ABSTRACT
PURPOSE: In PERTAIN's primary analysis (31 months' median follow-up), adding pertuzumab to trastuzumab and an aromatase inhibitor (AI) with/without chemotherapy significantly improved progression-free survival (PFS) in patients with previously untreated HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (M/LABC). A potentially enhanced treatment effect was observed in patients with no induction chemotherapy. We present the final analysis (>6 years' median follow-up). PATIENTS AND METHODS: Patients (N = 258) were randomized 1:1 to pertuzumab (loading/maintenance: 840/420 mg) plus trastuzumab (loading/maintenance: 8/6 mg/kg) every 3 weeks and an AI (1 mg anastrozole or 2.5 mg letrozole daily; Arm A), or trastuzumab and an AI (Arm B). Induction chemotherapy was at investigator discretion. Primary endpoint: PFS. Key secondary endpoints: overall survival (OS) and safety. RESULTS: Median PFS was 20.6 versus 15.8 months in Arms A and B, respectively (stratified HR, 0.67; P = 0.006). Median OS was 60.2 versus 57.2 months (stratified HR, 1.05; P = 0.78). Pertuzumab treatment effect was potentially enhanced in patients with no induction chemotherapy (26.6 vs. 12.5 months). Any-grade adverse events (AE) occurred in 122 patients per arm (96.1% vs. 98.4%); grade ≥ 3 AEs in 72 (56.7%) and 51 (41.1%); serious AEs in 46 (36.2%) and 28 (22.6%). CONCLUSIONS: The PFS benefit of pertuzumab was maintained and OS was similar between arms at final analysis. Adding pertuzumab may enhance activity in patients who do not require first-line chemotherapy for M/LABC. No new safety concerns were reported. These data provide additional evidence of the role of first-line pertuzumab and trastuzumab in HER2-positive M/LABC.
Subject(s)
Breast Neoplasms , Humans , Female , Trastuzumab , Breast Neoplasms/pathology , Aromatase Inhibitors/adverse effects , Receptor, ErbB-2 , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
INTRODUCTION: A good response to initial therapy is key to maximizing survival in patients with diffuse large B-cell lymphoma (DLBCL), but patients with chemorefractory disease and early progression have poor outcomes. PATIENTS AND METHODS: Data from the GOYA study in patients with DLBCL who received first-line rituximab or obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were analyzed. Positron emission tomography/computed tomography (PET/CT)-derived characteristics associated with total metabolic tumor volume (TMTV) and clinical risk factors for primary chemorefractory disease and disease progression within 12 months (POD12) were explored. RESULTS: Of those patients fulfilling the criteria for analysis, 108/1126 (10%) were primary chemorefractory and 147/1106 (13%) had POD12. Primary chemorefractory and POD12 status were strongly associated with reduced overall survival. After multivariable analysis of clinical and imaging-based risk factors by backward elimination, only very high TMTV (quartile [Q] 1 vs. Q4 odds ratio [OR]: 0.45; Pâ¯=â¯.006) and serum albumin levels (low vs. normal OR of 1.86; Pâ¯=â¯.004) were associated with primary chemorefractoriness. After additionally accounting for BCL2/MYC translocation in a subset of patients, TMTV and BCL2/MYC double-hit status remained as significant predictors of primary chemorefractoriness (Q1 vs. Q4 OR: 0.32, Pâ¯=â¯.01 and double-hit vs. no-hit OR of 4.47, Pâ¯=â¯.02, respectively). Risk factors including very high TMTV, high sum of the product of the longest diameters (SPD), geographic region (Asia), short time since diagnosis, extranodal involvement and low serum albumin were retained for POD12. CONCLUSION: PET-derived TMTV has prognostic value in identifying patients at risk of early treatment failure.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Positron Emission Tomography Computed Tomography , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Humans , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Prednisone/therapeutic use , Prognosis , Proto-Oncogene Proteins c-bcl-2 , Serum Albumin/therapeutic use , Tumor Burden , Vincristine/therapeutic useABSTRACT
AIM: The aim of the study was to assess patient preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in patients with HER2-positive early breast cancer in PHranceSCa (NCT03674112). MATERIALS AND METHODS: Patients who completed neoadjuvant P + H + chemotherapy + surgery were randomised 1:1 to three intravenous (IV) P + H cycles followed by three cycles of PH FDC SC or vice versa (crossover) and then chose subcutaneous (SC) injection or IV infusion to continue up to 18 cycles (continuation). Assessments were via patient and healthcare professional (HCP) questionnaires. RESULTS: One hundred and sixty patients were randomised (cut-off: 24 February 2020); 136 (85.0%, 95% confidence interval: 78.5-90.2%) preferred SC; 22 (13.8%) preferred IV; 2 (1.3%) had no preference. The main reasons for SC preference were reduced clinic time (n = 119) and comfort during administration (n = 73). One hundred and forty-one patients (88.1%) were very satisfied/satisfied with SC injection versus 108 (67.5%) with IV infusion; 86.9% chose PH FDC SC continuation. HCP perceptions of median patient treatment room time ranged from 33.0-50.0 min with SC and 130.0-300.0 min with IV. Most adverse events (AEs) were grade 1/2 (no 4/5s); serious AE rates were low. AE rates before and after switching were similar (cycles 1-3 IV â cycles 4-6 SC: 77.5% â 72.5%; cycles 1-3 SC â cycles 4-6 IV: 77.5% â 63.8%). CONCLUSION: Most patients strongly preferred PH FDC SC over P + H IV. PH FDC SC was generally well tolerated, with no new safety signals (even when switching), and offers a quicker alternative to IV infusion.