Treatment and survival of patients diagnosed with high-risk HR+/HER2- breast cancer in the Netherlands: a population-based retrospective cohort study.

BACKGROUND: Several factors may increase the risk of recurrence of patients diagnosed with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC). We aim to determine the proportion of patients with high-risk HR+/HER2- BC within the total HR+/HER2- BC cohort and compare their systemic treatments and survival rates with those of patients with low- and intermediate-risk HR+/HER2- BC and triple-negative (TN) BC. PATIENTS AND METHODS: Women diagnosed with nonmetastatic invasive HR+/HER2- BC and TNBC in the Netherlands between 2011 and 2019 were identified from the Netherlands Cancer Registry. Patients with HR+/HER2- BC were categorised according to risk profile, defined by nodal status, tumour size, and histological grade. High-risk HR+/HER2- BC was defined by either four or more positive lymph nodes or one to three positive lymph nodes with a tumour size of ≥5 cm or a histological grade 3 tumour. Overall survival (OS) and relative survival (RS) were calculated using the Kaplan-Meier and Pohar-Perme method. RESULTS: In this study of 87 455 patients with HR+/HER2- BC, 44 078 (50%) patients were diagnosed with low risk, 28 452 (33%) with intermediate risk, and 11 285 (13%) with high-risk HR+/HER2- BC. In 3640 (4%) patients, the risk profile could not be defined. Endocrine therapy and chemotherapy were used in 38% and 7% of low-risk, 90% and 47% of intermediate-risk, and 94% and 73% of high-risk patients, respectively. The 10-year OS and RS rates were 84.1% [95% confidence interval (95% CI) 83.5% to 84.7%] and 98.7% (95% CI 97.3% to 99.4%) in low-risk, 75.1% (95% CI 74.2% to 76.0%) and 91.7% (95% CI 89.7% to 93.3%) in intermediate-risk, and 63.4% (95% CI 62.0% to 64.7%) and 72.3% (70.1% to 74.3%) in high-risk patients. The 10-year OS and RS rates of 12 689 patients with TNBC were 69.7% (95% CI 68.6% to 70.8%) and 79.1% (95% CI 77.0% to 80.9%), respectively. CONCLUSION: The poor prognosis of patients with high-risk HR+/HER2- BC highlights the need for a better acknowledgement of this subgroup and supports ongoing clinical trials aimed at optimising systemic therapy.

Tumor-infiltrating lymphocytes in HER2-positive breast cancer treated with neoadjuvant chemotherapy and dual HER2-blockade.

Tumor-infiltrating lymphocytes (TILs) have been associated with outcomes in HER2-positive breast cancer patients treated with neoadjuvant chemotherapy and trastuzumab. However, it remains unclear if TILs could be a prognostic and/or predictive biomarker in the context of dual HER2-targeting treatment. In this study, we evaluated the association between TILs and pathological response (pCR) and invasive-disease free survival (IDFS) in 389 patients with stage II-III HER2 positive breast cancer who received neoadjuvant anthracycline-containing or anthracycline-free chemotherapy combined with trastuzumab and pertuzumab in the TRAIN-2 trial. Although no significant association was seen between TILs and pCR, patients with TIL scores ≥60% demonstrated an excellent 3-year IDFS of 100% (95% CI 100-100), regardless of hormone receptor status, nodal stage and attainment of pCR. Additionally, in patients with hormone receptor positive disease, TILs as a continuous variable showed a trend to a positive association with pCR (adjusted Odds Ratio per 10% increase in TILs 1.15, 95% CI 0.99-1.34, p = 0.070) and IDFS (adjusted Hazard Ratio per 10% increase in TILs 0.71, 95% CI 0.50-1.01, p = 0.058). We found no interactions between TILs and anthracycline treatment. Our results suggest that high TIL scores might be able to identify stage II-III HER2-positive breast cancer patients with a favorable prognosis.

BluePrint molecular subtypes predict response to neoadjuvant pertuzumab in HER2-positive breast cancer.

