Daratumumab,Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Three-year Follow-up of CASTOR

BackgroundIn the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed.Patients and MethodsEligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m²) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression.ResultsOf 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)–negativity rates (10⁻⁵) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed.ConclusionAfter 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.     

A Population-Based Study of Incidence and Survival of 1588 Thymic Malignancies: Results From the California Cancer Registry

BackgroundThymic malignancies are rare and there are limited contemporary population-based epidemiological studies for this uncommon cancer.Patients and MethodsAdults aged 20 years and older diagnosed with thymic malignancies between 1988 and 2015 were identified from the California Cancer Registry (n = 1588). Trends in age-adjusted incidence rates were examined overall and according to race/ethnicity, and the proportion diagnosed according to stage was evaluated over time. Cox proportional hazards regression was used to estimate hazard ratios (HRs) for overall survival (OS), and Fine and Gray competing risks regression for cause-specific survival (CSS).ResultsAge-adjusted incidence increased on average 2.08% per year over the study period (95% confidence interval [CI], 1.30%-2.86%; P < .0001), with an incidence of 0.277 cases per 100,000 in 2015. Incidence was highest among Asian/Pacific Islander and non-Hispanic black individuals. The proportion of unknown stage at diagnosis declined as localized diagnoses increased over time. Compared with patients with thymoma, those with thymic carcinoma had significantly worse OS (HR, 1.63; 95% CI, 1.33-2.01; P < .0001) and CSS (subdistribution HR, 2.99; 95% CI, 2.29-3.91; P < .0001). Advanced stage at diagnosis was also associated with worse survival. Surgical intervention was associated with better prognosis for patients with localized (HR, 0.08; 95% CI, 0.02-0.30; P = .0002) or regional disease (HR, 0.14; 95% CI, 0.06-0.34; P < .0001).ConclusionThymic malignancy incidence is increasing in California. There was incidence variation across race/ethnicity, which warrants future study. These findings provide contemporary insight into the incidence and prognostic factors of thymic malignancies.     

Tumor Infiltrating Lymphocytes Predict Survival in Solid Organ Transplant Recipients With Monomorphic Post-transplant Lymphoproliferative Disorders

IntroductionThe tumor microenvironment (TME) in post-transplant lymphoproliferative disorders (PTLDs) remains unexplored. Tumor infiltrating lymphocytes (TILs) are prognostic in other lymphomas. We assessed the prognostic impact of TILs in monomorphic B-cell PTLD.MethodsTIL density (CD3+ cells/mm²) was determined by CD3 immunohistochemistry in archived diagnostic biopsies from patients diagnosed with monomorphic B-cell PTLD.ResultsAmongst monomorphic PTLDs (N = 107), low TIL-count was associated with inferior 2-year progression-free survival (PFS) (41% versus 86%, P = .003) and 2-year overall survival (OS) (52% versus 93%, P = .003) by Kaplan-Meier analysis. Low TIL-count was significant on Cox univariate regression for inferior PFS (HR 4.5, 95% CI 2.0-9.9, P < .001) and OS (HR 4.6, 95% CI 1.8-11.8, P < .001). Multivariate analysis with clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) and TIL-count showed significance for PFS (HR 3.3, 95% CI 1.3-8.3, P = .010) and a non-significant trend for OS (HR 2.6, 95% CI 0.9-7.3, P = .064). A composite score including TILs and clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) effectively stratified monomorphic PTLD patients by PFS and OS (2-year OS: low-risk 93%, intermediate-risk 61%, high-risk 23%, P < .001).ConclusionsThe TME and TILs are prognostically relevant in monomorphic PTLD. Prognostic models including measures of the TME may improve risk stratification for patients with monomorphic PTLDs.     

Increased Bone Marrow Plasma-Cell Percentage Predicts Outcomes in Newly Diagnosed Multiple Myeloma Patients

