Clinicogenomic characterization of inflammatory breast cancer.

Background: Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. Patients and Methods: A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. Results: Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis revealed a significant enrichment in TP53 SNVs in IBC; particularly in HER2-positive and HR-positive disease which was associated with worse outcomes. Tumor mutational burden (TMB) did not differ substantially between IBC and non-IBC cases and a pathway analysis revealed an enrichment in NOTCH pathway alterations in HER2-positive disease. Conclusion: Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of TP53 mutations and a potential enrichment in NOTCH pathway activation-but overall; a lack of major genomic differences. These results both reinforce the importance of TP53 alterations in IBC pathogenesis as well as their influence on clinical outcomes; but also suggest additional analyses beyond somatic DNA-level changes are warranted.

Antibody Drug Conjugate Sacituzumab Govitecan Enables A Sequential TOP1/PARP Inhibitor Cancer Therapy Strategy in Breast Cancer Patients.

PURPOSE: The Antibody-Drug Conjugate (ADC) Sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly (ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1 inhibitors and SG, but previous studies combining systemic PARP and TOP1 inhibitors failed due to dose-limiting myelosuppression. Here, we assess proof-of-mechanism and clinical feasibility for SG and talazoparib employing an innovative sequential dosing schedule. PATIENTS AND METHODS: In vitro models tested pharmacodynamic endpoints, and in a phase 1b clinical trial (NCT04039230) 30 patients with metastatic Triple-Negative Breast Cancer (mTNBC) received SG and talazoparib using a concurrent (N=7) or sequential (N=23) schedule. Outcome measures included safety, tolerability, preliminary efficacy and establishment of a recommended phase 2 dose (RP2D). RESULTS: We hypothesized that tumor-selective delivery of TOP1i via SG would reduce non-tumor toxicity and create a temporal window, enabling sequential dosing of SG and PARP inhibition. In vitro, sequential SG followed by talazoparib delayed TOP1 cleavage complex clearance, increased DNA damage and promoted apoptosis. In the clinical trial, sequential SG/talazoparib successfully met primary objectives and demonstrated median PFS of 7.6 months without Dose-Limiting Toxicities (DLTs), while concurrent dosing yielded 2.3 months PFS and multiple DLTs including severe myelosuppression. CONCLUSIONS: While SG dosed concurrently with talazoparib is not tolerated clinically due to an insufficient therapeutic window, sequential dosing of SG then talazoparib proved a viable strategy. These findings support further clinical development of the combination and suggest that ADC-based therapy may facilitate novel, mechanism-based dosing strategies.

Health-related quality of life with sacituzumab govitecan in HR+/HER2- metastatic breast cancer in the phase III TROPiCS-02 trial.

BACKGROUND: The TROPiCS-02 study (NCT03901339) demonstrated that sacituzumab govitecan (SG) has superior clinical outcomes over treatment of physician's choice (TPC) chemotherapy in patients with hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) metastatic breast cancer (mBC). Here, we present health-related quality of life (HRQoL) patient-reported outcome (PRO) findings from this study. PATIENTS AND METHODS: Eligible adults with HR+/HER2- mBC who previously received a taxane, endocrine-based therapy, a CDK4/6 inhibitor, and 2-4 lines of chemotherapy were randomized 1:1 to receive SG or TPC until progression or unacceptable toxicity. PROs were assessed at baseline and on day 1 of each cycle, using the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 (EORTC QLQ-C30), EQ-5D-5L, and PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE). RESULTS: Compared to TPC, overall least square mean change from baseline was significantly better for SG for physical functioning and dyspnea, but worse for diarrhea. Time to first clinically meaningful worsening or death was significantly longer for SG in global health status/quality of life, physical functioning, fatigue, emotional functioning, dyspnea, insomnia, and financial difficulties of the EORTC QLQ-C30 and the EQ-VAS, but longer for TPC in diarrhea. Few patients in both arms reported experiencing any worsening to level 3 or 4 treatment-related symptomatic events during treatment, as assessed by 16 PRO-CTCAE items, except for diarrhea frequency and amount of hair loss, which favored TPC. CONCLUSIONS: SG was associated with an HRQoL benefit in most symptoms and functioning, compared with TPC. This supports the favorable profile of SG as a treatment option for patients with pretreated HR+/HER2- mBC.

