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1.
J Clin Oncol ; 41(16): 2998-3008, 2023 06 01.
Article in English | MEDLINE | ID: mdl-37075276

ABSTRACT

PURPOSE: The achievement of pathologic complete response (pCR) is strongly prognostic for event-free survival (EFS) and overall survival (OS) in patients with early breast cancer (EBC), and adapting postneoadjuvant therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR. We sought to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. MATERIALS AND METHODS: We used individual data from 3,710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive EBC with ≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone receptor-positive versus hormone receptor-negative disease, and for patients who had pCR (pCR+; ypT0/is, ypN0) versus patients who did not achieve a pCR (pCR-). RESULTS: The median follow-up overall was 61.2 months. In pCR+ patients, cT and cN were significant independent prognostic factors for EFS, whereas only cT was a significant predictor for OS. In pCR- patients, cT, cN, and hormone receptor status were significant independent predictors for both EFS and OS. Regardless of hormone receptor status, cT, and cN, the 5-year EFS/OS rates were higher in pCR+ patients than in pCR- patients. In most subsets with regards to hormone receptor and pCR status, cT and cN were independent prognostic factors for both EFS and OS, including pCR+ patients. CONCLUSION: These results confirm that patients achieving pCR have far better survival outcomes than patients who do not. The traditional poor prognostic features, namely tumor size and nodal status, remain important even after a pCR.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/pathology , Neoadjuvant Therapy , Trastuzumab/therapeutic use , Receptor, ErbB-2/metabolism , Prognosis , Hormones/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease-Free Survival
2.
J Clin Oncol ; 41(16): 2988-2997, 2023 06 01.
Article in English | MEDLINE | ID: mdl-36977286

ABSTRACT

PURPOSE: Pathologic complete response (pCR) has prognostic importance and is frequently used as a primary end point, but doubts remain about its validity as a surrogate for event-free survival (EFS) and overall survival (OS) in human epidermal growth factor receptor 2 (HER2)-positive, early breast cancer. METHODS: We obtained individual-patient data from randomized trials of neoadjuvant anti-HER2 therapy that enrolled at least 100 patients, had data for pCR, EFS, and OS, and a median follow-up of at least 3 years. We quantified the patient-level association between pCR (defined as ypT0/Tis ypN0) and both EFS and OS using odds ratios (ORs, with ORs >1.00 indicating a benefit from achieving a pCR). We quantified the trial-level association between treatment effects on pCR and on EFS and OS using R2 (with values above 0.75 considered as indicating strong associations). RESULTS: Eleven of 15 eligible trials had data for analysis (3,980 patients, with a median follow-up of 62 months). Considering all trials, we found strong patient-level associations, with ORs of 2.64 (95% CI, 2.20 to 3.07) for EFS and 3.15 (95% CI, 2.38 to 3.91) for OS; however, trial-level associations were weak, with an unadjusted R2 of 0.23 (95% CI, 0 to 0.66) for EFS and 0.02 (95% CI, 0 to 0.17) for OS. We found qualitatively similar results when grouping trials according to different clinical questions, when analyzing only patients with hormone receptor-negative disease, and when using a more stringent definition of pCR (ypT0 ypN0). CONCLUSION: Although pCR may be useful for patient management, it cannot be considered as a surrogate for EFS or OS in neoadjuvant trials of HER2-positive, operable breast cancer.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Trastuzumab/therapeutic use , Neoadjuvant Therapy , Disease-Free Survival , Receptor, ErbB-2/metabolism , Progression-Free Survival , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
3.
Int J Gynecol Cancer ; 31(4): 562-568, 2021 04.
Article in English | MEDLINE | ID: mdl-33664128