BackgroundPrevious reports have suggested that a higher bone marrow plasma-cell percentage (BMPC%) is associated with worse outcomes. However, it is unknown whether BMPC% is an independent predictor because genetic information was not available at that time. Currently the impact of BMPC% at diagnosis of multiple myeloma (MM) is not well described.Patients and MethodsWe evaluated the prognostic impact of BMPC% ≥ 60% versus < 60% in 1426 newly diagnosed MM patients. All patients had an estimation of their BMPC% at diagnosis, and the highest percentage was used. Progression-free survival (PFS) and overall survival (OS) analyses were performed by the Kaplan-Meier method. Univariate and multivariate analyses for PFS and OS using the Cox proportional hazards model were performed for age, Revised International Staging System (R-ISS) score, creatinine level, and BMPC%.ResultsBMPC% ≥ 60% was found in 562 patients (39%), and the median PFS was shorter for these patients compared to BMPC% < 60% (22.6 vs. 32.1 months; P < .0001). Also, for OS, the median was shorter for the higher BMPC% group (53.4 vs. 75.4 months; P < .0001). On the multivariate analysis for PFS, age ≥ 65 years (hazard ratio [HR], 1.46; P < .0001), R-ISS (1-2 vs. 3) (HR, 0.49; P < .0001), and BMPC% ≥ 60% (HR, 1.23; P = .015) were predictive. On the multivariate analysis for OS, age ≥ 65 years (HR, 2.23; P < .001), R-ISS (1-2 vs. 3) (HR, 0.41; P < .0001), and BMPC% ≥ 60% (HR, 1.24; P = .02) were also predictive.ConclusionBMPC% ≥ 60% at diagnosis is predictive for PFS and OS, even in a multivariate analysis that included known prognostic factors for MM.     

Validation of the Combination Gleason Score as an Independent Favorable Prognostic Factor in Prostate Cancer Treated With Dose-Escalated Radiation Therapy

PurposePrognostic factors for prostate cancer include tumor, node, metastases stage, pretreatment prostate-specific antigen, and pathology (via Gleason score [GS] or grade group). Of these, GS yields the largest effect on prostate cancer specific mortality. It was previously determined that those with cores with a mix of higher and lower GS at biopsy (which was termed a “ComboGS”) had decreased risk for prostate cancer specific mortality after either surgical or radiation treatment. We validate the effect of ComboGS in an independent cohort of patients with prostate cancer treated with definitive dose-escalated radiation therapy (DE-RT) at 2 institutions.Methods and MaterialsDE-RT was administered to 2539 men, of which 687 men had a ComboGS. To further ascertain the ComboGS effect we employed the modified Cancer of the Prostate Risk Assessment (mCAPRA) score. Rates of biochemical event-free survival and distant metastasis-free survival were compared across CAPRA scores, with and without modification, and the prognostic value of the CAPRA scores was compared using Harrel's concordance index.ResultsOn univariate analysis in Gleason 7 to 10 patients the presence of ComboGS improved 10-year biochemical event-free survival from 76.6% to 82.4% (hazard ratio [HR], 0.75; confidence interval [CI], 0.59-0.96; P = .021), 10-year distant metastasis-free survival from 89.3% to 93.2% (HR, 0.57; CI, 0.39-0.85; P = .005), 10-year prostate cancer specific survival from 93.9% to 97.4% (HR, 0.39; CI, 0.21-0.7; P = .001), and 10-year overall survival from 65.7% to 75.6% (HR, 0.69; CI, 0.57-0.83; P < .001). Multivariable analysis also supported that ComboGS is protective for biochemical failure (HR, 0.64; CI, 0.50-0.83; P < .001), distant metastasis (HR, 0.42; CI, 0.28-0.63; P < .001), death from prostate cancer (HR, 0.32; CI, 0.17-0.58; P < .001), and overall mortality (HR, 0.65; CI, 0.54-0.79; P < .001). Additionally, adjusting the mCAPRA score for ComboGS decreased the risk of biochemical failure by nearly 30% (HR, 0.70; 95% CI, 0.55-0.88; P = .003) and by 50% (HR, 0.54; 95% CI, 0.37-0.80; P = .002) for distant metastasis.ConclusionsComboGS is a useful and readily available independent prognostic factor for all clinical endpoints evaluated. Moreover, the ComboGS can be used in conjunction with the extensively validated CAPRA scoring to better risk stratify patients being treated with definitive DE-RT for GS 7 to 10 disease.     

