This study assessed the human epidermal growth factor receptor-2 (HER2) protein expression and its relationship with gene amplification in invasive bladder carcinoma, using the same criteria than for ...breast cancer.
In 1005 patients, paraffin-embedded tissues of transurethral resection or cystectomy were evaluated by immunohistochemistry (IHC), using antibodies against HER2. All samples with a 2+ or 3+ HER2 overexpression were evaluated by FISH.
HER2 overexpression was observed in 93 (9.2%) tumors (2+: 42 tumors and 3+: 51 tumors). Using FISH, all HER2 3+ tumors had a gene amplification, whereas no amplification was found in 2+ tumors. Intratumoral heterogeneity was observed in 35% of cases. These tumors showed the same heterogeneous pattern, with adjacent 3+ positive and negative areas by both IHC and FISH.
This study showed that 5.1% of invasive bladder carcinomas had a HER2 gene amplification. These findings may have clinical implications for the management of patients with HER2-positive locally advanced or metastatic bladder cancer, as they could be potential candidates for targeted therapy.
Sacituzumab govitecan (SG) is a Trop-2-directed antibody–drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration ...approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear.
TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up.
Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status.
With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.
•With longer follow-up, response rate remains high (28%) in patients with advanced UC treated with sacituzumab govitecan.•Safety profile of sacituzumab govitecan was tolerable with low treatment discontinuation rates (7%).•Although incidence and grade of AEs varied across subgroups, AEs were managed similarly regardless of the UGT1A1 status.•UGT1A1 testing before SG initiation is not currently recommended in advanced UC as patients are closely monitored for AEs.•Other cohorts of the TROPHY-U-01 and TROPiCS-04 trials will continue to inform the impact of UGT1A1 status on safety.
In the evolution of metastatic castration-resistant prostate cancer (mCRPC), patients present visceral metastases with or without neuroendocrine differentiation in 20% of cases.
We assessed the ...efficacy and toxicity of a platinum-based chemotherapy regimen in mCRPC patients with either neuroendocrine differentiation defined by high serum levels of chromogranin A (CgA) and neuron-specific enolase (NSE) or visceral metastases. Patients received the combination of carboplatin and etoposide every 3 weeks. Efficacy end points included prostate-specific antigen (PSA) and neuroendocrine marker response, objective response and toxicity.
Of the 60 patients included from April 2005 to January 2008, 78.6% had bone metastases, 46.4% had lymph node involvement and 57.1% had liver and/or lung localizations. The objective response rate was 8.9% in the 46 patients with measurable disease. A neuroendocrine response was observed in 31% of cases for NSE and 7% for CgA. The PSA response rate was 8%. The most common grade 3–4 treatment-related toxic effects were neutropenia (65.5%), thrombocytopenia (32.7%) and anemia (27.3%). There was 7.2% febrile neutropenia, with one toxicity-related death. The median follow-up was 9.3 months 95% confidence interval (CI) 0.2–27.1 and the median overall survival 9.6 months (95% CI 8.7–12.7).
The benefit–risk ratio of this regimen seems unfavorable due to poor response and high toxicity.
Although recent experimental data strongly suggest that platinum-based chemotherapy (PBCT) could improve the outcome of triple-negative breast cancer (TNBC), clinical data are lacking. Here, the ...authors reviewed clinical outcome in patients with metastatic TNBC treated with PBCT.
We conducted a retrospective analysis of all patients (N = 143) treated for metastatic breast cancer with PBCT between 2000 and 2008, at Institut Curie, Paris, France. Ninety-three of them (63.7%) had TNBC. One-hundred twenty patients received cisplatin (CDDP). The main combination used was CDDP–ifosfamide, in 101 patients (70.2%).
Median follow-up was 44 months. For the overall population (N = 143), median overall survival (OS) and median progression-free survival (PFS) were 11 and 5 months, respectively. Objective response rate was 33.3% in the TNBC group versus 22% in non-TNBC, P = 0.1. We observed no difference of OS, PFS and response duration. Other prognostic factors for poor OS were visceral metastasis sites (P < 0.001). One patient died from sepsis during aplasia, 15 had to switch from CDDP to carboplatin because of CDDP-related toxicity.
Metastatic TNBC patients treated with PBCT tended to have a higher response rate, without a significant improvement of PFS or OS, compared with other subtypes. Toxicity was acceptable. Longer observation and further analysis are warranted.
This single-center prospective study aims to assess the outcomes and the toxicities related to the concurrent administration of trastuzumab (T) with adjuvant locoregional radiotherapy (RT) in ...localized breast cancer. Data of 308 patients were analyzed. T was delivered every 3 weeks (loading dose of 8 mg/kg, then 6 mg/kg) for 1 year. Left ventricular ejection fraction (LVEF), measured by echocardiography or myocardial scintigraphy, was considered as impaired when below 55 %. Toxicities were assessed according to the Common Terminology Criteria for Adverse Events version 3.0. Univariate and multivariate analyses were carried out using the Cox model. Median follow-up was 50.2 months (13.0–126.0). Median age at diagnosis was 52 years (25–83). Internal mammary node (IMN) RT was performed in 227 patients (73.7 %). After completion of RT, 26 patients (8.4 %) presented an impaired LVEF: 17 (5.5 %) of grade 1, 7 (2.3 %) of grade 2, and 2 (0.6 %) of grade 3. At 48 months, locoregional control rate was 95 % 95 % CI 92; 98, and overall survival rate was 98 % 95 % CI 96; 100. In univariate analysis, neither the treated breast side (
p
= 0.655) nor IMN RT (
p
= 0.213) exposed patients to LVEF alteration. In multivariate analysis, clinical lymph node involvement was associated with an increased risk of locoregional and distant recurrence (
p
= 0.016 and
p
= 0.007, respectively). In this prospective study, the toxicities of concurrent T with locoregional breast RT were acceptable and the outcomes favorable. Longer follow-up is warranted to confirm these results.
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