Prognosis and treatment outcomes for patients with stage IA triple-negative breast cancer.

To evaluate the role of chemotherapy in stage IA triple-negative breast cancer, we conducted a retrospective population-based study including 8601 patients. The use of chemotherapy significantly increased from 2010 to 2019 in patients with T1b and T1c tumors (p = 0.001 and p < 0.001, respectively). Receipt of chemotherapy was associated with improved breast cancer-specific survival (BCSS, adjusted hazard ratio = 0.70; p = 0.006), particularly in patients with T1c tumors (5-year BCSS 94.5% vs. 91.2%).

Clinicopathological characteristics and eligibility for adjuvant olaparib of germline BRCA1/2 mutation carriers with HER2-negative early breast cancer.

Following the survival benefit demonstrated in the OlympiA trial, one year of adjuvant olaparib is now recommended for all patients with germline BRCA1/2 pathogenic/likely pathogenic variants (PV) and high-risk, HER2-negative early breast cancer after chemotherapy. However, optimal identification of high-risk patients who may derive benefit from this genomically-directed therapy is debated. In this study, we sought to characterize the real-world proportion of gBRCA1/2 PV carriers eligible for adjuvant olaparib according to the OlympiA criteria, and to compare clinicopathologic characteristics and outcomes between eligible and ineligible patients.

Impact of dose reductions on adjuvant abemaciclib efficacy for patients with high-risk early breast cancer: analyses from the monarchE study.

In monarchE, adjuvant abemaciclib significantly improved invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS), with sustained benefit beyond the 2-year treatment period. Abemaciclib dose reductions were allowed to proactively manage adverse events. Exploratory analyses to investigate the impact of dose reductions on efficacy were conducted. Across the three patient subgroups as defined by relative dose intensity (≤66%, 66-93%, ≥93%), the estimated 4-year IDFS rates were generally consistent (87.1%, 86.4%, and 83.7%, respectively). In the time-dependent Cox proportional hazard model, the effect of abemaciclib was consistent at the full dose compared to being reduced to a lower dose (IDFS hazard ratio: 0.905; 95% confidence interval: 0.727, 1.125; DRFS hazard ratio: 0.942; 95% confidence interval: 0.742, 1.195). These analyses showed that the efficacy of adjuvant abemaciclib was not compromised by protocol mandated dose reductions for patients with node positive, hormone receptor positive, human epidermal growth factor 2-negative, high-risk early breast cancer.

Subgroup analyses from the phase 3 ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer.

In this post hoc analysis of the ASCENT study, we compared outcomes with sacituzumab govitecan (SG) vs single-agent chemotherapy in clinically important subgroups of patients with metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC refractory to/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG or treatment of physician's choice (TPC) until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by central review in patients without brain metastases. Patients with brain metastases were allowed if metastases were stable ≥4 weeks. In the intention-to-treat (ITT) population, 19% of patients were age ≥65 years; 12% were Black, and 12% had brain metastases. SG improved PFS and overall survival (OS), respectively, vs TPC in patients age ≥65 years (7.1 vs 2.4 months and 14.7 vs 8.9 months), or of Black race (5.4 vs 2.2 months and 13.8 vs 8.5 months), consistent with outcomes in the ITT population. Patients with brain metastases had numerically higher median PFS with SG vs TPC, but median OS was similar between treatment groups. SG was well tolerated and had a manageable safety profile consistent with the full safety population across all subgroups; neutropenia and diarrhea were the most common treatment-emergent adverse events. These findings confirm the meaningful clinical benefit of SG vs standard chemotherapy in patient subgroups with high unmet needs. SG should be considered an effective and safe treatment option for patients with mTNBC eligible for second-line or later therapy. ClinicalTrials.gov Number: NCT02574455.