Prognostic value of microsatellite instability (MSI) and PTEN expression in women with endometrial cancer: Results from studies of the NCIC Clinical Trials Group (NCIC CTG)

AimThe impact of PTEN status and microsatellite instability (MSI) on the prognosis of women with endometrial cancer is controversial. The aim of this study was to investigate MSI and PTEN expression in two patient populations using data from NCIC CTG studies.MethodsArchival paraffin embedded tumour from women with endometrial cancer enrolled in NCIC CTG studies: EN5 (stage I/II) and IND 126, 148 and 160 (advanced/recurrent disease) were examined for MSI using BAT25/26 and for PTEN expression using immunohistochemistry. PTEN and MSI status were correlated with clinicopathologic variables and survival using data from NCIC CTG trial databases.ResultsPTEN and MSI results were available from 128 and 163 patients, respectively. MSI+ tumours were more common in women enrolled in EN5 compared to the IND studies (p = 0.01). PTEN negative tumours were associated with improved survival in both univariate (hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.32–0.94; p = 0.03) and multivariate (adjusted HR 0.54, 95% CI 0.30–0.96; p = 0.03) analyses in women enrolled in IND studies. Microsatellite stable tumours were associated with an improved prognosis in univariate (HR 0.18, 95% CI 0.06–0.51; p < 0.0001) and multivariate (adjusted HR 0.16, 95% CI 0.05–0.5; p < 0.0001) analyses in women enrolled in EN5. There was no significant correlation between MSI and PTEN status.ConclusionsPTEN negative tumours in women with advanced disease are associated with improved survival. MSI+ tumours are more common in early stage disease and in this group of women are associated with a worse prognosis.     

Disparity in Utilization of Multiagent Therapy for Acute Promyelocytic Leukemia in the United States

BackgroundDespite high rate of cure in acute promyelocytic leukemia (APL) in clinical trials, outcomes in real-world practice are dismal. We utilized National Cancer Database (NCDB) to explore utilization of multiagent therapy in APL and identify any disparities in treatment in real-world practices.Patients and MethodsNCDB categorizes use of systemic chemotherapy into single agent versus multiagent therapy. Some patients received hormonal therapy, immunotherapy, and unknown therapy; details of these treatments could not be ascertained. We therefore used multiple logistic regression analysis to evaluate effects of covariates on the probability of multiagent therapy use in 6678 patients.ResultsCompared to patients >60 years, patients aged 0 to 18 years (hazard ratio[HR] 3.2, 95% confidence interval [CI] 1.8-5.5, P< .0001), 19 to 40 years (HR 1.6, 95% CI 1.03-2.54, P= .03), and 41 to 60 years (HR 1.6, 95% CI 1.3-1.9, P< .0001) were more likely to receive multiagent therapy. Patients with Charlson comorbidity index (CCI) of 0 (HR 1.6, 95% CI 1.2-2.3, P= .001) and CCI of 1 (HR 1.4, 95% CI 1.0-1.9, P= .04) had a higher likelihood of receiving multiagent therapy than patients with CCI ≥ 3. Patients treated at academic cancer centers, compared to those treated at community cancer center (HR 0.5, 95% CI 0.3-0.7, P= .001), comprehensive community cancer center (HR 0.7, 95% CI 0.6-0.8, P< .0001), and integrated network cancer center (HR 0.8, 95% CI 0.6-0.9, P= .02) were more likely to be treated with multiagent therapy. Compared to the patients with private insurance, those with Medicaid had increased likelihood (HR 1.2, 95% CI 1.0-1.4, P= .04) whereas uninsured patients had a lower likelihood of receiving multiagent therapy (HR 0.6, 95% CI 0.5-0.8, P= .0005).ConclusionTo our knowledge, this study is the first and the largest scale analysis of treatment practices in APL in real-world practices. Our findings highlight significant disparities in treatment of APL based on age, insurance, and health-system factors.     

CAPOX Associated With Toxicities of Higher Grade but Improved Disease-Free Survival When Compared With FOLFOX in the Adjuvant Treatment of Stage III Colon Cancer