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/therapy , Neoadjuvant Therapy/methods , Patient Preference/statistics & numerical data , Trastuzumab/administration & dosage , Adult , Aged , Aged, 80 and over , Breast Neoplasms/diagnosis , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Chemotherapy, Adjuvant/methods , Chemotherapy, Adjuvant/psychology , Chemotherapy, Adjuvant/statistics & numerical data , Cross-Over Studies , Drug Combinations , Female , Humans , Infusions, Intravenous/adverse effects , Infusions, Intravenous/psychology , Injections, Subcutaneous/adverse effects , Injections, Subcutaneous/psychology , Middle Aged , Neoadjuvant Therapy/psychology , Neoadjuvant Therapy/statistics & numerical data , Neoplasm Staging , Patient Satisfaction , Receptor, ErbB-2/analysis , Receptor, ErbB-2/metabolism , Young AdultABSTRACT
Importance: DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown. Objective: To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations. Design, Setting, and Participants: In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019. Exposure: Treatment with platinum-based compounds either as monotherapy or combination therapy. Main Outcomes and Measures: The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations. Results: A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (P = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P = .07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively. Conclusions and Relevance: In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.
Subject(s)
DNA Repair-Deficiency Disorders/drug therapy , Drug Therapy/standards , Platinum Compounds/therapeutic use , Prostatic Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Docetaxel/therapeutic use , Drug Therapy/methods , Drug Therapy/statistics & numerical data , Humans , Male , Middle Aged , Paclitaxel/therapeutic use , Retrospective StudiesABSTRACT
BACKGROUND: The HER2 extracellular domain shed in blood (HER2ECD) is reported to rise and fall in parallel with HER2+ breast cancer behavior. In this study, we evaluated the clinical relevance of plasma HER2ECD values in patients with metastatic breast cancer treated in the SAKK22/99 trial comparing trastuzumab monotherapy followed by trastuzumab-chemotherapy combination at progression versus upfront combination therapy. METHODS: Quantitative assessment of plasma HER2ECD was performed in 133 patients at baseline; after 2-24 h; at 3 weeks; at first response evaluation (8-9 weeks); and at tumor progression. Associations with tumor characteristics, disease course and trial treatment were evaluated. RESULTS: Baseline HER2ECD levels were stable within 24 h after the first trastuzumab injection. These plasma values correlated positively with the HER2 gene ratio (rs = 0.39, P < 0.001) and HER2 protein expression levels (rs = 0.36, P < 0.001) but not with ER/PR status of the primary tumor. HER2ECD baseline levels were positively associated with the presence of visceral disease (P = 0.05) and poor patients' outcome (Cox-regression: P = 0.009). Patients with high baseline levels (> 35 ng/ml) had the worst overall survival (P = 0.03) if treated with upfront combination therapy. Conversely, patients with low HER2ECD baseline values (< 15 ng/ml) had longer time to progression on combined trastuzumab-chemotherapy when first treated with trastuzumab monotherapy (P = 0.02). Monitoring HER2ECD levels during the course of the trial revealed significant time (P = 0.001) and time-treatment arm interactions (P = 0.0007). Under upfront trastuzumab alone, the HER2ECD levels remained stable until just before disease progression. In patients responding to combination treatment HER2ECD levels decreased to > 20%. CONCLUSIONS: Plasma HER2ECD levels in patients with metastatic breast cancer reflect HER2 disease status. This robust biomarker might help identifying patients without visceral disease profiting from a sequential treatment's modality. Monitoring HER2ECD levels during trastuzumab monotherapy could help defining the optimal time to introduce chemotherapy. TRIAL REGISTRATION: Registration Number by ClinicalTrials.gov: NCT00004935, Trial number: SAKK22/99. Registered on 27 January 2003.