BACKGROUND: The introduction of pertuzumab has greatly improved pathological complete response (pCR) rates in HER2-positive breast cancer, yet effects on long-term survival have been limited and it is uncertain which patients derive most benefit. In this study, we determine the prognostic value of BluePrint subtyping in HER2-positive breast cancer. Additionally, we evaluate its use as a biomarker for predicting response to trastuzumab-containing neoadjuvant chemotherapy with or without pertuzumab. METHODS: From a cohort of patients with stage II-III HER2-positive breast cancer who were treated with neoadjuvant chemotherapy and trastuzumab with or without pertuzumab, 836 patients were selected for microarray gene expression analysis, followed by readout of BluePrint standard (HER2, Basal and Luminal) and dual subtypes (HER2-single, Basal-single, Luminal-single, HER2-Basal, Luminal-HER2, Luminal-HER2-Basal). The associations between subtypes and pathological complete response (pCR), overall survival (OS) and breast cancer-specific survival (BCSS) were assessed, and pertuzumab benefit was evaluated within the BluePrint subgroups. RESULTS: BluePrint results were available for 719 patients. In patients with HER2-type tumors, the pCR rate was 71.9% in patients who received pertuzumab versus 43.5% in patients who did not (adjusted Odds Ratio 3.43, 95% CI 2.36-4.96). Additionally, a significantly decreased hazard was observed for both OS (adjusted hazard ratio [aHR] 0.45, 95% CI 0.25-0.80) and BCSS (aHR 0.46, 95% CI 0.24-0.86) with pertuzumab treatment. Findings were similar in the HER2-single subgroup. No significant benefit of pertuzumab was seen in other subtypes. CONCLUSIONS: In patients with HER2-type or HER2-single-type tumors, pertuzumab significantly improved the pCR rate and decreased the risk of breast cancer mortality, which was not observed in other subtypes. BluePrint subtyping may be valuable in future studies to identify patients that are likely to be highly sensitive to HER2-targeting agents.

The effect of attendance in the Dutch breast cancer screening program on breast tumor characteristics among migrant women.

BACKGROUND: In general, migrant women have a lower breast cancer (BC) incidence rate and higher BC mortality than autochthonous women. Further, migrant women show lower participation in the national BC screening program. To further investigate those aspects, we aimed to determine differences in incidence and tumor characteristics between autochthonous and migrant BC patients in Rotterdam, the Netherlands. METHODS: We selected women diagnosed with BC in Rotterdam during 2012-2015 from the Netherlands Cancer Registry. Incidence rates were calculated by migrant status (i.e., women with or without migration background). Multivariable analyses revealed adjusted odds ratios (OR) and 95% confidence intervals (CI) on the association between migration status and patient and tumor characteristics, additionally stratified by screening attendance (yes/no). RESULTS: In total 1372 autochthonous and 450 migrant BC patients were included for analysis. BC incidence was lower among migrants than among autochthonous women. Overall, migrant women were younger at BC diagnosis (53 vs. 64 years, p < 0.001), and had higher risks of positive lymph nodes (OR 1.76, 95% CI 1.33-2.33) and high grade tumors (OR 1.35, 95% CI 1.04-1.75). Especially non-screened migrant women had higher risk of positive nodes (OR 2.73, 95% CI 1.43-5.21). Among the subgroup of screened women, we observed no significant differences between migrant and autochthonous patients. CONCLUSION: Migrant women have lower BC incidence than autochthonous women, but diagnosis was more often at younger age and with unfavorable tumor characteristics. Attending the screening program strongly reduces the latter. Therefore, promotion of participation in the screening program is recommended.

Predictors of delayed breast reconstruction in the Netherlands: a 5-year follow-up study in stage I-III breast cancer patients.