Introduction/BackgroundAdjuvant treatment of colon cancer relies on fluoropyrimidine-containing regimens as the intravenous formulation, 5-FU, or its oral prodrug, CA, combined with oxaliplatin (FOLFOX and CAPOX). There is currently no clinical trial comparing the 2 regimens; however, both are considered standard of care treatment options.Materials and MethodsWe performed a retrospective chart review comparing average relative dose intensity (ARDI), percentage of intended total dose (PITD), overall survival (OS), DFS, and toxicity profiles of these regimens. The patients (n = 176) received either modified FOLFOX6 (n = 93) or CAPOX (n = 83).ResultsOxaliplatin ARDI (80.72% vs. 87.11%; P = .0033) and PITD (70.09% vs. 88.11%; P = .0013) was significantly lower in those treated with CAPOX compared with FOLFOX. CA ARDI (87.10% vs. 93.60%; P < .0001) and PITD (77.19% vs. 88.11%; P = .0006) was significantly lower than 5-FU dosing. Patients treated with CAPOX had more ≥ Grade 2 toxicities and trended toward more dose-limiting toxicities. Survival analysis demonstrated a trend toward improved OS with CAPOX (hazard ratio [HR], 0.4741; 95% confidence interval [CI], 0.1660-1.354; P = .1663) and improved DFS with CAPOX (HR, 0.4949; 95% CI, 0.2512-0.9749; P = .0420). Multivariate analysis demonstrated similar results with CAPOX being associated with a trend toward improved OS (HR, 0.396; 95% CI, 0.110-1.429; P = .1571) and DFS (HR, 0.458; 95% CI, 0.210-1.001; P = .0504).ConclusionPatients receiving CAPOX had significantly lower ARDI and PITD compared with FOLFOX, but showed trends toward improved outcomes when treated with CAPOX in the adjuvant setting when compared with FOLFOX.     

Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin

BackgroundThe aim was to determine the values of p53 tumour expression and microsatellite instability (MSI) phenotype to predict benefit from adjuvant chemotherapy of colon cancer by 5-fluorouracil and leucovorin (FL) alone or with oxaliplatin (FOLFOX).Patients and methodsThis retrospective study included 233 unselected patients with stage III colon cancer treated by FL (n = 124) or FOLFOX (n = 109). The impact of p53 expression and MSI on disease-free survival (DFS) was defined using univariate and multivariate analyses. A Cox proportional hazards model was specifically designed to evaluate the interaction between chemotherapy and these genetic alterations.ResultsIn univariate analyses, addition of oxaliplatin significantly improved DFS provided that tumour overexpressed p53 [hazard ratio (HR) 0.39; 95% confidence interval (CI) 0.19–0.82; P = 0.01] or displayed MSI phenotype (HR 0.17; 95% CI 0.04–0.68; P = 0.01). In multivariate analyses, p53 was confirmed as an independent factor predictive of benefit from FOLFOX (P = 0.03), while the interaction of MSI with chemotherapy could not be determined in the absence of relapse in the MSI group treated with FOLFOX.ConclusionOur observations indicate that MSI status and p53 expression may influence the impact of oxaliplatin on adjuvant treatment of stage III colon cancer patients.     

Aberrant Expression of CD13 Identifies a Subgroup of Standard-Risk Adult Acute Lymphoblastic Leukemia With Inferior Survival

BackgroundThe standard-risk (SR) subgroup of acute lymphoblastic leukemia in adults (aALL) is a heterogeneous category, with a 20% to 40% relapse rate and a wide range of relapse-free survival (RFS) and overall survival (OS). There is a need to identify at the outset those patients with SR-aALL who are likely to have shorter RFS and OS, so they can be treated more aggressively.Patients and MethodsFlow cytometric data of 81 patients with SR-aALL treated with a standardized protocol were retrospectively analyzed. Thirty-two patients (40%) relapsed; the median RFS and OS were 12.5 months (range, 1-136 months) and 30 months (range, 3-235 months), respectively. Twenty-six patients survived ≥ 48 months.ResultsExpression of myeloid antigen CD13, using the conventional ≥ 20% threshold and a lower ≥ 5% threshold, was seen in 17 (29%) of 59 and 29 (49%) of 59 patients, respectively, whereas dual expression of CD13 and CD33 was seen in 8 patients. CD13 positivity at ≥ 20% and ≥ 5% threshold was associated with a shorter RFS (P = .0158 and P < .0001, respectively) and OS (P = .0072 and P < .0001, respectively). Dual expression of CD13 (at ≥ 5% or ≥ 20% threshold) and CD33 was associated with inferior OS (P = .0038 and P = .0032, respectively) and RFS (P = .0705 and P = .2516, respectively). For ≥ 20% and ≥ 5% threshold of positivity, 16 of 42 and 28 of 42 who survived < 48 months were positive, compared with 1 of 17 and 1 of 17 who survived ≥ 48 months (P = .0133 and P < .0001, respectively).ConclusionAberrant expression of CD13 in ≥ 5% of blasts of patients with SR-aALL is an adverse prognostic factor, delineating a subgroup of patients with SR-aALL that should be considered for more aggressive treatment.     

