535 Background: Clinical trials suggest that adjuvant radiotherapy (RT) may be omitted in women aged ≥65 with early-stage, hormone-receptor positive breast cancer provided completion of 5 years of ...endocrine therapy (ET). However, at the time of RT consult, it is often unknown whether the patient will start ET, or will start ET but not complete 5 years, either of which, if known in advance, would alter RT recommendations. We studied a cohort of patients who would have been eligible for these trials to examine which factors were related to declining or discontinuing ET. Methods: Using a prospectively maintained institutional database, we identified patients age ≥65 who underwent surgery between 2010 and 2017 with stage I breast cancer, hormone receptor positive. Missing data were replaced using multiple imputation. Recurrence statistics were calculated using Kaplan-Meier analysis. Multivariate (MVA) logistic regression was used to assess which factors were associated with not starting or discontinuing ET. Results: We identified 590 patients who met eligibility criteria. 453 (76.8%) patients started ET, of whom 315 (69.5%) completed at least 5 years, 84 (18.5%) stopped ET before 5 years, and 54 patients (11.9%) were lost to follow up. Median follow up was 67.2 months. Among the 137 patients who did not start ET, the most common reasons were osteopenia or osteoporosis (27.7%), arthritis (18.2%), and declined consultation with medical oncology (15.3%). On MVA, not starting ET was significantly associated with older age (OR 1.10, p < 0.0001), osteopenia (OR 2.27, p = 0.005) or osteoporosis (OR 3.82, p = 0.009), or not undergoing radiation (OR 1.92, p = 0.006) or chemotherapy (OR 6.45, p = 0.02). The most common reason for stopping ET was joint pain (50.0%), with other reasons including hot flashes (10.7%) and fatigue (7.1%). Not completing 5 years of ET was significantly associated with older age (OR 1.09, p = 0.002) and prior/current smoking history (OR 1.75, p = 0.037), while patients whose marital status was single or never married were significantly more likely to complete 5 years of ET (OR 0.26, p = 0.019). Recurrence-free survival was lower among the group which never started ET (p < 0.0001) or which stopped ET before 5 years (p < 0.0001) as compared to those who completed 5 years, with 5-year recurrence-free survival of 97.5% (95% CI: 95.6-99.3) for patients who completed 5 years of ET, compared to 88.7% (95% CI: 82.5-95.4) for those who did not undergo ET and 87.6% (95% CI: 80.4-95.6) for those who started ET but did not complete 5 years. Conclusions: Patients who are older, have osteopenia/osteoporosis, or who have declined prior treatment such as chemotherapy or RT are more likely not to start ET, while patients who are older or prior/current smokers are more likely to discontinue ET after starting and single / never married patients are more likely to complete ET. These factors may be used to guide discussion of omission of adjuvant radiotherapy.
Tumor-associated macrophages (TAMs) promote metastasis and inhibit T cells, but macrophages can be polarized to kill cancer cells. Macrophage polarization could thus be a strategy for controlling ...cancer. We show that macrophages from metastatic pleural effusions of breast cancer patients can be polarized to kill cancer cells with monophosphoryl lipid A (MPLA) and interferon (IFN) γ. MPLA + IFNγ injected intratumorally or intraperitoneally reduces primary tumor growth and metastasis in breast cancer mouse models, suppresses metastasis, and enhances chemotherapy response in an ovarian cancer model. Both macrophages and T cells are critical for the treatment's anti-metastatic effects. MPLA + IFNγ stimulates type I IFN signaling, reprograms CD206+ TAMs to inducible NO synthase (iNOS)+ macrophages, and activates cytotoxic T cells through macrophage-secreted interleukin-12 (IL-12) and tumor necrosis factor alpha (TNFα). MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach for engaging a systemic anti-tumor immune response.
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•MPLA + IFNγ repolarizes TAMs from mice and patients to tumoricidal macrophages•MPLA + IFNγ activates cytotoxic T cells through macrophage-secreted IL-12 and TNFα•MPLA + IFNγ suppresses tumor growth and metastasis in breast and ovarian cancer models•MPLA + IFNγ enhances the response to chemotherapy in ovarian cancer
Sun et al. combine monophosphoryl lipid A (MPLA) with interferon γ (IFNγ) to reprogram macrophages, activate cytotoxic T cells, suppress tumor growth and metastasis, and enhance chemotherapy response in mice. MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach for eliciting anti-metastatic responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients.