ABSTRACT

OBJECTIVE: To investigate the efficacy and safety of hu3S193, a humanized anti-Lewis-Y monoclonal antibody, as a consolidation strategy in patients with platinum-sensitive recurrent epithelial ovarian cancer who achieved a second complete response after salvage platinum-doublet chemotherapy. METHODS: This single-arm phase II study accrued patients with recurrent epithelial ovarian cancer with Lewis-Y expression by immunohistochemistry who had achieved a second complete response after five to eight cycles of platinum-based chemotherapy. Patients received intravenous infusions of hu3S193, 30 mg/m2 every 2 weeks starting no more than 8 weeks after the last dose of chemotherapy and continuing for 12 doses, until disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival of the second remission. Secondary objectives were safety and pharmacokinetics. RESULTS: Twenty-nine patients were enrolled. Most had a papillary/serous histology tumor (94%), stage III disease at diagnosis (75%), and five (17%) underwent secondary cytoreduction before salvage chemotherapy. Two patients were not eligible for efficacy but were considered for toxicity analysis. Eighteen patients (62%) completed the full consolidation treatment while nine patients progressed on treatment. At the time of analysis, 23 patients (85%) of the eligible population had progressed and seven of these patients (26%) had died. Median progression-free survival of the second remission was 12.1 months (95% CI: 10.6-13.9), with a 1-year progression-free survival of the second remission rate of 50.1%. The trial was terminated early since it was unlikely that the primary objective would be achieved. The most commonly reported treatment-related adverse events were nausea (55%) and vomiting (51%). CONCLUSIONS: Hu3S193 did not show sufficient clinical activity as consolidation therapy in patients with recurrent epithelial ovarian cancer who achieved a second complete response after platinum-based chemotherapy. TRIAL REGISTRATION: NCT01137071.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Consolidation Chemotherapy/methods , Remission Induction/methods , Adult , Aged , Antibodies, Monoclonal, Humanized/pharmacology , Disease-Free Survival , Female , Humans , Middle Aged
4.
Int J Gynecol Cancer, v. 31, n. 4, p. 562-568, abr. 2021
Article in English | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-3667

ABSTRACT

Objective To investigate the efficacy and safety of hu3S193, a humanized anti-Lewis-Y monoclonal antibody, as a consolidation strategy in patients with platinum-sensitive recurrent epithelial ovarian cancer who achieved a second complete response after salvage platinum-doublet chemotherapy. Methods This single-arm phase II study accrued patients with recurrent epithelial ovarian cancer with Lewis-Y expression by immunohistochemistry who had achieved a second complete response after five to eight cycles of platinum-based chemotherapy. Patients received intravenous infusions of hu3S193, 30 mg/m2 every 2 weeks starting no more than 8 weeks after the last dose of chemotherapy and continuing for 12 doses, until disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival of the second remission. Secondary objectives were safety and pharmacokinetics. Results Twenty-nine patients were enrolled. Most had a papillary/serous histology tumor (94%), stage III disease at diagnosis (75%), and five (17%) underwent secondary cytoreduction before salvage chemotherapy. Two patients were not eligible for efficacy but were considered for toxicity analysis. Eighteen patients (62%) completed the full consolidation treatment while nine patients progressed on treatment. At the time of analysis, 23 patients (85%) of the eligible population had progressed and seven of these patients (26%) had died. Median progression-free survival of the second remission was 12.1 months (95% CI: 10.6–13.9), with a 1-year progression-free survival of the second remission rate of 50.1%. The trial was terminated early since it was unlikely that the primary objective would be achieved. The most commonly reported treatment-related adverse events were nausea (55%) and vomiting (51%). Conclusions Hu3S193 did not show sufficient clinical activity as consolidation therapy in patients with recurrent epithelial ovarian cancer who achieved a second complete response after platinum-based chemotherapy.

5.
Clin Breast Cancer ; 16(1): 38-44, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26642810

ABSTRACT

BACKGROUND: Novel targeted agents and combinations have become available in multiple lines of treatment for human epidermal growth factor receptor 2-positive (HER2(+)) metastatic breast cancer (MBC). In this context, alternatives to the lapatinib (L) and capecitabine (C) regimen, evaluating L combined with other cytotoxic drugs, are warranted. PATIENTS AND METHODS: In the present phase II, multicenter study, patients with HER2(+) MBC with progression after taxane were randomized between L, 1250 mg, combined with C, 2000 mg/m(2) on days 1 to 14 (LC), vinorelbine (V), 25 mg/m(2) on days 1 and 8 (LV), or gemcitabine (G), 1000 mg/m(2) on days 1 and 8 (LG), every 21 days. The primary endpoint was the overall response rate. RESULTS: A total of 142 patients were included from 2009 to 2012. No differences were found in the patient baseline characteristics. The median age was 51 years, 69% were postmenopausal, 32% had liver metastasis, 57% were hormone receptor negative, and 48% had been previously treated with trastuzumab. The overall response rate was 49% (95% confidence interval [CI], 34.8%-63.4%), 56% (95% CI, 40%-70.4%), and 41% (95% CI, 27%-56.8%) in the LC, LV, and LG groups, respectively. The median progression-free survival was 9 months in the LC arm and 7 months in the other 2 arms (P = .28). The most common grade 3 and 4 adverse events were hand-foot syndrome (18%), diarrhea (6%), and increased alanine aminotransferase/aspartate aminotransferase (4%) in the LC arm; neutropenia (36%), diarrhea (9%), and febrile neutropenia (6%) in the LV arm; and neutropenia (47%), alanine aminotransferase/aspartate aminotransferase (13%), and rash (4%) in the LG arm. CONCLUSION: LV and LG seem to be active combinations in patients with HER2(+) MBC after taxane failure. The overall toxicity was manageable in all regimens.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Drug Resistance, Neoplasm/drug effects , Salvage Therapy/methods , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Capecitabine/administration & dosage , Capecitabine/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Disease Progression , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lapatinib , Middle Aged , Quinazolines/administration & dosage , Quinazolines/adverse effects , Receptor, ErbB-2/biosynthesis , Taxoids/therapeutic use , Vinblastine/administration & dosage , Vinblastine/adverse effects , Vinblastine/analogs & derivatives , Vinorelbine , Young Adult , Gemcitabine
6.
J Chemother ; 25(4): 239-46, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23906077