PURPOSE: Delayed breast reconstruction (DBR) is a valid option for postmastectomy breast cancer patients who have a desire for breast reconstruction but are not considered suitable for immediate breast reconstruction (IBR). The objective of this study was to investigate the clinical practice and predictors of the use of DBR in the Netherlands. METHODS: Stage I-III breast cancer patients diagnosed from January to March 2012 and treated with mastectomy were selected from the Netherlands Cancer Registry. Routinely collected patient, tumor, treatment and hospital characteristics were complemented with data about DBR up to 2018. Multivariable logistic regression analyses were performed to identify factors independently associated with postmastectomy DBR. Factors associated with time to DBR were identified through Cox regression analyses. RESULTS: Of all patients who underwent mastectomy (n = 1,415), 10.2% underwent DBR. DBR patients more often received autologous reconstruction compared to IBR patients (37.5% vs 6.2%, p < 0.001). Age below 50 years (age < 35 OR 15.55, age 35-49 OR 4.18) and neoadjuvant and adjuvant chemotherapy (OR 2.59 and OR 2.83, respectively) were significantly associated with DBR. Mean time to DBR was 2.4 years [range 1-6 years]. Time to DBR was significantly associated with age < 35 years (HR 2.22), and a high hospital volume (HR 1.87). DISCUSSION: The use of DBR after mastectomy could not be fully explained by age below 50 years, chemotherapy, and hospital volume. Treatment with radiotherapy and adjuvant chemotherapy increased time to DBR. More information about patient preferences is needed to understand the use and timing of reconstruction.

Effect of omission of surgery on survival in patients aged 80 years and older with early-stage hormone receptor-positive breast cancer.

BACKGROUND: Surgery is increasingly being omitted in older patients with operable breast cancer in the Netherlands. Although omission of surgery can be considered in frail older patients, it may lead to inferior outcomes in non-frail patients. Therefore, the aim of this study was to evaluate the effect of omission of surgery on relative and overall survival in older patients with operable breast cancer. METHODS: Patients aged 80 years or older diagnosed with stage I-II hormone receptor-positive breast cancer between 2003 and 2009 were selected from the Netherlands Cancer Registry. An instrumental variable approach was applied to minimize confounding, using hospital variation in rate of primary surgery. Relative and overall survival was compared between patients treated in hospitals with different rates of surgery. RESULTS: Overall, 6464 patients were included. Relative survival was lower for patients treated in hospitals with lower compared with higher surgical rates (90·2 versus 92·4 per cent respectively after 5 years; 71·6 versus 88·2 per cent after 10 years). The relative excess risk for patients treated in hospitals with lower surgical rates was 2·00 (95 per cent c.i. 1·17 to 3·40). Overall survival rates were also lower among patients treated in hospitals with lower compared with higher surgical rates (48·3 versus 51·3 per cent after 5 years; 15·0 versus 19·7 per cent after 10 years respectively; adjusted hazard ratio 1·07, 95 per cent c.i. 1·00 to 1·14). CONCLUSION: Omission of surgery is associated with worse relative and overall survival in patients aged 80 years or more with stage I-II hormone receptor-positive breast cancer. Future research should focus on the effect on quality of life and physical functioning.