Subject(s)
Biomarkers, Tumor , Breast Neoplasms/blood , Breast Neoplasms/mortality , Protein Domains , Receptor, ErbB-2/blood , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/diagnosis , Breast Neoplasms/drug therapy , Enzyme-Linked Immunosorbent Assay , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Molecular Targeted Therapy , Prognosis , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/chemistry , Treatment OutcomeABSTRACT
PURPOSE: Clinical stage I (CSI) nonseminoma (NS) is a disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant chemotherapy. Little is known about the outcome of patients who experience relapse after such treatment. PATIENTS AND METHODS: Data from 51 patients with CSI NS who experienced a relapse after adjuvant bleomycin, etoposide, and cisplatin (BEP) from 18 centers/11 countries were collected and retrospectively analyzed. Primary outcomes were overall and progression-free survivals calculated from day 1 of treatment at first relapse. Secondary outcomes were time to, stage at, and treatment of relapse and rate of subsequent relapses. RESULTS: Median time to relapse was 13 months, with the earliest relapse 2 months after start of adjuvant treatment and the latest after 25 years. With a median follow-up of 96 months, the 5-year PFS was 67% (95% CI, 54% to 82%) and the 5-year OS was 81% (95% CI, 70% to 94%). Overall, 19 (37%) of 51 relapses occurred later than 2 years. Late relapses were associated with a significantly higher risk of death from NS (hazard ratio, 1.10 per year; P = .01). Treatment upon relapse was diverse: the majority of patients received a combination of chemotherapy and surgery. Twenty-nine percent of patients experienced a subsequent relapse. At last follow-up, 41 patients (80%) were alive and disease-free, eight (16%) had died of progressive disease, and one patient (2%) each had died from therapy-related or other causes. CONCLUSION: Outcomes of patients with relapse after adjuvant BEP seem better compared with patients who experience relapse after treatment of metastatic disease but worse compared with those who have de-novo metastatic disease. We found a substantial rate of late and subsequent relapses. There seem to be three patterns of relapse with different outcomes: pure teratoma, early viable NS relapse (< 2 years), and late viable NS relapse (> 2 years).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms, Germ Cell and Embryonal/drug therapy , Testicular Neoplasms/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bleomycin/administration & dosage , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Etoposide/administration & dosage , Humans , Male , Neoplasm Staging , Neoplasms, Germ Cell and Embryonal/surgery , Orchiectomy , Progression-Free Survival , Retrospective Studies , Survival Rate , Testicular Neoplasms/pathology , Testicular Neoplasms/surgery , Treatment OutcomeABSTRACT
BACKGROUND: The impact of HER2-targeted therapy alone followed by the addition of chemotherapy at disease progression (PD) versus upfront combination was investigated by the SAKK 22/99 trial. The aim of this exploratory analysis of the SAKK 22/99 trial was to characterize the specific subset of patients deriving long-term benefit from trastuzumab monotherapy alone and to identify potential predictive factors of long-term response. METHODS: This is an unplanned post-hoc analysis of patients randomized to Arm A (trastuzumab monotherapy). Patients were divided in two groups: patients with durable clinical benefit from trastuzumab monotherapy and short-term responders without durable clinical benefit from trastuzumab monotherapy Univariate and multivariate analyses of clinical characteristics correlating with response duration was performed. RESULTS: Eighty six patients were randomized in arm A, 24 patients (28%) were long-term responders and 62 (72%) were short-term responders with a 5y-overall survival (OS) of 54% (95% CI 31-72) and of 18% (95%CI 10-30), respectively. Absence of ER expression, absence of PgR expression and presence of visceral disease emerged as possible negative predictive factors for durable clinical benefit. CONCLUSION: Durable clinical benefit can be achieved with trastuzumab monotherapy in a subgroup of HER2-positive patients with advanced disease and it is predictive for longer OS. Further investigations of predictive biomarkers are necessary to better characterize this subgroup of patients and develop further de-escalating strategies. TRIAL REGISTRATION: NCT00004935 ; first posted 27.01.2003, retrospectively registered.