Tumor-Infiltrating PD-1+ Immune Cell Density is Associated with Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

BackgroundElevated tumor-infiltrating T-cell density is associated with favorable outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). Here, we evaluated the significance of programmed cell death 1 (PD-1)-positive cells, regulatory T cells, and macrophages in response to CRT and prognosis.Patients and MethodsWe assessed CD8+, PD-1+, FOXP3+, CD68+, and CD163+ intratumoral and stromal cell densities by immunohistochemistry using pre-treatment biopsies from 275 patients with rectal cancer treated with neoadjuvant CRT. We determined the impact of these measurements on response to CRT and survival. Response to CRT was determined by tumor regression grade (TRG) of surgical specimens, with good responders defined as TRG3-4.ResultsIntratumoral CD8+ and PD-1+ cell densities were significantly higher in good responders than in poor responders, whereas stromal CD68+ cell density was significantly lower in good responders as compared with poor responders. The multivariable analysis revealed high intratumoral CD8+ and PD-1+ cell densities to be independently associated with good responders (CD8: odds ratio [OR], 2.27; 95% confidence interval [CI], 1.21 – 4.34, P = .010; PD-1: OR, 1.97; 95%CI, 1.03 – 3.84, P = .039), and improved recurrence-free survival (CD8: hazard ratio [HR], 0.56; 95%CI, 0.32 – 0.98, P = .044; PD-1: HR, 0.37; 95%CI, 0.19 – 0.71, P = .002). Only high intratumoral CD8+ cell density was associated with improved overall survival (P = .022).ConclusionPre-treatment high intratumoral PD-1+ and CD8+ cell densities were independently associated with good response to CRT and improved recurrence-free survival, with high intratumoral CD8+ cell density additionally associated with improved overall survival. These values may serve as predictive and prognostic biomarkers in rectal cancer.     

Outcomes for Young Men With Localized Intermediate-Risk Prostate Cancer: An Analysis of the NCDB

BackgroundPrimary management of localized, intermediate-risk prostate cancer consists of radical prostatectomy (RP), radiotherapy (RT) with short-course androgen deprivation therapy (ADT), or RT alone. The purpose of this study was to determine if these treatment strategies have equivalent overall survival (OS) in patients < 55 years old with intermediate-risk prostate cancer.Patients and MethodsWe identified 35,134 patients in the National Cancer Data Base with localized intermediate-risk prostate cancer treated with RP, RT + ADT, or RT from 2004 to 2013. Ten-year OS rates were estimated by the Kaplan-Meier method. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were computed by multivariate Cox regression.ResultsA total of 29,920 patients (85.2%) underwent RP, 1393 (4.0%) RT + ADT, and 3821 (10.9%) RT. Median patient age was 51 years old, and median follow-up was 59.9 months. Ten-year OS was estimated to be 94.2% for RP, 80.7% for RT + ADT, and 85.2% for RT (P < .0001). On multivariate analysis, treatment with RT + ADT or RT was associated with significantly worse OS compared to treatment with RP (RT + ADT HR = 2.06, 95% CI 1.67-2.54, P < .0001; RT HR = 2.0, 95% CI 1.71-2.33, P < .0001). Patients who met all 3 of the intermediate-risk criteria showed worse OS compared to patients who met only one criterion (HR = 1.80; 95% CI, 1.32-2.44; P = .0002).ConclusionRP is significantly more likely than RT + ADT or RT to be used as a primary treatment for young men with localized intermediate prostate cancer. RP was also associated with improved OS compared to RT + ADT and RT.     

Reproductive Factors and Subtypes of Breast Cancer Defined by Estrogen Receptor,Progesterone Receptor,and Human Epidermal Growth Factor Receptor 2: A Register-Based Study From Korea

