Pathologic response of ductal carcinoma in situ to neoadjuvant systemic treatment in HER2-positive breast cancer.

PURPOSE: The presence of extensive ductal carcinoma in situ (DCIS) adjacent to HER2-positive invasive breast cancer (IBC) is often a contra-indication for breast-conserving surgery, even in case of excellent treatment response of the invasive component. Data on the response of DCIS to neoadjuvant systemic treatment (NST) are limited. Therefore, we estimated the response of adjacent DCIS to NST-containing HER2-blockade in HER2-positive breast cancer patients and assessed the association of clinicopathological and radiological factors with response. METHODS: Pre-NST biopsies were examined to determine presence of DCIS in all women with HER2-positive IBC treated with trastuzumab-containing NST ± pertuzumab between 2004 and 2017 in a comprehensive cancer center. When present, multiple DCIS factors, including grade, calcifications, necrosis, hormone receptor, and Ki-67 expression, were scored. Associations of clinicopathological and radiological factors with complete response were assessed using logistic regression models. RESULTS: Adjacent DCIS, observed in 138/316 patients with HER2-positive IBC, was eradicated after NST in 46% of patients. Absence of calcifications suspicious for malignancy on pre-NST mammography (odds ratio (OR) 3.75; 95% confidence interval (95% CI) 1.72-8.17), treatment with dual HER2-blockade (OR 2.36; 95% CI 1.17-4.75), a (near) complete response on MRI (OR 3.55; 95% CI 1.31-9.64), and absence of calcifications (OR 3.19; 95% CI 1.34-7.60) and Ki-67 > 20% in DCIS (OR 2.74; 95% CI 1.09-6.89) on pre-NST biopsy were significantly associated with DCIS response. CONCLUSIONS: As DCIS can respond to NST containing HER2-blockade, the presence of extensive DCIS in HER2-positive breast cancer before NST should not always indicate a mastectomy. The predictive factors we found could be helpful when considering breast-conserving surgery in these patients.

High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes: 20-Year Follow-up of a Phase 3 Randomized Clinical Trial.

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 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/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, 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. Trial Registration: ClinicalTrials.gov Identifier: NCT03087409.

Cardiovascular Disease Risk in a Large, Population-Based Cohort of Breast Cancer Survivors.

PURPOSE: To conduct a large, population-based study on cardiovascular disease (CVD) in breast cancer (BC) survivors treated in 1989 or later. METHODS AND MATERIALS: A large, population-based cohort comprising 70,230 surgically treated stage I to III BC patients diagnosed before age 75 years between 1989 and 2005 was linked with population-based registries for CVD. Cardiovascular disease risks were compared with the general population, and within the cohort using competing risk analyses. RESULTS: Compared with the general Dutch population, BC patients had a slightly lower CVD mortality risk (standardized mortality ratio 0.92, 95% confidence interval [CI] 0.88-0.97). Only death due to valvular heart disease was more frequent (standardized mortality ratio 1.28, 95% CI 1.08-1.52). Left-sided radiation therapy after mastectomy increased the risk of any cardiovascular event compared with both surgery alone (subdistribution hazard ratio (sHR) 1.23, 95% CI 1.11-1.36) and right-sided radiation therapy (sHR 1.19, 95% CI 1.04-1.36). Radiation-associated risks were found for not only ischemic heart disease, but also for valvular heart disease and congestive heart failure (CHF). Risks were more pronounced in patients aged <50 years at BC diagnosis (sHR 1.48, 95% CI 1.07-2.04 for left- vs right-sided radiation therapy after mastectomy). Left- versus right-sided radiation therapy after wide local excision did not increase the risk of all CVD combined, yet an increased ischemic heart disease risk was found (sHR 1.14, 95% CI 1.01-1.28). Analyses including detailed radiation therapy information showed an increased CVD risk for left-sided chest wall irradiation alone, left-sided breast irradiation alone, and internal mammary chain field irradiation, all compared with right-sided breast irradiation alone. Compared with patients not treated with chemotherapy, chemotherapy used ≥1997 (ie, anthracyline-based chemotherapy) increased the risk of CHF (sHR 1.35, 95% CI 1.00-1.83). CONCLUSION: Radiation therapy regimens used in BC treatment between 1989 and 2005 increased the risk of CVD, and anthracycline-based chemotherapy regimens increased the risk of CHF.