Subject(s)
Breast Neoplasms/drug therapy , Receptor, ErbB-2 , Trastuzumab/therapeutic use , Aged , Antineoplastic Agents, Immunological/therapeutic use , Breast Neoplasms/metabolism , Disease-Free Survival , Female , Humans , Middle Aged , Prognosis , Retrospective StudiesABSTRACT
The assessment of Ki-67 in early-stage breast cancer has become an important diagnostic tool in planning adjuvant therapy, particularly for the administration of additional chemotherapy to hormone-responsive patients. An accurate determination of the Ki-67 index is of the utmost importance; however, the reproducibility is currently unsatisfactory. In this study, we addressed the predictive/prognostic value of Ki-67 index assessed by using the most reproducible methods, which were identified in the pilot phase. Paraffin blocks obtained from patients with moderately differentiated, estrogen receptor (ER)-positive early-stage breast cancer in Switzerland, who were originally randomized to the treatment arms with and without chemotherapy in the IBCSG VIII-IX trials, were retrieved. Of these 344 randomized patients, we identified 158 patients (82 treated with and 76 treated without chemotherapy) for whom sufficient tumour tissue was available. The presence of Ki-67 was assessed visually by counting 2000 cells at the periphery (A) and estimating the number of positive cells in five different peripheral regions (C), which was determined to be the most reproducible method identified the pilot phase. The prognostic and predictive value was assessed by calculating the breast cancer-free interval (BCFI) and overall survival (OS) rate. Ki-67 was considered a numerical and categorical variable when different cut-off values were used (10%, 14%, 20% and 30%). An mRNA-based subtyping by using the MammaTyper kit with the application of a 20% Ki-67 immunohistochemistry (IHC) cut-off equivalent was also performed. 158 of 344 randomized patients could be included in the Ki-67 analysis. The mean Ki-67 values obtained by using the two methods differed (A: 21.32% and C: 16.07%). Ki-67 assessed by using method A with a cut-off of 10% was a predictive marker for OS, as the hazard ratio (>10% vs. <=10%) in patients with chemotherapy was 0.48 with a 95% confidence interval of [0.19-1.19]. Further, the HR of patients treated without chemotherapy was 3.72 with a 95% confidence interval of [1.16-11.96] (pinteraction=0.007). Higher Ki-67 index was not associated with outcome and using the 10% Ki-67 cut-off there was an opposite association for patients with and without chemotherapy. Ki-67 assessments with IHC significantly correlated with MammaTyper results (p=0.002). The exact counting method (A) performed via a light-microscope revealed the predictive value of Ki-67 assessment with a 10% cut-off value. Further analyses employing image analyses and/or mRNA-based-assessments in larger populations are warranted.
Subject(s)
Breast Neoplasms/classification , Breast Neoplasms/metabolism , Ki-67 Antigen/metabolism , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Pharmacological/analysis , Breast Neoplasms/pathology , Chemotherapy, Adjuvant/methods , Cohort Studies , Disease-Free Survival , Female , Humans , Immunohistochemistry/methods , Ki-67 Antigen/immunology , Middle Aged , Prognosis , Proportional Hazards Models , Receptor, ErbB-2 , Receptors, Estrogen , Receptors, Progesterone , Reproducibility of Results , SwitzerlandABSTRACT
BACKGROUND: To provide rapid evaluation of patients with advanced urological malignancies, a joint urological-oncological clinic was initiated at our institution in January 2015. We present the first 3-year evaluation of this joint urological-oncological clinic in Switzerland. METHOD: We performed a retrospective analysis of the characteristics and treatment of all patients reviewed at the joint clinic between January 2015 and December 2017. Statistical analysis was performed by survival analysis. A patient satisfaction questionnaire was handed out to new patients (from April to September 2017). RESULTS: A total of 135 new patients were counseled in the joint clinic and 563 consultations were performed in the period from January 2015 to December 2017. The majority were men with prostate cancer (85%), followed by bladder cancer (9%), and renal cell carcinoma (4%). Men with newly diagnosed metastatic prostate cancer (n = 69) received ADT alone (57%), ADT with docetaxel or abiraterone (33%), and metastasis-directed therapy (10%). High rates of patient satisfaction were reported based on the questionnaire. CONCLUSIONS: The joint clinic model has been successfully implemented at our institution and continues on a weekly basis. The clinic is increasingly used, not only for newly diagnosed metastatic prostate cancer, but also for other complex uro-oncological cases. The clinic allows optimized oncological treatment without delay and with a reduced effort for patients.