ANTECEDENTES: En los Países Bajos cada vez es más frecuente descartar la cirugía en pacientes mayores con cáncer de mama operable. Aunque la omisión de la cirugía puede ser adecuada en pacientes mayores frágiles, ello puede determinar peores resultados en pacientes no frágiles. Por tanto, el objetivo de este estudio fue evaluar el efecto de omitir la cirugía en la supervivencia relativa y en la supervivencia global en pacientes mayores con cáncer de mama operable. MÉTODOS: A partir del Registro de Cáncer de los Países Bajos se seleccionaron las pacientes de ≥ 80 años de edad diagnosticadas de cáncer de mama entre 2003-2009 en estadios 1-2 y con receptores hormonales positivos. Se aplicó un método de variables instrumentales para minimizar los factores de confusión utilizando la tasa de variación hospitalaria de la cirugía primaria. Se compararon las supervivencias relativa y global de las pacientes tratadas en hospitales con diferentes tasas de cirugía. RESULTADOS: Se incluyeron 6.464 pacientes. La supervivencia relativa fue menor en las pacientes tratadas en hospitales con tasas quirúrgicas más bajas en comparación con las tratadas en hospitales con tasas altas (90,2% versus 92,4% a los 5 años y 71,6% versus 88,2% a los 10 años, respectivamente). El exceso de riesgo relativo para las pacientes tratadas en hospitales con tasas quirúrgicas más bajas fue de 2,00 (i.c. del 95% 1,17-3,40). La supervivencia global también fue menor para las pacientes tratadas en hospitales con tasas quirúrgicas más bajas en comparación con las más altas (48,3% versus 51,3% a los 5 años y 15,0% versus 19,7% a los 10 años, respectivamente, cociente de riesgos instantáneos, hazard ratio, HR, ajustado 1,07) i.c. del 95% 1,00-1,14)). CONCLUSIÓN: Omitir la cirugía se asocia con una peor supervivencia relativa y global en pacientes de ≥ 80 años con cáncer de mama en estadios 1-2 y receptores hormonales positivos. Las investigaciones futuras deberían centrarse en el efecto de este enfoque en la calidad de vida y la funcionalidad física.

Risk of Positive Sentinel Lymph Node After Neoadjuvant Systemic Therapy in Clinically Node-Negative Breast Cancer: Implications for Postmastectomy Radiation Therapy and Immediate Breast Reconstruction.

BACKGROUND: Residual axillary lymph node involvement after neoadjuvant systemic therapy (NST) is the determining factor for postmastectomy radiation therapy (PMRT). Preoperative identification of patients needing PMRT is essential to enable shared decision-making when choosing the optimal timing of breast reconstruction. We determined the risk of positive sentinel lymph node (SLN) after NST in clinically node-negative (cN0) breast cancer. METHODS: All cT1-3N0 patients treated with NST followed by mastectomy and SLNB between 2010 and 2016 were identified from the Netherlands Cancer Registry. Rate of positive SLN for different breast cancer subtypes was determined. Logistic regression analysis was performed to determine correlated clinicopathological variables with positive SLN. RESULTS: In total 788 patients were included, of whom 25.0% (197/788) had positive SLN. cT1-3N0 ER+HER2+, cT1-3N0 ER-HER2+ , and cT1-2N0 triple-negative patients had the lowest rate of positive SLN: 7.2-11.5%, 0-6.3%, and 2.9-6.2%, respectively. cT1-3N0 ER+HER2- and cT3N0 triple-negative patients had the highest rate of positive SLN: 23.8-41.7% and 30.4%, respectively. Multivariable regression analysis showed that cT2 (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.01-3.96), cT3 (OR 2.56; 95% CI 1.30-5.38), grade 3 (OR 0.44; 95% CI 0.21-0.91), and ER+HER2- subtype (OR 3.94; 95% CI 1.77-8.74) were correlated with positive SLN. CONCLUSIONS: In cT1-3N0 ER+HER2+, cT1-3N0 ER-HER2+, and cT1-2N0 triple-negative patients treated with NST, immediate reconstruction can be considered an acceptable option due to low risk of positive SLN. In cT1-3N0 ER+HER2- and cT3N0 triple-negative patients treated with NST, risks and benefits of immediate reconstruction should be discussed with patients due to the relatively high risk of positive SLN.

Breast cancer-related deaths according to grade in ductal carcinoma in situ: A Dutch population-based study on patients diagnosed between 1999 and 2012.

