was similar to the ≥ 50 yo cohort. Outcomes in the African American and Hispanic subpopulations were comparable to the overall cohort. CONCLUSION: Younger women had a similar overall survival rate to older women despite receiving more aggressive treatment.

Comparing the rate of immunotherapy treatment change due to toxicity by sex.

BACKGROUND: Immuno-oncology therapy (IO) is associated with a variety of treatment-related toxicities. However, the impact of toxicity on the treatment discontinuation rate between males and females is unknown. We hypothesized that immune-related adverse events would lead to more frequent treatment changes in females since autoimmune diseases occur more frequently in females. AIMS: Our aim was to determine if there was a difference in the rate of immunotherapy treatment change due to toxicity between males and females. METHODS AND RESULTS: The Oncology Research Information Exchange Network Avatar Database collected clinical data from 10 United States cancer centers. Of 1035 patients receiving IO, 447 were analyzed, excluding those who did not have documentation noting if a patient changed treatment (n = 573). Fifteen patients with unknown or gender-specific cancer were excluded. All cancer types and stages were included. The primary endpoint was documented treatment change due to toxicity. Four hundred and forty-seven patients (281 males and 166 females) received IO treatment. The most common cancers treated were kidney, skin, and lung for 99, 84, and 54 patients, respectively. Females had a shorter IO course than males (median 3.7 vs. 5.1 months, respectively, p = .02). Fifty-four patients changed treatment due to toxicity. There was no significant difference between females and males on chi-square test (11.4% vs. 12.5%, respectively, p = 0.75) and multivariable logistic regression (OR 0.924, 95% CI 0.453-1.885, p = .827). Significantly more patients with chronic obstructive pulmonary disease (COPD) changed therapy due to toxicity (OR 2.491, 95% CI 1.025-6.054, p = .044). CONCLUSION: Females received a shorter course of IO than males. However, there was no significant difference in the treatment discontinuation rate due to toxicity between males and females receiving IO. Toxicity-related treatment change was associated with COPD.

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.

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.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Perspectives of patients undergoing neoadjuvant chemotherapy for breast cancer during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic resulted in a lapse in routine health care and cancer screenings for many individuals. This study sought to improve our understanding of the impact of the COVID-19 pandemic on women being treated for breast cancer, both in general, and specifically related to their diagnosis. METHODS: Semi-structured interviews were conducted between August 2021 and February 2022 with women who were receiving neoadjuvant chemotherapy for early-stage breast cancer at the Stefanie Spielman Comprehensive Breast Center in Columbus, Ohio. Interviews were recorded and transcribed verbatim. Transcripts were coded using deductive dominant thematic analysis and inductive coding that allowed for categorization of data as well as identification of emergent themes. RESULTS: Data collected from our 19 interviews revealed that the COVID-19 pandemic posed important challenges for breast cancer patients including fear of COVID-19 infection and feelings of isolation. Most interviewees noted they had been vaccinated against COVID-19 because of a desire to protect themselves and others from getting sick. Some women also expressed concerns about having delayed their screening mammograms due to the pandemic. Several patients described unexpected positive aspects of the pandemic such as being able to spend more time with family and having the ability to continue working because of the option to work from home during their cancer treatment. CONCLUSIONS: Our findings provide important insight about the impact of COVID-19 on breast cancer patients. We highlight the positives that have been reported because of the pandemic, as well as the need to address delayed breast cancer screening.

Immune correlates with response in patients with metastatic solid tumors treated with a tumor targeting immunocytokine NHS-IL12.

The immunocytokine NHS-IL12 delivers IL-12 to the tumor microenvironment by targeting DNA/histones in necrotic areas. The first-in-human clinical trial administered NHS-IL12 subcutaneously in 59 patients treated every four weeks (Q4W), with a maximum tolerated dose of 16.8 mcg/kg. The phase I study was expanded to include a high-exposure cohort that received bi-weekly treatment (Q2W) with two dose levels of NHS-IL12: 12.0 mcg/kg and 16.8 mcg/kg. Here, patients given NHS-IL12 were analyzed both prior to and early after treatment for effects on 10 serum soluble analytes, complete blood counts, and 158 peripheral immune subsets. Higher levels of immune activation were seen with a dose of 16.8 mcg/kg versus 12.0 mcg/kg in patients in the high-exposure cohort, as evidenced by greater increases in serum IFNγ, TNFα, and soluble PD-1, and greater increases in frequencies of peripheral ki67+ mature natural killer (NK), CD8+T, and NKT cells. Greater immune activation was also seen in the Q2W versus Q4W cohort, as demonstrated by greater increases in pro-inflammatory serum analytes, ki67+ CD8+ T, NK, and NKT cells, intermediate monocytes, and a greater decrease in CD73+ T cells. Specific immune analytes at baseline including lower levels of monocytes and plasmacytoid dendritic cells, and early changes after treatment such as an increase in refined NK cell subsets and total CD8+ T cells, associated with better clinical response. These findings may help to guide future schedule and dosing regimens of clinical studies of NHS-IL12 as monotherapy and in combination therapies.

Awareness of alcohol as a breast cancer risk factor and intentions to reduce alcohol consumption among U.S. young adult women.

Alcohol consumption is prevalent in young adult women and linked with breast cancer risk. Research to inform interventions targeting alcohol consumption as a breast cancer prevention strategy is limited. We examined young women's awareness of alcohol use as a breast cancer risk factor, identified correlates of awareness, and determined how awareness and conceptual predictors relate to intentions to reduce drinking. Women aged 18-25 years who drank alcohol in the past month (N = 493) completed a cross-sectional survey. Measures captured sociodemographics, breast cancer risk factors, awareness of alcohol use as a breast cancer risk factor, intentions to reduce drinking, and conceptual predictors. Analyses examined correlates of awareness and associations between awareness, conceptual predictors, and intentions to reduce drinking. Awareness was low (28%) and intentions to reduce drinking were moderate (M = 2.60, SD = 0.73, range 1-4). In multivariable analyses, awareness was associated with greater worry about cancer, beliefs that there's not much one can do to reduce cancer risk and everything causes cancer, higher perceived breast cancer risk, and stronger beliefs that reducing drinking reduces breast cancer risk. Awareness was not associated with intentions to reduce drinking. Younger age, older age of alcohol initiation, negative attitudes towards alcohol, fewer friends consuming alcohol, and stronger self-efficacy were associated with intentions to reduce drinking. Few young women recognize alcohol consumption as a breast cancer risk factor. Researchers and policymakers can apply our findings to design new or refine existing interventions to optimize their impact on awareness and alcohol consumption in young women.

Alcohol use is common among young adult women and is linked to an increased risk of breast cancer later in life. This study aimed to identify factors linked to young women's awareness of alcohol as a breast cancer risk factor and factors linked to intentions to reduce drinking. We surveyed 493 women aged 18­25 who resided in Ohio and reported drinking alcohol in the past month. Only 28% of the women were aware that alcohol use increases breast cancer risk, and intentions to reduce drinking were moderate. Factors associated with awareness of alcohol use as a breast cancer risk factor included cancer worry, believing there's not much you can do to lower your risk of cancer, believing everything causes cancer, higher perceived risk of breast cancer, and stronger beliefs that drinking less reduces breast cancer risk. Factors linked to intentions to reduce drinking included younger age, older age at first drinking, more negative attitudes about alcohol, believing fewer friends drink, and higher confidence to reduce drinking. The findings can help researchers and policymakers create new interventions to educate young women about the link between alcohol consumption and breast cancer risk and reduce alcohol use as a breast cancer prevention strategy.