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.

PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer.

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting. METHODS: The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P. RESULTS: Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations. CONCLUSION: The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial.

The landscape of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) resistance is still being elucidated and the optimal subsequent therapy to overcome resistance remains uncertain. Here we present the final results of a phase Ib/IIa, open-label trial (NCT02871791) of exemestane plus everolimus and palbociclib for CDK4/6i-resistant metastatic breast cancer. The primary objective of phase Ib was to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase II dose (100 mg palbociclib, 5 mg everolimus, 25 mg exemestane). The primary objective of phase IIa was to determine the clinical benefit rate (18.8%, n = 6/32), which did not meet the predefined endpoint (65%). Secondary objectives included pharmacokinetic profiling (phase Ib), objective response rate, disease control rate, duration of response, and progression free survival (phase IIa), and correlative multi-omics analysis to investigate biomarkers of resistance to CDK4/6i. All participants were female. Multi-omics data from the phase IIa patients (n = 24 tumor/17 blood biopsy exomes; n = 27 tumor transcriptomes) showed potential mechanisms of resistance (convergent evolution of HER2 activation, BRAFV600E), identified joint genomic/transcriptomic resistance features (ESR1 mutations, high estrogen receptor pathway activity, and a Luminal A/B subtype; ERBB2/BRAF mutations, high RTK/MAPK pathway activity, and a HER2-E subtype), and provided hypothesis-generating results suggesting that mTOR pathway activation correlates with response to the trial's therapy. Our results illustrate how genome and transcriptome sequencing may help better identify patients likely to respond to CDK4/6i therapies.

Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physician's choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

Mortality Risks Over 20 Years in Men With Stage I to III Hormone Receptor-Positive Breast Cancer.

Importance: In women with hormone receptor-positive (HR+) breast cancer, the risk of distant recurrence and death persists for at least 20 years from diagnosis. The risk of late mortality in men with HR+ breast cancer has not been reported. Objective: To report 20-year risks of breast cancer-specific mortality (BCSM) and non-BCSM in men with stage I to III HR+ breast cancer and identify factors associated with late BCSM. Design, Setting, and Participants: An observational cohort study was conducted of men diagnosed with HR+ breast cancer from 1990 to 2008, using population-based data from the Surveillance, Epidemiology, and End Results program. Men diagnosed with stage I to III HR+ breast cancer were included in the analysis. Cumulative incidence function was used to estimate the outcomes of baseline clinicopathologic variables regarding cumulative risk of BCSM and non-BCSM since diagnosis. Smoothed hazard estimates over time were plotted for BCSM. Fine and Gray multivariable regression evaluated the association of preselected variables with BCSM, conditional on having survived 5 years. Main Outcome Measure: BCSM. Results: A total of 2836 men with stage I to III HR+ breast cancer were included, with a median follow-up of 15.41 (IQR, 12.08-18.67) years. Median age at diagnosis was 67 (IQR, 57-76) years. The cumulative 20-year risk of BCSM was 12.4% for stage I, 26.2% for stage II, and 46.0% for stage III. Smoothed annual hazard estimates for BCSM revealed an increase in late hazard rates with each incremental node category, reaching a bimodal distribution in N3 and stage III, with each having peaks in hazard rates at 4 and 11 years. Among patients who survived 5 years from diagnosis, the adjusted BCSM risk was higher for those younger than 50 years vs older than 64 years, those with grade II or III/IV vs grade I tumors, and stage II or III vs stage I disease. Conclusions and Relevance: The findings of this study suggest that, in men with stage I to III HR+ breast cancer, the risk of BCSM persists for at least 20 years and depends on traditional clinicopathologic factors, such as age, tumor stage, and tumor grade. Among men with higher stages of disease, the kinetics of the BCSM risk appear different from the risk that has been reported in women.

Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor-positive Breast Cancer.

Estrogen receptor-positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant to immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ breast cancers. However, constitutively activating mutations in the estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors resistant to endocrine therapy. Although these mutations represent a pathway of resistance, they also represent a potential source of neoepitopes that can be targeted by immunotherapy. In this study, we investigated ESR1 mutations as novel targets for breast cancer immunotherapy. Using machine learning algorithms, we identified ESR1-derived peptides predicted to form stable complexes with HLA-A*0201. We then validated the binding affinity and stability of the top predicted peptides through in vitro binding and dissociation assays and showed that these peptides bind HLA-A*0201 with high affinity and stability. Using tetramer assays, we confirmed the presence and expansion potential of antigen-specific CTLs from healthy female donors. Finally, using in vitro cytotoxicity assays, we showed the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies. SIGNIFICANCE: Estrogen receptor (ESR1) mutations have emerged as a key factor in endocrine therapy resistance. We identified and validated five novel, immunogenic ESR1-derived peptides that could be targeted through vaccine-based immunotherapy.

Evolution of HER2 expression between pre-treatment biopsy and residual disease after neoadjuvant therapy for breast cancer.

INTRODUCTION: We have previously found that HER2 expression is dynamic, and can change from the primary breast tumor to matched recurrences. With this work, we aimed to assess the dynamics of HER2 during neoadjuvant treatment.(NAT). METHODS: We reviewed HER2 expression in pre- and post-treatment samples from consecutive patients with early-stage breast cancer that received NAT and underwent surgery at Dana-Farber Brigham Cancer Center between 01/2016-08/2022. The primary outcome was evolution of HER2 expression from pre- to post-NAT specimens in patients with residual disease. RESULTS: Among 1613 patients receiving NAT, 1080 had residual disease at surgery. A total of 319 patients (29.5%) experienced a change in HER2 expression (HER2 0 vs. HER2-low vs. HER2-positive) from the pre-treatment sample to residual disease, with roughly equal distribution between decreased (50.5%) and increased HER2 expression (49.5%). Similar rates of change in HER2 expression were observed with anthracycline-based (31.8%) or taxane/platinum-based regimens (32.4%). Patients with HER2-0 or HER2-low tumors at diagnosis were likelier to experience a change in HER2 expression post-NAT compared to HER2-positive (32.3% vs. 21.3%, p < 0.001). Changes in HER2 expression post-NAT were prognostic among patients with HER2-positive tumors at diagnosis (3-year recurrence-free survival for change vs. no change: 71.6% vs. 89.6%, p = 0.006) but not among those with HER2-negative tumors at diagnosis (3-year recurrence-free survival for change vs. no change: 79.3% vs. 81.1%, p = 0.31). CONCLUSIONS: Nearly 30% of patients with early-stage breast cancer showed a change in HER2 expression after NAT. Changes in HER2 expression post-NAT were only prognostic in the setting of HER2-positive tumors becoming HER2-negative at surgery.

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer.

BACKGROUND: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. METHODS: Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. RESULTS: At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. CONCLUSION: PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.

Prevalence, Dynamics, and Prognostic Role of Clonal Hematopoiesis of Indeterminate Potential in Patients With Breast Cancer.

PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is frequent in patients with solid tumors. Prospective data about CHIP prevalence at breast cancer diagnosis and its dynamic evolution under treatment selective pressure are limited. PATIENTS AND METHODS: We performed targeted error-corrected sequencing on 614 samples from 380 patients with breast cancer. We investigated the dynamics of CHIP on prospectively collected paired samples from patients with early breast cancer (eBC) receiving chemotherapy (CT) or endocrine therapy (ET). We assessed the correlation of CHIP with survival in patients with metastatic triple-negative breast cancer (mTNBC). We estimated the risk of progression to treatment-related myeloid neoplasms (t-MN) according to the clonal hematopoiesis risk score (CHRS). In exploratory analyses, we considered clonal hematopoiesis (CH) with variant allele fraction (VAF) ≥0.005. RESULTS: CHIP was identified in 15% of patients before treatment. Few CHIP emerged after treatment, and the risk of developing new mutations was similar for patients receiving CT versus ET (odds ratio [OR], 1.16; P = .820). However, CT increased the risk of developing new CH with VAF ≥0.005 (OR, 3.45; P = .002). Five TP53-mutant CH with VAF ≥0.005 emerged among patients receiving CT. Most patients had low risk of t-MN according to the CHRS score. CHIP did not correlate with survival in mTNBC. CONCLUSION: CHIP is frequent in patients with breast cancer. In this study, CT did not lead to emergence of new CHIP, and most patients had low risk of developing t-MN. This finding is reassuring, given long life expectancy of patients with eBC and the association of CHIP with morbidity and mortality. However, TP53-mutant CH with VAF ≥0.005 emerged with CT, which carries high risk of t-MN. Evolution of these small clones and their clinical significance warrant further investigation.

Immunotherapy for Early-Stage Triple Negative Breast Cancer: Is Earlier Better?

PURPOSE OF REVIEW: In this narrative review, we discuss the optimal timing of immune checkpoint inhibitors (ICI) in early triple negative breast cancer (TNBC), the landscape of predictive biomarkers for the use of immunotherapy, and the mounting literature suggesting a benefit for an early use of ICI. RECENT FINDINGS: TNBC is associated with a poor prognosis relative to other breast cancer subtypes, and until recently, the treatment of TNBC was limited to cytotoxic chemotherapy. In 2021, the immune-checkpoint inhibitor, pembrolizumab, was approved in combination with neoadjuvant chemotherapy for patients with high-risk early stage TNBC. This approval changed the treatment paradigm of early TNBC concomitantly raised several challenges in clinical practice, pertaining to patient selection, toxicity management, and post-neoadjuvant treatment, among others. The introduction of neoadjuvant chemoimmunotherapy has transformed the treatment landscape for early TNBC. However, several challenges, including patient selection, toxicity management, and the identification of predictive biomarkers, need to be addressed. Future research should focus on refining the timing and duration of immunotherapy, optimizing the chemotherapy partner, and exploring novel predictive biomarkers of response or toxicity.

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

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

Impact of personalized diabetes care on distress and treatment satisfaction in people with breast cancer.

AIMS: In patients with breast cancer (BCa) and diabetes (DM), diabetes distress (DD) and treatment satisfaction (DTS) can influence BCa management and outcomes. We assessed the impact of implementing a personalized diabetes care model in patients with BCa. METHODS: Patients in active treatment or surveillance for BCa with an HbA1c > 53 mmol/mol (7%) or random blood glucose >11.1 mmol/L were included. Participants were offered continuous glucose monitoring (CGM), virtual care and a dedicated diabetes provider for 6 months. Primary outcomes included DD measured by the Diabetes Distress Survey (DDS) and DTS measured by the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Questionnaires were conducted at 0, 3 and 6 months. RESULTS: Thirty-one women were enrolled (median age 61, IQR 49.0-69.0). Compared to baseline, the mean DDS score was lower at both 3 months (2.2 vs. 1.8 [n = 27], p = 0.004, SD = 0.70) and 6 months (2.3 vs. 1.8 [n = 23], p = 0.002, SD = 0.70). The mean DTSQ score was higher at 3 months (baseline: 20.5 vs. 3 months: 28.7 [n = 28], p < 0.001, SD = 9.2) and 6 months (baseline: 20.4 vs. 6 months: 30.0 [n = 26], p < 0.001, SD = 9.7). CONCLUSIONS: Personalized diabetes care models that emphasize remote management and optimize access for those with BCa may lower DD and improve DTS.