Subject(s)
Decision Making, Shared , Interprofessional Relations , Urologic Neoplasms/classification , Urologic Neoplasms/drug therapy , Abiraterone Acetate/therapeutic use , Aged , Aged, 80 and over , Clinical Decision-Making , Docetaxel/therapeutic use , Humans , Male , Medical Oncology , Middle Aged , Patient Satisfaction/statistics & numerical data , Retrospective Studies , Survival Analysis , Switzerland , Treatment Outcome , UrologyABSTRACT
BACKGROUND: There is evidence linking metformin to improved prostate cancer-related outcomes. PATIENTS AND METHODS: Twenty-five men with metastatic castration-resistant prostate cancer and prostate-specific antigen (PSA) progression while receiving treatment with abiraterone from 3 Swiss centers were included in this single-arm phase 2 trial between November 2013 and September 2016. Metformin was added to abiraterone continuously at 1000 mg twice daily in uninterrupted 4-week cycles. The primary end point was the absence of disease progression at 12 weeks (PFS12). The Fleming single-stage design was applied. With a 5% significance level and 80% power, 25 patients were required to test PFS12 ≤ 15% (H0) compared to ≥ 35% (H1). Secondary end points included toxicity and safety issues. The study was registered at ClinicalTrials.gov (NCT01677897). RESULTS: The primary end point PFS12 was 12% (3 of 25 patients) (95% confidence interval, 3-31). Most patients had PSA progression, almost half had radiographic progression, but only 1 patient had symptomatic progression. Eleven (44%) of 25 patients had grade 1 and 2 patients each grade 2 (8%) or grade 3 (8%) gastrointestinal toxicity (nausea, diarrhea, loss of appetite). One patient discontinued treatment at week 5 because of intolerable grade 3 diarrhea. CONCLUSION: The addition of metformin to abiraterone for patients with metastatic castration-resistant prostate cancer and PSA progression while receiving abiraterone therapy does not affect further progression and has no meaningful clinical benefit. A higher-than-expected gastrointestinal toxicity attributed to metformin was observed.
Subject(s)
Abiraterone Acetate/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Metformin/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Abiraterone Acetate/adverse effects , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease Progression , Drug Administration Schedule , Humans , Male , Metformin/adverse effects , Pilot Projects , Survival Analysis , Treatment OutcomeABSTRACT
PURPOSE: Residual lesions after chemotherapy are frequent in metastatic seminoma. Watchful waiting is recommended for lesions < 3 cm as well as for fluorodeoxyglucose (FDG) positron emission tomography (PET)-negative lesions ≥ 3 cm. Information on the optimal management of PET-positive residual lesions ≥ 3 cm is lacking. PATIENTS AND METHODS: We retrospectively identified 90 patients with metastatic seminoma with PET-positive residual lesions after chemotherapy. Patients with elevated α-fetoprotein or nonseminomatous histology were excluded. We analyzed the post-PET management and its impact on relapse and survival and calculated the positive predictive value (PPV) for PET. RESULTS: Median follow-up time was 29 months (interquartile range [IQR], 10 to 62 months). Median diameter of the largest residual mass was 4.9 cm (range, 1.1 to 14 cm), with masses located in the retroperitoneum (77%), pelvis (16%), mediastinum (17%), and/or lung (3%). Median time from the last day of chemotherapy to PET was 6.9 weeks (IQR, 4.4 to 9.9 weeks). Post-PET management included repeated imaging in 51 patients (57%), resection in 26 patients (29%), biopsy in nine patients (10%) and radiotherapy in four patients (4%). Histology of the resected specimen was necrosis in 21 patients (81%) and vital seminoma in five patients (19%). No biopsy revealed vital seminoma. Relapse or progression occurred in 15 patients (17%) after a median of 3.7 months (IQR, 2.5 to 4.9 months) and was found in 11 (22%) of 51 patients on repeated imaging, in two (8%) of 26 patients after resection, and in two (22%) of nine patients after biopsy. All but one patient who experienced relapse were successfully treated with salvage therapy. The PPV for FDG-PET was 23%. CONCLUSION: FDG-PET has a low PPV for vital tumor in residual lesions after chemotherapy in patients with metastatic seminoma. This cautions against clinical decisions based on PET positivity alone.