ABSTRACT

CupPrint® is a genomic signature able to identify 47 different cancer types. The aim of our study was to compare the accuracy of this genomic signature to that of a full clinical work-up in diagnosing the primary tumour site. Patients with newly diagnosed, untreated metastatic tumours were eligible for this trial. The clinical work-up and gene expression profiling on a biopsy from a metastatic site were started at the same time. The study was planned using a one-stage Fleming design. Patients in whom no primary site was diagnosed by the clinical work-up were excluded. Out of the 67 patients registered, the primary site was identified by clinical work-up in 36 patients, and diagnosis with CupPrint was obtained in 53. There were 31 evaluable patients with both clinical and CupPrint diagnoses, and out of these a similar diagnosis was obtained in 11 patients, i.e. the concordance rate was 35% (95% confidence interval: 19-55%). The median time to diagnosis through the clinical work-up was 48 days, and 10 days with CupPrint (P<0·001). We concluded that in patients with newly diagnosed metastatic tumours, CupPrint has low accuracy in diagnosing the primary cancer site.


Subject(s)
Gene Expression Profiling/methods , Neoplasms, Unknown Primary/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Intention to Treat Analysis , Male , Middle Aged , Neoplasms, Unknown Primary/genetics , Prospective Studies , Sensitivity and Specificity
7.
Lancet Oncol ; 13(9): 869-78, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22884505

ABSTRACT

BACKGROUND: A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. METHODS: The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1:1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C(trough)) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0·80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12·5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300. FINDINGS: 299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C(trough) was 51·8 µg/mL (coefficient of variation 52·5%) in the intravenous group and 69·0 µg/mL (55·8%) in the subcutaneous group. The geometric mean ratio of C(trough) subcutaneous to C(trough) intravenous was 1·33 (90% CI 1·24-1·44). 107 (40·7%) of 263 patients in the intravenous group and 118 (45·4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4·7% (95% CI -4·0 to 13·4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33·2%] of 298 patients in the intravenous group vs 86 [29·0%] of 297 in the subcutaneous group), leucopenia (17 [5·7%] vs 12 [4·0%]), and febrile neutropenia (10 [3·4%] vs 17 [5·7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8·1%] in the subcutaneous group vs 13 [4·4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two--both in the subcutaneous group--were deemed to be treatment related. INTERPRETATION: Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative. FUNDING: F Hoffmann-La Roche.


Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Adenocarcinoma/chemistry , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/chemistry , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Infusions, Intravenous , Infusions, Subcutaneous , Middle Aged , Neoadjuvant Therapy/methods , Neoplasm Grading , Neoplasm Staging , Receptor, ErbB-2/analysis , Trastuzumab , Young Adult
8.
Cancer Treat Rev ; 34(1): 81-91, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17905518

ABSTRACT

The discovery of cytotoxic agents was revolutionary for anticancer therapy in the last century, improving survival rates and the quality of life of patients with different types of tumours. However, the development of agents that combine efficacy, safety and convenience remains a great challenge, due to the narrow therapeutic index of some drugs, the fact that they may damage not only cancer cells, but also normal and healthy tissue and the occurrence of resistance, limiting anticancer efficacy. Novel cytotoxic agents have brought certain advantages over the conventional ones, such as shorter administration time, mechanisms to overcome drug resistance and lower incidence of adverse events. In this review we highlight the development of promising novel cytotoxic drugs that will hopefully offer not only gains in efficacy, but also in safety, tolerability and convenience in the treatment of patients with cancer.