Incidence and prognosis of parathyroid gland carcinoma: a population-based study in The Netherlands estimating the preoperative diagnosis.

BACKGROUND: Parathyroid carcinoma is a rare malignancy and generally is diagnosed after surgery for primary hyperparathyroidism. Lack of a preoperative diagnosis and ill-considered surgical planning with its impact on survival are ill-described. METHODS: In a retrospective population-based cohort study the clinical features, treatment, recurrences, and survival of 41 parathyroid cancer patients are reported and compared with characteristics of patients with primary hyperparathyroidism. RESULTS: Patients with parathyroid carcinoma had significantly higher serum parathyroid hormone and calcium levels compared with patients with primary hyperparathyroidism. Nineteen patients (46%) had a palpable neck mass. A parathyroid hormone level more than 3 times the upper normal limits was suspicious and levels more than 10 times carried a positive predictive value of 84% for carcinoma. Ten-year recurrence-free and disease-specific survival rates were 71% and 79%, respectively. CONCLUSIONS: Parathyroid hormone levels of more than 3 times upper normal limits, palpable neck mass, and profound hypercalcemia are suspicious signs of carcinoma necessitating surgical exploration by an experienced surgeon.

High risk bladder cancer: current management and survival.

PURPOSE: To evaluate the pattern of care in patients with high risk non muscle invasive bladder cancer (NMIBC) in the Comprehensive Cancer Center North-Netherlands (CCCN) and to assess factors associated with the choice of treatment, recurrence and progression free survival rates. MATERIALS AND METHODS: Retrospective analysis of 412 patients with newly diagnosed high risk NMIBC. Clinical, demographic and follow-up data were obtained from the CCCN Cancer Registry and a detailed medical record review. Uni and multivariate analysis was performed to identify factors related to choice of treatment and 5 year recurrence and progression free survival. RESULTS: 74/412 (18%) patients with high risk NMIBC underwent a transurethral resection (TUR) as single treatment. Adjuvant treatment after TUR was performed in 90.7% of the patients treated in teaching hospitals versus 71.8% in non-teaching hospitals (p < 0.001). In multivariate analysis, age (60-79 years OR 0.40 and > 80 years OR 0.1 p = 0.001) and treatment in non-teaching hospitals (OR 0.25; p < 0.001) were associated with less adjuvant treatment after TUR. Tumor recurrence occurred in 191/392 (49%) and progression in 84/392 (21.4%) patients. The mean 5-years progression free survival was 71.6% (95% CI 65.5-76.8). CONCLUSION: In this pattern of care study in high risk NMIBC, 18% of the patients were treated with TUR as single treatment. Age and treatment in non-teaching hospitals were associated with less adjuvant treatment after TUR. None of the variables sex, age, comorbidity, hospital type, stage and year of treatment was associated with 5 year recurrence or progression rates.

High risk bladder cancer: current management and survival

PURPOSE: To evaluate the pattern of care in patients with high risk non muscle invasive bladder cancer (NMIBC) in the Comprehensive Cancer Center North-Netherlands (CCCN) and to assess factors associated with the choice of treatment, recurrence and progression free survival rates. MATERIALS AND METHODS: Retrospective analysis of 412 patients with newly diagnosed high risk NMIBC. Clinical, demographic and follow-up data were obtained from the CCCN Cancer Registry and a detailed medical record review. Uni and multivariate analysis was performed to identify factors related to choice of treatment and 5 year recurrence and progression free survival. RESULTS: 74/412 (18 percent) patients with high risk NMIBC underwent a transurethral resection (TUR) as single treatment. Adjuvant treatment after TUR was performed in 90.7 percent of the patients treated in teaching hospitals versus 71.8 percent in non-teaching hospitals (p < 0.001). In multivariate analysis, age (60-79 years OR 0.40 and > 80 years OR 0.1 p = 0.001) and treatment in non-teaching hospitals (OR 0.25; p < 0.001) were associated with less adjuvant treatment after TUR. Tumor recurrence occurred in 191/392 (49 percent) and progression in 84 /392 (21.4 percent) patients. The mean 5-years progression free survival was 71.6 percent (95 percent CI 65.5-76.8). CONCLUSION: In this pattern of care study in high risk NMIBC, 18 percent of the patients were treated with TUR as single treatment. Age and treatment in non-teaching hospitals were associated with less adjuvant treatment after TUR. None of the variables sex, age, comorbidity, hospital type, stage and year of treatment was associated with 5 year recurrence or progression rates.