ABSTRACT
BACKGROUND: Response to immune checkpoint inhibitors depends on tumor intrinsic properties and also on host factors in the tumour microenvironment including the presence of immune cells (IC). We hypothesized that nivolumab efficacy varies across different metastatic sites. METHODS: We retrospectively analyzed computed tomography scans of patients with metastatic non-small cell lung carcinoma (NSCLC) receiving nivolumab. RECIST 1.1 criteria were applied to assess the overall response rate (ORR) and organ-specific response rate (OSRR). RESULTS: We analyzed 52 patients including 44% females, 58% adenocarcinoma and 8% never smokers. Involved organs had target-lesions in the lung (42%), liver (25%), lymph nodes (56%) and soft tissue (13%) and non-target lesions in the bones (23%). ORR and disease control rate (DCR) were 20% and 45%, respectively. Median overall survival, progression-free survival and duration of response were 11.9, 2.3 and 10.3 months. OSRR and organ-specific DCR (OSDCR) were 28% and 90% in lymph nodes, 8% and 54 in the liver, and 9% and 55% in lung metastases. Nine out of 12 patients with bone metastases had progressive lesions. The cumulative incidence probability of organ-specific progression at 6 months was 14% in lymph nodes, 42% in the liver, 36% in lung metastases and 26% in the primary tumor, 29% in soft tissue and 33% in adrenal metastases. CONCLUSION: In conclusion, the efficacy of immunotherapy is dependent on the metastatic location. Treatment appears more active in lymph nodes compared to other organ sites such as liver, adrenals and bone. Future strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Immunomodulation/drug effects , Lung Neoplasms/drug therapy , Nivolumab/therapeutic use , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/pharmacology , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/immunology , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Molecular Targeted Therapy , Nivolumab/pharmacology , Organ Specificity/drug effects , Organ Specificity/immunology , Retrospective Studies , Survival Analysis , Treatment Outcome , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunologyABSTRACT
INTRODUCTION: There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). METHODS: Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative (<5%), intermediate (5%-49%), and high (≥50%). RESULTS: A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. CONCLUSION: These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti-PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Lung Neoplasms/drug therapy , Mesothelioma/drug therapy , Pleural Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Female , Humans , Immunotherapy/methods , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Male , Mesothelioma/immunology , Mesothelioma/pathology , Mesothelioma, Malignant , Middle Aged , Pleural Neoplasms/immunology , Pleural Neoplasms/pathologyABSTRACT
PURPOSE: Irinotecan (CPT-11) in combination with 5-fluorouracil (5FU) is widely used in the treatment of colorectal cancer. We assessed potential clinical variables that may predict toxicity and more specifically the role of UGT1A1 polymorphisms associated with irinotecan toxicity. We used data from the PETACC3 trial, which randomised patients in adjuvant setting to 6 months of leucovorin (LV) and 5FU (LV5/FU2) or LV5/FU2 + irinotecan. PATIENTS AND METHODS: Clinical and toxicity data were available for 2982 patients, DNA was available for 1200 (40%) of these patients. We genotyped the polymorphisms UGT1A1*28 and UGT1A1-3156G > A. Risk factors for neutropenia and diarrhoea were assessed by univariable and multivariable analyses. RESULTS: In univariable analysis, UGT1A*28 genotype was associated with an increased incidence of grade III-IV neutropenia (incidence: 44% versus 26%; odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.4-3.7). In multivariable analysis, the most important predictors (ordered in terms of contribution to R2) were baseline neutrophil count (OR for 1-unit (109/l) decrease: 1.8, 95% CI: 1.3-1.7), female sex (OR: 1.8, 95% CI: 1.1-3.0), body surface area (OR for 0.1-unit increase: 0.8, 95% CI: 0.7-1.0), UGT1A1 (OR: 2.8, 95% CI: 1.6-5.0), age (OR per 10 years: 1.3, 95% CI: 1.1-1.6) and poor performance status (OR: 1.6, 95% CI: 1.0-2.6). The main predictors for grade IV neutropenia were sex, age, performance score and UGT1A1. The main predictors for diarrhoea were sex and age. CONCLUSIONS: We found that a complex of risk factors is involved in the development of toxicity, including UGT1A1. Parameters that are readily available in clinical practice, notably sex, age and performance status, are stronger predictors than the UGT1A1*28 genotype. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the determinants of toxicity risk, notably in females.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/drug therapy , Diarrhea/epidemiology , Glucuronosyltransferase/genetics , Neutropenia/epidemiology , Adult , Age Factors , Aged , Biomarkers, Pharmacological/blood , Body Surface Area , Colorectal Neoplasms/blood , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Diarrhea/chemically induced , Female , Fluorouracil/adverse effects , Humans , Incidence , Irinotecan/adverse effects , Leucovorin/adverse effects , Leukocyte Count , Male , Middle Aged , Neoplasm Staging , Neutropenia/blood , Neutropenia/chemically induced , Neutropenia/genetics , Neutrophils , Sex Factors , Treatment Outcome , Young AdultABSTRACT