Prospective randomized trial comparing ...two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum.
Twenty-three patients were randomized, median age 57 (range 35-77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose hazard ratio: 2.73 with 95% confidence interval (CI), 1.02-7.30;
= 0.039. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool.
TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group.
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In the phase III IMpassion130 study, atezolizumab plus nab-paclitaxel (A+nP) showed clinical benefit in advanced or metastatic triple-negative breast cancer patients who were programmed death-ligand ...1 (PD-L1)+ (tumor-infiltrating immune cells IC ≥1%) using the SP142 immunohistochemistry assay. Here we evaluate 2 other PD-L1 assays for analytical concordance with SP142 and patient-associated clinical outcomes.
Samples from 614 patients (68.1% of intention-to-treat population) were centrally evaluated by immunohistochemistry for PD-L1 status on IC (VENTANA SP142, SP263, Dako 22C3) or as a combined positive score (CPS; 22C3).
Using SP142, SP263, and 22C3 assays, PD-L1 IC ≥1% prevalence was 46.4% (95% confidence interval CI = 42.5% to 50.4%), 74.9% (95% CI = 71.5% to 78.3%), and 73.1% (95% CI = 69.6% to 76.6%), respectively; 80.9% were 22C3 CPS ≥1. At IC ≥1% (+), the analytical concordance between SP142 and SP263 and 22C3 was 69.2% and 68.7%, respectively. Almost all SP142+ cases were captured by other assays (double positive), but several SP263+ (29.6%) or 22C3+ (29.0%) cases were SP142- (single positive). A+nP clinical activity vs placebo+nP in SP263+ and 22C3+ patients (progression-free survival PFS hazard ratios HRs = 0.64 to 0.68; overall survival OS HRs = 0.75 to 0.79) was driven by double-positive cases (PFS HRs = 0.60 to 0.61; OS HRs = 0.71 to 0.75) rather than single-positive cases (PFS HRs = 0.68 to 0.81; OS HRs = 0.87 to 0.95). Concordance for harmonized cutoffs for SP263 (IC ≥4%) and 22C3 (CPS ≥10) to SP142 (IC ≥1%) was subpar (approximately 75%).
22C3 and SP263 assays identified more patients as PD-L1+ (IC ≥1%) than SP142. No inter-assay analytical equivalency was observed. Consistent improved A+nP efficacy was captured by the SP142 PD-L1 IC ≥1% subgroup nested within 22C3 and SP263 PD-L1+ (IC ≥1%) populations.
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Background: Improving outcomes in patients (pts) with TNBC remains a high unmet need. Immune checkpoint inhibitors (ICIs) + chemotherapy (chemo) is approved for newly diagnosed pts with ...PD-L1+ tumors. Further, single-agent sacituzumab govitecan (SG), a Trop-2–directed antibody-drug conjugate, is approved for pts with mTNBC who received ≥2 prior systemic therapies (≥1 for metastatic disease). However, more options are needed for pts with PD-L1–negative mTNBC and for those with disease progression on chemo ± ICI. Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal often overexpressed on TNBC cells. Magrolimab blockade of CD47 induces macrophage-mediated phagocytosis of tumor cells and has shown preclinical activity and promising clinical efficacy in hematologic malignancies. Certain chemos, including taxanes, enhance prophagocytic signals on tumor cells, which may lead to synergistic antitumor activity with magrolimab. This study is evaluating the safety, tolerability, and efficacy of magrolimab + nab-paclitaxel/paclitaxel or + SG in mTNBC. Methods: This open-label study has 2 cohorts (C) with safety run-in and phase (ph) 2 portions. Eligible pts are ≥18 y with measurable disease per RECIST 1.1. C1 pts have PD-L1–negative untreated mTNBC. C2 pts have mTNBC and received 1 prior line of therapy in the advanced setting, a taxane in the neoadjuvant/adjuvant or metastatic setting, and, if PD-L1+, an ICI. Exclusion criteria include active central nervous system disease, RBC transfusion dependence, and prior treatment with CD47/SIRPα-targeting agents. C1 assesses nab-paclitaxel/paclitaxel + magrolimab (safety run-in) or ± magrolimab (ph 2; randomized 1:1). C2 assesses magrolimab + SG (safety run-in and ph 