BackgroundThe relationship between reproductive breast risk factors and breast cancer survival in patients with different breast cancer subtypes is not well known.MethodsWe examined a large-sized, retrospective study of 23,882 subjects from the Korean Breast Cancer Registry. The breast cancer subtype was determined by immunohistochemical staining for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Information regarding reproductive factors, including breastfeeding, age at first birth (AFB), and parity, was gathered. Multivariate Cox regression analysis was used to estimate the association among breast cancer subtypes, such as luminal A, luminal B, Her-2/neu overexpressing, and triple negative breast cancer (TNBC), and breast cancer survival as dependent variables and adjusting for age and stage.ResultsHigh parity (≥ 5) increased the recurrence risk of luminal A and B breast cancer (hazard ratio [HR], 1.95; 95% confidence interval [CI], 0.96-3.97; P = .0055 and HR, 1.12; 95% CI, 0.42-3.02, respectively; P = .0073) in breast cancer–specific survival (BCSS), but 1 to 3 child births decreased the recurrence risk of luminal A breast cancer (HR, 0.56; 95% CI, 0.34-0.91; P = .0055) and luminal B breast cancer (HR, 0.32; 95% CI, 0.17-0.61; P = .0073) in BCSS. Early AFB (< 20 years) increased the recurrence risk of luminal A breast cancers (HR, 1.61; 95% CI, 0.62-4.26; P = .039) in BCSS and of TNBC (HR, 1.31; 95% CI, 0.78-2.21; P = .0006) in overall survival. Her-2/neu overexpressing breast cancer had no correlation with parity and AFB in breast cancer survival.ConclusionsHigh parity (≥ 5) and early AFB (< 20 years) were correlated with worse clinical outcomes in patients with luminal breast cancer, but not with other subtyped breast cancers.     

The Impact of Locoregional Treatment on Survival in Patients With Metastatic Breast Cancer: A National Cancer Database Analysis

BackgroundAlthough systemic therapy is the standard treatment for metastatic breast cancer, the value of locoregional treatment (LRT) of the primary tumor and its impact on survival is controversial. This study evaluates survival outcomes in patients with metastatic breast cancer after receiving LRT (surgery and/or radiation therapy) of the primary tumor.Materials and MethodsThe National Cancer Database was used to identify 16,128 qualifying cases of metastatic breast cancer who received systemic therapy with or without LRT from 2004 to 2013. Treatment modality was divided into surgery (Sx), radiation therapy (RT), surgery followed by RT (Sx + RT), and no LRT. The median survival and 3-year actuarial survival rates (OS) were analyzed for each treatment group. On multivariate analyses, adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using Cox regression modeling to adjust for patient and clinicopathologic characteristics.ResultsOverall, the median follow-up was 28.3 months, and the median survival for all patients was 37.2 months. With 9761 deaths reported, the estimated 3-year OS was 51.3%. The Sx + RT group (n = 2166) had the highest 3-year OS of 69.4%, followed by the Sx group (n = 4293) with 57.6%, the no LRT group (n = 8955) with 44.3%, and the RT group (n = 714) with 41.5% (P < .0001). On multivariate analysis, compared with the no LRT group, a decreased HR was noted in patients receiving Sx (adjusted HR, 0.68; 95% CI, 0.65-0.71; P < .0001) and Sx + RT (adjusted HR, 0.46; 95% CI, 0.43-0.49; P < .0001).ConclusionLRT, especially surgery followed by RT, in addition to systemic therapy, was associated with improved survival in patients with metastatic breast cancer.     

Clinical Outcomes of First-line Sunitinib Followed by Immuno-oncology Checkpoint Inhibitors in Patients With Metastatic Renal Cell Carcinoma

BackgroundThe present retrospective, longitudinal cohort study assessed the association between the first-line sunitinib treatment duration and clinical outcomes with second-line immuno-oncology (IO) therapy among patients with metastatic renal cell carcinoma (mRCC).Patients and MethodsA total of 161 patients with mRCC who had been treated with first-line sunitinib and subsequent IO therapy from select International mRCC Database Consortium centers were included. The overall survival, time to next therapy, time to treatment discontinuation, and real-world physician-assessed best response measured from IO therapy initiation were analyzed and compared between patients treated with first-line sunitinib for ≥ 6 months and those treated for < 6 months.ResultsThe 116 patients treated with sunitinib for ≥ 6 months tended to be older and to have a better International mRCC Database Consortium risk than the 45 patients treated for < 6 months (favorable, 36% vs. 8%, P = .001; intermediate, 59% vs. 70%, P = .21; poor, 5% vs. 22%, P = .007). The receipt of sunitinib for ≥ 6 months versus < 6 months was associated with longer survival (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.21-0.87; P = .02). No significant association was observed between the first-line sunitinib duration and second-line IO outcomes, including the time to next therapy (HR, 0.89; 95% CI, 0.52-1.51; P = .66), time to treatment discontinuation (HR, 0.85; 95% CI, 0.54-1.34; P = .49), and tumor response (odds ratio, 0.73; 95% CI, 0.22-2.49; P = .62).ConclusionsWe found no statistically significant association between the first-line sunitinib duration and clinical outcomes with second-line IO therapy. Patients receiving first-line sunitinib for ≥ 6 months compared with < 6 months was associated with better overall survival, although potential unadjusted confounders could have been present. These findings support the paradigm that previous therapy will not dictate the effectiveness of subsequent immunotherapy.     