Purpose: BRAF mutation occurs in 8-15% of colon cancers (CC), and is associated with poor prognosis in metastatic disease. Compared to wild-type BRAF (BRAFWT) disease, stage II/III CC patients with BRAF mutant (BRAFMT) tumors have shorter overall survival after relapse; however, time-to-relapse is not significantly different. The aim of this investigation was to identify, and validate, novel predictors of relapse of stage II/III BRAFMT CC. Experimental design: We used gene expression data from a cohort of 460 patients (GSE39582) to perform a supervised classification analysis based on risk-of-relapse within BRAFMT stage II/III CC, to identify transcriptomic biomarkers associated with prognosis within this genotype. These findings were validated using immunohistochemistry in an independent population-based cohort of Stage II/III CC (n = 691), applying Cox proportional hazards analysis to determine associations with survival. Results: High gene expression levels of Bcl-xL, a key regulator of apoptosis, were associated with increased risk of relapse, specifically in BRAFMT tumors (HR = 8.3, 95% CI 1.7-41.7), but not KRASMT/BRAFWT or KRASWT/BRAFWT tumors. High Bcl-xL protein expression in BRAFMT, untreated, stage II/III CC was confirmed to be associated with an increased risk of death in an independent cohort (HR = 12.13, 95% CI 2.49-59.13). Additionally, BRAFMT tumors with high levels of Bcl-xL protein expression appeared to benefit from adjuvant chemotherapy (P for interaction = 0.006), indicating the potential predictive value of Bcl-xL expression in this setting. Conclusions: These findings provide evidence that Bcl-xL gene and/or protein expression identifies a poor prognostic subgroup of BRAFMT stage II/III CC patients, who may benefit from adjuvant chemotherapy.
ABSTRACT
BACKGROUND: Cholecalciferol (vitamin D3) is widely supplemented in breast cancer survivors because of the role of vitamin D in multiple health outcomes. METHODS: We conducted an observational study in 332 women in Eastern Switzerland with early, i.e., nonmetastatic breast cancer. Tumour-, patient-related and sociodemographic variables were recorded. Cholecalciferol intake and serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were measured at the first visit (baseline) and during a follow-up visit in a median of 210 days (range 87-857) after the first visit. Patients presenting 25(OH)D deficiency were advised to take cholecalciferol supplementation. RESULTS: At baseline, 60 (18%) patients had 25(OH)D deficiency (≤50 nmol/l, ≤20 ng/l), and 70 (21%) had insufficiency (50-74 nmol/l, 20-29 ng/l). Out of 121 patients with ongoing cholecalciferol supplementation at baseline, 25(OH)D deficiency and insufficiency was observed in 9 (7%) and 16 (13%) patients, respectively, whereas out of 52 patients with no supplementation, 15 (29%) had deficiency and 19 (37%) had insufficiency. Only 85 (26%) patients had optimal 25(OH)D levels (75-100 nmol/l, 30-40 ng/l) at baseline. Seasonal variation was significant for 25(OH)D (p = 0.042) and 1,25(OH)2D (p = 0.001) levels. Living in a rural area was associated with a higher median 25(OH)D concentration as compared with living in an urban area (87 nmol/l, range 16-216 vs 72 nmol/l, range 17-162; p = 0.001). Regular sporting activity was positively associated with 25(OH)D (p = 0.045). Body mass index was inversely related to both 25(OH)D and 1,25(OH)2D (Spearman's rho = -0.24, p <0.001; rho = -0.23, p <0.001, respectively). The levels of 25(OH)D and 1,25(OH)2D were correlated (rho = 0.21, p <0.001). Age and bone mineral density had no significant correlation with the levels of 25(OH)D. Follow-up 25(OH)D was available for 230 patients, 44 (19%) of whom had 25(OH)D deficiency and 47 (21%) had insufficiency; 25 (41.6%) initially 25(OH)D-deficient patients attained sufficient 25(OH)D levels, whereas 33 (16.5%) patients with sufficient baseline 25(OH)D levels became deficient. Only 67 (30%) patients presented optimal 25(OH)D at the follow-up. CONCLUSION: A remarkable fraction of the patients had serum 25(OH)D below (40%) or above (30%) optimal levels, and only around 30% of patients had optimal levels. Levels of 25(OH)D and 1,25(OH)2D increased on cholecalciferol supplementation, but the usual supplementation regimens were not adequate to bring 25(OH)D to the optimal range for a large proportion of patients. TRIAL REGISTRATION NUMBER: EKSG 08/082/2B.