Treatment and outcome in muscle invasive bladder cancer: a population-based survey.

OBJECTIVE: To assess treatments and survival of patients with muscle invasive bladder cancer (MIBC) in the Comprehensive Cancer Center Northern Netherlands (CCCN) region. STUDY DESIGN AND SETTING: Retrospective cohort analysis. Data of 548 patients with MIBC diagnosed between 1997 and 2002 were collected from the CCCN cancer registry. All had a follow-up of at least 5 years. Logistic regression analysis on treatments as well as survival analysis was performed. RESULTS: The treatments were radical cystectomy in 205/548 (37.5%) patients. TUR plus radiotherapy in 246 (44.9%) and palliation in 97 (17.7%). Multivariate analysis identified TNM stage (P < 0.0001) and age (P < 0.0001) as independent variables for cystectomy. Hospital type and year of diagnosis were not significant different between patients treated by cystectomy versus other type of treatment. TNM stage (P < 0.0001), age (P = 0.0043), and comorbidity (P = 0.0028) were independent variables for disease-specific survival (DSS) after cystectomy. CONCLUSION: In the CCCN region, only 1/3 of patients with MIBC were treated with radical cystectomy. TNM stage and age were identified as main variables for the choice for cystectomy. TNM stage, age, and comorbidity were independent variables for disease-specific survival after cystectomy.

The value of surveillance mammography of the contralateral breast in patients with a history of breast cancer.

PURPOSE: To determine the contribution of surveillance mammography to the early detection of metachronous contralateral breast cancer (MCBC) and to assess its impact on the survival of breast cancer patients with relation to compliance. METHOD: Breast cancer patients (5589) were identified using files from the regional cancer registry of the Comprehensive Cancer Centre North Netherlands (CCCN Groningen, The Netherlands). The programme sensitivity and the impact on prognosis of follow-up mammography with relation to compliance were evaluated in 114 patients who developed MCBC during hospital follow-up. RESULTS: The cumulative MCBC incidence rate at year 10 was 3.4% (95% CI: 2.8-4.0%). The programme sensitivity of surveillance mammography was 59.6% (95% CI: 50.6-68.7). In patients who complied with annual mammography, sensitivity was increased to 70.8% (95% CI: 61.7-80.0). Patients with MCBCs detected by routine mammography have better survival rates than patients with MCBCs detected by other means (HR: 3.18; 95% CI: 1.59-6.34). Though there was a trend towards improved survival in patients being compliant with regular clinical follow-up (HR: 1.69; 95% CI: 0.72-3.96), this was not the case for patients being compliant with annual mammography (HR:1.02; 95% CI:0.50-2.09). CONCLUSION: Mammography is a valuable tool for the early detection of MCBC during hospital follow-up of breast cancer patients and is probably beneficial to survival. The utilisation of follow-up surveillance in breast cancer patients and its potential impact on survival deserve further investigation.

Implementation of sentinel node biopsy in breast cancer patients in the Netherlands.