Subject(s)
Drug Design , Neoplasms/drug therapy , Albumins/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm , Epothilones/therapeutic use , Humans , Models, Biological , Paclitaxel/therapeutic use , Taxoids/therapeutic use
9.
Cancer Treat Rev ; 34(1): 61-80, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17826917

ABSTRACT

Over the past decade, molecular-targeted therapies have been added to cytotoxic and anti-endocrine drugs in the treatment of cancer, with the aim to target the molecular pathways that underlie the carcinogenic process and maintain the cancer phenotype. Success with some of these agents has suggested that identification and validation of the drug target is the starting point for the route of development of active, safe and effective drugs. Main molecular targets used to the development of anticancer drugs are cell surface receptors, signal transduction pathways, gene transcription targets, ubiquitin-proteasome/heat shock proteins and tumour microenvironment components (especially antiangiogenic agents). Here, we review the development of the main molecular targeted non-cytotoxic agents studied in cancer, highlighting lessons derived from the development of these novel drugs and proposing new horizons for the clinical development of molecular-targeted therapies.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Delivery Systems , Drug Design , Neoplasms/drug therapy , Angiogenesis Inhibitors/therapeutic use , Humans , Models, Biological , Neoplastic Stem Cells/transplantation , Signal Transduction
10.
Hematol Oncol Clin North Am ; 21(2): 239-56, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17512447

ABSTRACT

Breast cancer patients who have HER2 gene amplification and, consequently, protein overexpression, generally show an aggressive course with short disease-free and overall survivals. Trastuzumab, a humanized monoclonal antibody against the extracellular domain of HER2 protein, has been shown to benefit patients who have HER2-positive metastatic breast cancer, and recently, the results of five adjuvant trials involving more than 13,000 women have been released. Here, the authors summarize the main results and outline the differences among these trials, which have demonstrated an important role of trastuzumab in the treatment of women who have HER2-overexpressing/amplified early breast cancer.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Clinical Trials as Topic , Female , Humans , Neoplasm Staging , Receptor, ErbB-2/biosynthesis , Receptor, ErbB-2/genetics , Trastuzumab , Treatment Outcome
11.
Curr Opin Oncol ; 19(3): 177-9, 2007 May.
Article in English | MEDLINE | ID: mdl-17414633

ABSTRACT

There have been important advances in the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). For patients with unresectable disease, the use of platinum-based chemoradiotherapy has improved the 3-year survival rate from 15-20% to 35-50%. The results of recent studies involving sequential therapy of induction chemotherapy including taxanes and chemoradiation have shown encouraging survival rates, near to 60-70%. Moreover, progress in the understanding of the molecular changes that lead to the development of these tumors is bringing novel diagnostic and therapeutic approaches into clinical practice, promising new hope to patients with a devastating and lethal disease.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Cisplatin/therapeutic use , Head and Neck Neoplasms/drug therapy , Taxoids/therapeutic use , Carboplatin/therapeutic use , Carcinoma, Squamous Cell/radiotherapy , Cisplatin/administration & dosage , Combined Modality Therapy , Head and Neck Neoplasms/radiotherapy , Humans , Survival Rate , Treatment Outcome
12.
Cancer Treat Rev ; 33(1): 64-77, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17113234

ABSTRACT

Her2 and topoisomerase-IIalpha (T2A) gene amplification are separate events, although the latter is more frequently seen in Her2 amplified (34-90%) than in Her2 non-amplified (5-10%) tumours. There is a better correlation between Her2 amplification and protein overexpression in breast cancer (BC) than in other tumour types. This marker is also considered a powerful prognostic factor in BC, with similar data emerging in other solid tumours such as bladder, ovarian, endometrial, gastro-oesophageal and non-small cell lung cancer. Her2 amplification and/or overexpression are highly predictive of response to HER2-targeted compounds such as trastuzumab and lapatinib but have been inconsistent predictors of response to cytotoxic chemotherapy. There is also evidence that these tumours are relatively resistant to anti-oestrogen therapy (tamoxifen) but not to oestrogen deprivation (e.g. with aromatase inhibitors). T2A aberrations are uncommon events in solid tumours, with an overall prevalence of approximately 10%. T2A amplification has shown inconsistent correlation with T2A protein expression in preclinical and clinical studies, mainly because non-genetic events such as proliferation rate can also affect protein expression. Expression of T2A protein has not been shown to reliably predict response to T2A inhibitors, despite the fact that this enzyme is the direct target for these compounds. In BC, T2A amplification appears to be a good predictor of response to anthracyclines, but these data are still in the process of validation. The significance of T2A deletions is currently under investigation, but contrary to what was previously thought, it may also predict benefit from treatment with T2A inhibitors. The prognostic significance of T2A aberrations is currently unknown.


Subject(s)
Antigens, Neoplasm/genetics , Chromosomes, Human, Pair 17 , DNA Topoisomerases, Type II/genetics , DNA-Binding Proteins/genetics , Drug Resistance, Neoplasm/genetics , Gene Amplification/genetics , Genes, erbB-2/genetics , DNA, Neoplasm/metabolism , Genetic Markers , Humans , Prognosis
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