Subject(s)
Breast Neoplasms , Cancer Survivors , Cholecalciferol/administration & dosage , Vitamin D Deficiency/drug therapy , Vitamin D/analogs & derivatives , Cholecalciferol/blood , Dietary Supplements , Female , Humans , Middle Aged , Surveys and Questionnaires , Switzerland , Vitamin D/blood , Vitamin D Deficiency/bloodABSTRACT
BACKGROUND: KRAS mutation occurs in â¼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. RESULTS: Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3-75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). CONCLUSIONS: Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Rectal Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Capecitabine/administration & dosage , Capecitabine/adverse effects , Chemoradiotherapy/adverse effects , Female , Humans , Male , Middle Aged , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Radiotherapy, Adjuvant/adverse effects , Rectal Neoplasms/genetics , SorafenibABSTRACT
BACKGROUND: The SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC). Although activating EGFR mutations were the strongest predictors of the response to BE, some patients not harboring driver mutations could benefit from the combined therapy. The identification of predictive biomarkers before or short after initiation of therapy is therefore paramount for proper patient selection, especially among EGFR wild-types. The first aim of this study was to investigate the early change in blood gene expression in unselected patients with advanced non-squamous NSCLC treated by BE. The second aim was to assess the predictive value of blood gene expression levels at baseline and 24h after BE therapy. METHODS: Blood samples from 43 advanced non-squamous NSCLC patients taken at baseline and 24h after initiation of therapy were profiled using Affymetrix' exon arrays. The 24h gene dysregulation was investigated in the light of gene functional annotations using gene set enrichment analysis. The predictive value of blood gene expression levels was assessed and validated using an independent dataset. RESULTS: Significant gene dysregulations associated with the 24h-effect of BE were detected from blood-based whole-genome profiling. BE had a direct effect on "Pathways in cancer", by significantly down-regulating genes involved in cytokine-cytokine receptor interaction, MAPK signaling pathway and mTOR signaling pathway. These pathways contribute to phenomena of evasion of apoptosis, proliferation and sustained angiogenesis. Other signaling pathways specifically reflecting the mechanisms of action of erlotinib and the anti-angiogenesis effect of bevacizumab were activated. The magnitude of change of the most dysregulated genes at 24h did not have a predictive value regarding the patients' response to BE. However, predictive markers were identified from the gene expression levels at 24h regarding time to progression under BE. CONCLUSIONS: The 24h-effect of the combined targeted therapy BE could be accurately monitored in advanced non-squamous NSCLC blood samples using whole-genome exon arrays. Putative predictive markers at 24h could reflect patients' response to BE after adjusting for their mutational status. Trial registration ClinicalTrials.gov: NCT00354549.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Erlotinib Hydrochloride/therapeutic use , Exons/genetics , Lung Neoplasms/blood , Lung Neoplasms/genetics , Adult , Aged , Bevacizumab/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Disease Progression , Erlotinib Hydrochloride/pharmacology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Signal Transduction/drug effectsABSTRACT
BACKGROUND/PURPOSE: Recently, the mutational background of diffuse large B cell lymphoma (DLBCL) has been revealed, identifying specific genetic events that drive lymphomagenesis. However, the prognostic value of these mutations remains to be determined. Prognostic biomarkers in DLBCL are urgently needed, since the current clinical parameter-based factors (e.g., International Prognostic Index (IPI)) are insufficient, particularly in identifying patients with poor prognosis who might benefit from alternative treatments. METHODS: We investigated the prognostic value of somatic mutations in DLBCL in a clinical trial (NCT00544219) patient cohort homogenously treated with six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP), followed by two cycles of R (R-CHOP-14). The primary endpoint was event-free survival (EFS) at 2 years. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Targeted high-throughput sequencing (HTS) of tumor genomic DNA was performed on all exons or hotspots of 68 genes frequently mutated in B cell lymphomas. Mutational data was correlated with the endpoints to identify prognostic associations. RESULTS: Targeted HTS detected somatic mutations in 71/76 (93%) of investigated cases. The most frequently mutated genes were KMT2D, SOCS1, GNA13, and B2M. Survival analysis revealed that CREBBP- and EP300-mutated cases had significantly worse OS, PFS, and EFS. In addition, ATM mutations predicted worse outcomes for all three clinical endpoints in germinal center B cell-like DLBCL. In contrast, SOCS1 mutations were associated with better PFS. On multivariable analysis taken into account IPI and failure to achieve complete remission, CREBBP and EP300 mutations remained significant to predict worse OS, PFS, and EFS. CONCLUSION: Targeted mutation analysis of a uniformly treated prospective clinical trial DLBCL cohort identifies tumor-based genetic prognostic markers that could be useful in the clinical management of such patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00544219.