2). In C1 safety run-in, magrolimab is given intravenously (IV) as a 1-mg/kg priming dose on day (D) 1 of cycle 1 to mitigate on-target anemia, followed by 30 mg/kg (cycle 1: D8, 15, 22; cycle 2: D1, 8, 15, 22; cycle 3+: D1, 15) (28-d cycles). In C2 safety run-in, pts receive a 1-mg/kg priming dose on D1, followed by 30 mg/kg (cycle 1: D8, 15; cycle 2: D1, 8, 15) and 60 mg/kg (cycle 3+: D1) (21-d cycles). The recommended ph 2 dose (RP2D) is determined in the safety run-in, with de-escalation if prespecified dose-limiting toxicity (DLT) criteria are met. Once RP2D is determined, the ph 2 cohorts will follow their respective dose schedules. Nab-paclitaxel/paclitaxel and SG are given IV per standard of care. The primary endpoints are incidence of DLTs, adverse events, and abnormal lab results by CTCAE v5.0 (safety run-in); progression-free survival by RECIST 1.1 (ph 2 C1); and confirmed objective response rate by RECIST 1.1 (C2; pooled safety run-in and ph 2). Planned enrollment is ≈144 pts. Clinical trial information: NCT04958785 .
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Background: For survivors of early stage breast cancer, the fear of cancer recurrence (FCR) can be distressing. A clinical challenge is recognizing which patients reporting FCR may need ...psychological intervention. Prior studies have suggested clinically significant FCR if the validated FCR Inventory (FCRI) scale score is > = 22 while others suggest as low as > = 13 may be an optimal threshold. Our goal was to understand the optimal thresholds for detection of clinically significant impairments in quality of life and high levels of stress. We thus examined FCRI thresholds that optimized detection with two standardized screening modalities of quality of life and perceived stress respectively: the Functional Assessment of Cancer Therapy-General (FACT-G) and the Perceived Stress Scale (PSS). Methods: A previously published cohort of breast cancer survivors at our institution consented to complete self-reported psychological measures and gave access to their medical records. The 2 measures being compared to the FCRI were PSS and FACT-G. FCRI, is a 9-item self-report measure, that evaluates worry about health status and illness returning, triggers that influence worry, uncertainty, and the concerns of significant others. FACT-G, a 28-item self-report measure, assesses quality of life in cancer patients, including physical well-being, social/family well-being, emotional well-being, and functional well-being; we examined the binary threshold score for reduced health related quality of life ( < = 62) vs not reduced health related quality of life (> 62). PSS, assesses the degree to which situations in one’s life are appraised as stressful; we examined the threshold score for low stress (0-13) vs moderate or high stress ( > 13). Sensitivity (Sen) and specificity (Spe) were calculated for each cutoff value for the FCRI score between 16 and 22 (two proposed cutoffs) when compared to the FACT-G and the PSS binary cut points. Results: A total of 177 breast cancer survivors participated in the study. The mean age of participants was 57.6 (SD 13.1) years. Mean scores were 18.6 (SD 7.5) for the FCRI (n = 170), 13.92 (SD 7.0) for the PSS (n = 176) and 80.6 (SD 14.9) for the FACT-G (n = 155). FCRI > = 20 appeared to optimize sensitivity and specificity both on the FACT-G (Sen: 82.4, Spe: 56.1) and PSS (Sen: 63.2 Spe: 69.1) in our patient population. Conclusions: Our results suggest that a FCRI cutoff of 20 may optimize inclusion of patients likely to have poorer quality of life and higher levels of stress. This may allow for more patients in this vulnerable population to be identified for possible intervention, without losing specificity to those with significant distress.Table: see text
Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented ...in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.
Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting ...response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.
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