BACKGROUND: This population-based study describes the implementation of the sentinel node biopsy (SNB) in breast cancer patients in the Netherlands. We examined the extent of use over time of SNB in women who were considered eligible for SNB on the basis of their clinical status. METHODS: The study included a total of 35,465 breast cancer patients who were diagnosed with T1-2 tumours (5.0 cm), negative axillary lymph node status and no distant metastases upon clinical examination between 1st January 1998 and 31st December 2003 in six Comprehensive Cancer Centre regions in the Netherlands. Information on axillary surgery was classified as SNB alone, SNB+axillary lymph node dissection (ALND), ALND alone or none. Patterns of use of axillary surgery were summarised as the proportion of patients receiving each surgery type. RESULTS: Overall, 25.7% of patients underwent SNB alone, 19.1% underwent SNB+ALND, 50.0% had ALND alone and 5.2% did not have axillary surgery. SNB was more common in women who had breast-conserving surgery: 50.5% of patients who received breast-conserving surgery underwent SNB compared to 40.7% of patients who had mastectomy (p<0.0001). Amongst patients receiving breast-conserving treatment, 31.7% had SNB as final axillary surgery, whilst 20.5% of patients who had mastectomy had SNB alone (p<0.0001). The proportion of women who underwent a SNB alone or in combination with ALND increased over the period 1998-2003, from 2.1% to 45.8% and from 6.7% to 24.8%, respectively. There were marked differences in the patterns of dissemination of the use of SNB between regions: by 2003, the difference between the regions with the highest and lowest proportion of use was 25%. CONCLUSIONS: SNB has become the standard-of-care for the treatment of breast cancer patients clinically diagnosed with T1-2 tumours, clinically negative lymph nodes and without distant metastases. In 2003, 70.6% of patients with early breast cancer in the Netherlands received SNB, and within this group, 64.9% of patients had SNB as the final axillary treatment. Implementation of SNB may depend on factors associated with regional organisation of care.

Better survival in patients with esophageal cancer after surgical treatment in university hospitals: a plea for performance by surgical oncologists.

BACKGROUND: In primary esophageal cancer, studies have frequently focused on surgical patients in an effort to link outcome to hospital- or surgeon-related experience, with operative mortality used as the main outcome measure. Many studies have found an inverse relationship between operative mortality and hospital volume and surgical expertise. This study aims to assess the influence of surgeon-related expertise and hospital volume on the relative survival of operated esophageal cancer patients. METHODS: From January 1994 to January 2002, a total of 1149 consecutive patients with primary esophageal cancer were diagnosed in the region of the Comprehensive Cancer Center North-Netherlands. As a proxy for surgeon-related expertise, hospitals in this region were categorized into three types: university, teaching nonuniversity, and nonteaching hospitals. The influence of hospital type on the relative survival of operated patients was studied by a multivariate Poisson regression model. RESULTS: Of the 1149 patients, 18.5% underwent surgery. There was no evidence of selective referral for surgery between the three hospital types with regard to age, tumor stage, and location. For operated patients, the 5-year relative survival was 49.2% for the university hospital versus 32.6% and 27.3% for teaching nonuniversity and nonteaching hospitals, respectively (P = .0039). When adjusted for age, tumor stage, hospital volume and referral frequency, the relative excess risk of death for the university hospital was considerably lower at .57 (95% confidence interval, .29-1.12) compared with nonteaching hospitals and .43 (95% confidence interval, .24-.76) compared with teaching nonuniversity hospitals (P = .0126). CONCLUSIONS: In our region, patients with esophageal cancer who underwent esophagectomy in the university hospital had a markedly better relative survival compared with those who underwent surgery at teaching nonuniversity and nonteaching hospitals, emphasizing the need for referral of esophageal surgery to centers with a greater experience.

Surgery by consultant gynecologic oncologists improves survival in patients with ovarian carcinoma.

BACKGROUND: Consultant gynecologic oncologists from the regional Comprehensive Cancer Center assisted community gynecologists in the surgical treatment of patients with ovarian carcinoma when they were invited. For this report, the authors evaluated the effects of primary surgery by a gynecologic oncologist on treatment outcome. METHODS: The hospital files from 680 patients with epithelial ovarian carcinoma who were diagnosed between 1994 and 1997 in the northern part of the Netherlands were abstracted. Treatment results were analyzed according to the operating physician's education by using survival curves and univariate and multivariate Cox regression analyses. RESULTS: Primary surgery was performed on 184 patients by gynecologic oncologists, and on 328 patients by general gynecologists. Gynecologic oncologists followed surgical guidelines more strictly compared with general gynecologists (patients with International Federation of Gynecology and Obstetrics [FIGO] Stage I-II disease, 55% vs. 33% [P=0.01]; patients with FIGO Stage III disease, 60% vs. 40% [P=0.003]) and more often removed all macroscopic tumor in patients with FIGO Stage III disease (24% vs. 12%; P=0.02). When patients were stratified according to FIGO stage, the 5-year overall survival rate was 86% versus 70% (P=0.03) for patients with Stage I-II disease and 21% versus 13% (P=0.02) for patients with Stage III-IV disease who underwent surgery by gynecologic oncologists and general gynecologists, respectively. The hazards ratio for patients who underwent surgery by gynecologic oncologists was 0.79 (95% confidence interval [95%CI], 0.61-1.03; adjusted for patient age, disease stage, type of hospital, and chemotherapy); when patients age 75 years and older were excluded, the hazards ratio fell to 0.71 (95% CI, 0.54-0.94) in multivariate analysis. CONCLUSIONS: The surgical treatment of patients with ovarian carcinoma by gynecologic oncologists occurred more often according to surgical guidelines, tumor removal more often was complete, and survival was improved.

Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients.

PURPOSE: Microsatellite instability (MSI), TP53 mutation, and KRAS mutation status have been reported as prognostic factors in colon cancer. Most studies, however, have included heterogeneous groups of patients with respect to cancer stage. We determined the prognostic relevance of high-frequency MSI (MSI-H), TP53 mutations, and KRAS mutations in a well-defined group of patients with stage III colon cancer (N = 391), randomly assigned for adjuvant treatment with fluorouracil-based chemotherapy. METHODS: Three hundred ninety-one tumor specimens were available. MSI was determined in 273 specimens, and mutation analyses of TP53 and KRAS were performed in 220 and 205 specimens, respectively. RESULTS: In a univariate analysis, MSI-H (44 of 273; 16%) was associated with a longer disease-free survival (DFS; P = .038), but in a multivariate model adjusting for nodal involvement, histology, invasion, and grade of tumor, the association of MSI status with DFS did no longer reach statistical significance, though the risk estimate for microsatellite stability versus MSI-H tumors did not change much. Mutant TP53, found in 116 (53%) of 220 tumors, was associated with a shorter DFS, both in univariate (P = .009) and multivariate analyses (P = .018), whereas KRAS mutations (58 of 205; 28%) did not show any prognostic significance. CONCLUSION: Both mutant TP53 and MSI-H seem to be prognostic indicators for disease-free survival, but only TP53 retains statistical significance after adjusting for clinical heterogeneity. Thus, in adjuvantly treated patients with stage III colon cancer, presence or absence of a TP53 mutation should be considered as a better predictor for DFS than MSI status.

Quality of adjuvant CMF chemotherapy for node-positive primary breast cancer: a population-based study.

PURPOSE: Adjuvant 'classical' oral cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) has long been the mainstay of adjuvant chemotherapy for premenopausal breast cancer patients. The Comprehensive Cancer Center North Netherlands (CCCN) breast cancer working group performed a retrospective audit of treatment guideline adherence and quality of CMF in hospitals in the CCCN area. METHODS: The CMF treatment data of 251 consecutive axillary lymph node-positive breast cancer patients <50 years old, diagnosed between 1993 and 1996, were analyzed. RESULTS: Ninety-four patients (42%) completed adjuvant CMF without dose adjustment or delay. Overall median relative dose intensity (RDI) was 92.6 (IQR 85.5-97.7). Sixty patients (24%) had an RDI <85, and 7% had an RDI <65. Myelotoxicity was the main reason for reductions and delays. Of 176 irradiated patients, 96% received radiotherapy simultaneously with CMF. Median CMF dose intensity nor median duration differed between patients who underwent mastectomy, mastectomy and radiotherapy, or breast-conserving therapy. Radiotherapy did not influence the median RDI (94 without versus 92 with radiotherapy). G-CSF, administered at least once to 76 patients, did not result in a higher median RDI. Median RDI was slightly higher when >3 patients/year (P=0.014) were treated by one specialist or >10 patients classified for adjuvant chemotherapy yearly in a hospital (P=0.037). CONCLUSION: The adherence to CMF treatment guidelines was generally good. Simultaneous radiotherapy did not affect the median RDI of CMF. G-CSF had no impact on the median RDI but patient volume did influence the RDI.