Background: The validity of the PREDICT breast cancer prognostic model is unclear for young patients without adjuvant systemic treatment. This study aimed to validate PREDICT and assess its... Show moreBackground: The validity of the PREDICT breast cancer prognostic model is unclear for young patients without adjuvant systemic treatment. This study aimed to validate PREDICT and assess its clinical utility in young women with node-negative breast cancer who did not receive systemic treatment.Methods: We selected all women from the Netherlands Cancer Registry who were diagnosed with node-negative breast cancer under age 40 between 1989 and 2000, a period when adjuvant systemic treatment was not standard practice for women with node-negative disease. We evaluated the calibration and discrimination of PREDICT using the observed/expected (O/E) mortality ratio, and the area under the receiver operating characteristic curve (AUC), respectively. Additionally, we compared the potential clinical utility of PREDICT for selectively administering chemotherapy to the chemotherapy-to-all strategy using decision curve analysis at predefined thresholds.Results: A total of 2264 women with a median age at diagnosis of 36 years were included. Of them, 71.2% had estrogen receptor (ER)-positive tumors and 44.0% had grade 3 tumors. Median tumor size was 16 mm. PREDICT v2.2 underestimated 10-year all-cause mortality by 33% in all women (O/E ratio:1.33, 95%CI:1.22-1.43). Model discrimination was moderate overall (AUC10-year:0.65, 95%CI:0.62-0.68), and poor for women with ER-negative tumors (AUC10-year:0.56, 95%CI:0.51-0.62). Compared to the chemotherapy-to-all strategy, PREDICT only showed a slightly higher net benefit in women with ER-positive tumors, but not in women with ER-negative tumors. Conclusions: PREDICT yields unreliable predictions for young women with node-negative breast cancer. Further model updates are needed before PREDICT can be routinely used in this patient subset. Show less
Purpose: Measuring health-related quality of life (HRQoL) in ovarian cancer patients is critical to understand the impact of disease and treatment. Preference-based HRQoL measures, called health... Show morePurpose: Measuring health-related quality of life (HRQoL) in ovarian cancer patients is critical to understand the impact of disease and treatment. Preference-based HRQoL measures, called health state utilities, are used specifically in health economic evaluations. Real-world patient-reported data on HRQoL and health state utilities over the long-term course of ovarian cancer are limited. This study aims to determine HRQoL and health state utilities in different health states of ovarian cancer.Methods: This cross-sectional, multicenter study included patients with stage III-IV ovarian cancer in six health states: at diagnosis, during chemotherapy, after cytoreductive surgery (CRS), after chemotherapy, in remission, and at first recurrence. HRQoL was measured using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire C30, and the ovarian cancer-specific module OV28. Health state utilities were assessed using the EuroQol five-dimension five-level (EQ-5D-5L) questionnaire. Descriptive analyses were performed for each health state.Results: Two hundred thirty-two patients participated, resulting in 319 questionnaires. Median age was 66 years. The lowest HRQoL was observed during chemotherapy and shortly after CRS. Physical and role functioning were most affected and the highest symptom prevalence was observed in the fatigue, nausea, pain, dyspnea, gastrointestinal, neuropathy, attitude, and sexuality domains. Patients in remission had the best HRQoL. Mean utility values ranged from 0.709 (+/- 0.253) at diagnosis to 0.804 (+/- 0.185) after chemotherapy.Conclusions: This study provides clinicians with a valuable resource to aid in patient counseling and clinical decision-making. The utilities, in particular, are crucial for researchers conducting economic analyses to inform policy decisions. Show less
Vliek, S.; Hilbers, F.S.; Werkhoven, E. van; Mandjes, I.; Kessels, R.; Kleiterp, S.; ... ; Linn, S.C. 2023
Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of... Show moreExploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI). Secondary endpoints included recurrence-free survival (RFS) and overall survival (OS). In total, 122 patients were randomized. No difference in NRI-score distribution (p = 0.41) was found. A statistically non-significant RFS difference was found (HR 0.54; 95% CI 0.23–1.25; p = 0.15). Exploratory RFS analyses showed benefit in stage III (n = 35; HR 0.16; 95% CI 0.03–0.75), but not stage II (n = 86; HR 1.00; 95% CI 0.30–3.30) patients. For stage III, 4-year RFS was 46% (95% CI 24–87%), 71% (95% CI 48–100%) and 88% (95% CI 74–100%), for ddAC/ddAC-CD, ddAC-CP and high-dose chemotherapy, respectively. No significant differences were found between high-dose and conventional chemotherapy in stage II-III, triple-negative, BRCA-altered breast cancer patients. Further research is needed to establish if there are patients with stage III, triple negative BRCA-altered breast cancer for whom outcomes can be improved with high-dose alkylating chemotherapy or whether the current standard neoadjuvant therapy including carboplatin and an immune checkpoint inhibitor is sufficient. Trial Registration: NCT01057069. Show less
Voorwerk, L.; Isaeva, O.I.; Horlings, H.M.; Balduzzi, S.; Chelushkin, M.; Bakker, N.A.M.; ... ; Kok, M. 2023
Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset... Show moreInvasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial (NCT03147040), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml–1 min–1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials. Show less
Geyer, C.E.; Garber, J.E.; Gelber, R.D.; Yothers, G.; Taboada, M.; Ross, L.; ... ; OlympiA Clinical Trial Steering Committee and Investigators 2022
Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for... Show moreBackground: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Delta 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 35 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDES and DDFS with no new safety signals. Show less
BackgroundHodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit... Show moreBackgroundHodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit BC treatment options. It is unknown how treatment adaptations affect BC and CVD outcomes.MethodsThe authors compared 195 BC patients treated with chest/axillary radiotherapy for HL (BC-HL) with 5988 age- and calendar year-matched patients with first primary BC (BC-1). Analyses included cumulative incidence functions and Cox regression models, accounting for tumor characteristics and BC treatment.ResultsCompared to BC-1 patients, BC-HL patients received anthracycline-containing chemotherapy (23.7% vs. 43.8%, p < .001) and breast-conserving surgery followed by radiotherapy (7.1% vs. 57.7%, p < .001) less often. BC treatment considerations were reported for 71% of BC-HL patients. BC-HL patients had a significantly higher risk of 15-year overall mortality than BC-1 patients (61% vs. 23%). Furthermore, risks of BC-specific mortality and nonfatal BC events were significantly increased among BC-HL patients, also when accounting for tumor and treatment characteristics (2.2- to 4.5-fold). BC-HL patients with a screen-detected BC had a significantly reduced (61%) BC-specific mortality. One-third of BC-HL patients had CVD at BC-diagnosis, compared to <0.1% of BC-1 patients. Fifteen-year CVD-specific mortality and CVD incidence were significantly higher in BC-HL patients than in BC-1 patients (15.2% vs. 0.4% and 40.4% vs. 6.8%, respectively), which was due to HL treatment rather than BC treatment.ConclusionsBC-HL patients experience a higher burden of CVD and worse BC outcomes than BC-1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. Show less
In't Veld, S.G.J.G.; Arkani, M.; Post, E.; Antunes-Ferreira, M.; D'Ambrosi, S.; Vessies, D.C.L.; ... ; Wurdinger, T. 2022
Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising... Show moreCancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening. Show less
Jong, V.M.T. de; Wang, Y.W.; Hoeve, N.D. ter; Opdam, M.; Stathonikos, N.; Józwiak, K.; ... ; Linn, S.C. 2022
PURPOSE Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating... Show morePURPOSE Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naive, and thus can be used for chemotherapy de-escalation strategies, is unknown.METHODS We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population-based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and >= 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk.RESULTS sTILs were scored for 441 patients. High sTILs (>= 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (chi(2) = 46.7, P < .001).CONCLUSION Chemotherapy-naive, young patients with N0 TNBC with high sTILs (>= 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies. (c) 2022 by American Society of Clinical Oncology Show less
Background: Patients with advanced endometrial cancer have a poor prognosis, and treatment options are limited. The investigator-initiated, multicenter, phase II DOMEC trial (NCT03951415) is the... Show moreBackground: Patients with advanced endometrial cancer have a poor prognosis, and treatment options are limited. The investigator-initiated, multicenter, phase II DOMEC trial (NCT03951415) is the first trial to report data on efficacy and safety of combined treatment with PD-L1 and PARP inhibition for advanced endometrial cancer. Patients and methods: Patients with metastatic or recurrent endometrial cancer were enrolled. Patients received durvalumab 1500 mg intravenously q4w and olaparib 300 mg 2dd until disease progression, unacceptable toxicity, or patient withdrawal. Patients with at least 4 weeks of treatment were evaluable for analysis. The primary endpoint was progression-free survival at 6 months. Evidence for efficacy was defined as progression-free survival at 6 months in >= 50% of patients. Secondary endpoints included safety, objective response and overall survival. Results: From July 2019, through November 2020, 55 patients were enrolled. At data cut-off (September 2021), 4 of the 50 evaluable patients were still on treatment. Seventeen patients (34%) were progression-free at 6 months. Objective response rate was 16% (95% CI, 8.3 to 28.5) with 1 complete and 7 partial responses. With a median follow-up of 17.6 months, median progression-free survival was 3.4 months (95% CI, 2.8 to 6.2) and median overall survival was 8.0 months (95% CI, 7.5 to 14.3). Grade 3 treatment-related adverse events occurred in 8 patients (16%), predominantly anemia. There were no grade 4 or 5 treatment-related adverse events. Conclusion: The combination of durvalumab and olaparib was well tolerated, but did not meet the prespecified 50% 6-month progression-free survival in this heterogeneous patient population with advanced endometrial cancer. (C) 2022 The Authors. Published by Elsevier Inc. Show less
Steenbruggen, T.G.; Steggink, L.C.; Seynaeve, C.M.; Hoeven, J.J.M. van der; Hooning, M.J.; Jager, A.; ... ; Gietema, J.A. 2020
Importance Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking. Objective To... Show moreImportance Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking. Objective To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer. Design, Setting, and Participants This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019. Interventions Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m(2), epirubicin, 90 mg/m(2), and cyclophosphamide, 500 mg/m(2), or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m(2), thiotepa, 480 mg/m(2), and carboplatin, 1600 mg/m(2), followed by hematopoietic stem cell transplant. Main Outcomes and Measures Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events. Results Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P = .10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P = .02), hypercholesterolemia (15.7% vs 10.6%, P = .04), and dysrhythmias (8.6% vs 4.6%, P = .005). Conclusions and Relevance High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with >= 10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events. Show less
Ommen-Nijhof, A. van; Konings, I.R.; Zeijl, C.J.J. van; Uyl-de Groot, C.A.; Noort, V. van der; Jager, A.; ... ; SONIA Study Steering Comm 2018