Comparative Efficacy of Teclistamab Versus Physician's Choice of Therapy in the Long-term Follow-up of APOLLO,POLLUX, CASTOR,and EQUULEUS Clinical Trials in Patients With Triple-class Exposed Relapsed or Refractory Multiple Myeloma

BackgroundThe efficacy and safety of teclistamab in patients with RRMM who received ≥3 prior lines of therapy and were triple-class exposed (TCE) are being evaluated in the single-arm, multicohort, phase I/II MajesTEC-1 trial (NCT04557098). We evaluated the comparative effectiveness of teclistamab versus physician's choice (PC) of therapy in TCE RRMM patients.MethodsIndividual patient-level data from MajesTEC-1 patients who received teclistamab (1.5 mg/kg weekly; clinical cutoff March 16, 2022) were included. An external control arm was created from patients in long-term follow-up of 4 clinical trials of daratumumab who were treated with PC therapy after discontinuation of trial treatments. In the primary analysis, inverse probability of treatment weighting was used to adjust for imbalances in 9 baseline covariates. A fully adjusted model included 5 additional prognostic factors. Outcomes included overall response rate (ORR), very good partial response or better (≥VGPR) rate, overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT).ResultsAfter adjustment, baseline characteristics were balanced between cohorts. In the primary analysis, outcomes were significantly improved with teclistamab versus PC: ORR (OR [95% CI] 4.81 [3.04-7.72]; P < .0001); ≥VGPR rate (OR, 12.07 [6.91-22.11]; P < .0001); OS (HR, 0.54 [0.40-0.73]; P < .0001); PFS (HR, 0.59 [0.46-0.78]; P = .0001); and TTNT (HR, 0.32 [0.24-0.42]; P < .0001). Results of the fully adjusted model were consistent with the primary analysis.ConclusionTeclistamab showed significantly improved effectiveness versus PC on all outcomes, highlighting its clinical benefit in patients with TCE RRMM and limited treatment options.     

Tracing Leukemia Stem Cells and Their Influence on Clinical Course of Adult Acute Myeloid Leukemia

BackgroundAcute myeloid leukemia (AML) evolves from neoplastic transformation of stem cell disease termed “leukemia stem cells” (LSCs). An unsatisfactory response to AML therapy is determined by the presence of minimal residual disease (MRD). The predominance of LSCs might anticipate sustained MRD results. The present study aimed to demonstrate the effect of LSCs on MRD at induction days 14 and 28 on overall survival (OS) and disease-free survival (DFS) and to compare LSC expression with MRD status.Patients and MethodsA total of 84 patients with de novo adult AML underwent testing using LSC panels for CD38/CD123/CD34/CD45 and CD90/CD133/CD45/CD33 and different regular MRD panels.ResultsAt day 14 after induction, the high expression of CD123 and CD133 had adverse effects on both OS and DFS (P = .004 and P ≤ .001 and P ≤ .001 and P ≤ .001, respectively). Greater expression of CD34⁺/CD38⁻/CD123⁺ resulted in unfavorable OS and DFS (P ≤ .001 for both). Both CD34⁺/CD38⁻/CD123⁺ and CD34⁻/CD38⁺/CD123⁺ expression at day 14 after induction had an adverse effect on DFS only (P < .001 and P = .029, respectively). On multivariate analysis, CD133 expression and MRD status were independent prognostic parameters (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.2-4.4; P = .015; and HR, 2.9; 95% CI, 1.0-7.9; P = .041). At day 28 after induction, MRD and increased CD123⁺/CD34⁻, CD34⁺/CD38⁻/CD123⁺, CD133⁺/CD33⁻ expression were associated with inferior OS (P = .016, P = .0035, P = .0.002, and P = .002, respectively). MRD and high expression of CD34⁺CD123⁺, CD133⁺/CD33⁻, CD34⁺/CD38⁻/CD123⁺ were associated with inferior DFS (P < .001, P = .002, P < .001, P < .001, respectively). On multivariate analysis, only CD133⁺/CD33⁻ expression was the independent prognostic factor (HR, 3.1; 95% CI, 1.5-6.7; P = .003).ConclusionsEstimation of LSC expression is a sensitive indicator of the response to therapy in adult patients with AML and might be a better prognosticator than the findings from regular MRD panels.     

PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non–small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors

BackgroundRapid disease progression of patients with advanced epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) has been recently associated with tumor heterogeneity, which may be mirrored by coexisting concomitant alterations. The aim of this analysis was to investigate the correlation between loss of function of PTEN and the efficacy of tyrosine kinase inhibitors in this population.Materials and MethodsArchival tumor blocks from patients with EGFR-mutant NSCLC who were administered upfront tyrosine kinase inhibitors were retrospectively collected. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry, and it was correlated with overall response rate, overall survival (OS), and progression-free survival (PFS).ResultsFifty-one patients were included. In multivariate analysis, PTEN loss (hazard ratio [HR], 3.46; 95% confidence interval [CI], 1.56-7.66; P = .002), IGFR overexpression (HR, 2.22; 95% CI, 1.03-4.77; P = .04), liver metastases (HR, 3.55; 95% CI, 1.46-8.65; P = .005), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 (HR, 2.57; 95% CI, 1.04-6.34; P = .04) were significantly associated with shorter PFS. Patients with PTEN loss had a median PFS of 6 months (2-year PFS, 11.6%), whereas patients without PTEN loss had a median PFS of 18 months (2-year PFS, 43.6%) (log-rank P < .005). In the multivariate analysis, PTEN loss (HR, 5.92; 95% CI, 2.37-14.81; P < .005), liver metastases (HR, 2.63; 95% CI, 1.06-6.51; P = .037), and ECOG PS ≥ 1 (HR, 2.80; 95% CI, 1.15-6.81; P = .024) were significantly associated with shorter OS. Patients with PTEN loss had a median OS of 6 months (2-year OS, 12.2%), whereas in patients without PTEN loss, OS was not reached (2-year OS, 63.9%) (log-rank P < .0005).ConclusionsA low-cost and reproducible immunohistochemistry assay for PTEN loss analysis represents a potential tool for identifying tumor heterogeneity in patients with advanced EGFR-mutant NSCLC.     

Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency

BackgroundPatients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs.Patients and methodsMSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation.ResultsAmong 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (37%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44).ConclusionsLS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations.     

Systemic Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphoma: A Population-based Analysis of Incidence and Survival

IntroductionSystemic ALK-positive anaplastic large cell lymphoma (ALK-positive ALCL) is a T-cell lymphoma. Owing to its rarity, variations in incidence and survival at the population level are not clearly known.Materials and MethodsUsing the Surveillance Epidemiology and End Results database (SEER 18), we selected patients aged ≥ 20 years with ALK-positive ALCL, diagnosed between 2001 and 2013. Incidence rate, overall survival (OS), and its determinants were analyzed with a significance level of P < .05.ResultsWe identified 1604 patients with a median age of 54 years. The disease incidence increased significantly with advancing age, with higher incidence in Blacks and lower incidence in American Indians and Asian/Pacific Islanders as compared with Whites. The 5-year OS significantly declined as the age advanced (age 20-40 years, 68.7%; age 41-60 years, 53.8%; age 61-80 years, 28.9%; age > 80 years, 15.2%; P < .01) and varied with race (Whites, 49.7% vs. Blacks, 37.7% vs. Asian/Pacific Islander, 42.8% vs. American Indian, 35.8%; P = .03). On multivariate analysis, treatment with radiation (hazard ratio [HR], 0.72; 95% confidence interval [95% CI], 0.59-0.87; P < .01) and year of diagnosis from 2009 through 2013 (HR, 0.77; 95% CI, 0.65-0.93; P < .01) were associated with lower mortality. Advanced age, Black race (HR, 1.37; 95% CI, 1.14-1.65; P < .01), and advanced disease stage (HR, 1.74; 95% CI, 1.51-2.02; P < .01) were associated with higher mortality.ConclusionIncidence and survival of ALK-positive ALCL varies significantly with patients' demographic characteristics as identified in our study. Treatment strategies need to be tailored accordingly to address these variations and ensure uniform access to care.