BACKGROUND: The incidence of ductal carcinoma in situ (DCIS) has drastically increased over the past decades. Because DCIS is resected after diagnosis similar to invasive breast cancer, the natural cause and behaviour of DCIS is not well known. We aimed to determine breast cancer-specific survival (BCSS) and overall survival (OS) according to grade in DCIS patients after surgical treatment in the Netherlands. PATIENTS AND METHODS: All DCIS patients diagnosed between 1999 and 2012 were selected from the Netherlands Cancer Registry. The cause of death was obtained from 'Statistics Netherlands'. BCSS and OS were estimated using multivariable Cox regression in the entire cohort and stratified for grades. RESULTS: In total, 12,256 patients were included, of whom 1509 (12.3%) presented with grade I, 3675 (30.0%) with grade II, 6064 (49.5%) with grade III and 1008 (8.2%) with an unknown grade. During a median follow-up of 7.8 years, 1138 (9.3%) deaths were observed, and 179 (1.5%) were breast cancer-related. Of these, 10 patients had grade I; 46 grade II; 95 grade III and 28 an unknown grade. After adjustment for confounding, grade II and III were related to worse BCSS than grade I with hazard ratios of 1.92 (95% confidence interval [CI]: 0.97-3.81) and 2.14 (95% CI: 1.11-4.12), respectively. No association between grades and OS was observed. CONCLUSION: BCSS and OS in DCIS patients were excellent. Because superior rates were observed for low-grade DCIS, it seems justified to investigate whether active surveillance may be a balanced alternative for conventional surgical treatment.

TNM classification and the need for revision of pN3a breast cancer.

BACKGROUND: According to the seventh edition of tumour-node-metastasis (TNM) classification, pN3a status in breast cancer patients consists of presence of an infraclavicular lymph node metastasis (LNM) and/or presence of ≥10 axillary LNMs. The aim of this study was to determine whether prognosis of pN3a based on at least an infraclavicular LNM differs from ≥10 axillary LNMs. METHODS: Data were obtained from the Netherlands Cancer Registry. All patients were diagnosed between 2005 and 2008 with primary invasive epithelial breast cancer and pN2a or pN3a status as pathologic result. Patients with pN3a were subdivided in pN3a based on at least an infraclavicular LNM or ≥10 axillary LNMs. Disease-free survival (DFS) included any local, regional or contralateral recurrence, distant metastasis or death within 5 years. Kaplan-Meier curves provided information on 5-year DFS and 8-year overall survival (OS). In addition, Cox proportional hazards model was used to measure the effect of relevant clinicopathological variables on DFS and OS. RESULTS: A total of 3400 patients with pN2a and 1788 patients with pN3a were included. In 83 patients, pN3a was based on at least an infraclavicular LNM (4.6%) and in 1705 patients because of ≥10 axillary LNMs (95.4%). After multivariable analyses, DFS and OS were inferior in patients with pN3a based on ≥10 axillary LNMs compared to infraclavicular LNM (DFS 48.8% versus 63.8%, hazard ratio [HR] 1.59, p = 0.036; OS 46.6% versus 63.9%, HR 1.46, p = 0.042). Furthermore, pN2a and pN3a based on infraclavicular LNM had comparable DFS and OS. CONCLUSION: PN3a status based on an at least an infraclavicular LNM is rare, yet its prognosis is superior to ≥10 axillary LNMs. Reclassification of infraclavicular LNM in the next TNM should therefore be considered into pN2a.

Chenodeoxycholic acid stimulated fibroblast growth factor 19 response - a potential biochemical test for bile acid diarrhoea.

BACKGROUND: Bile acid diarrhoea is underdiagnosed and better diagnostic tests are needed. Fasting serum fibroblast growth factor-19 (FGF19) has insufficient diagnostic value, but this may be improved by stimulation. AIM: To explore if an impaired FGF19 response identifies primary bile acid diarrhoea. METHODS: Eight patients with primary bile acid diarrhoea and eight healthy volunteers ingested (i) a meal plus 1250 mg chenodeoxycholic acid (CDCA), (ii) 1250 mg CDCA or (iii) the meal. Blood was sampled at fasting and repeatedly after stimulation. We analysed FGF19 by enzyme-linked immunosorbent assay and bile acids including 7α-hydroxy-4-cholesten-3-one by liquid chromatography-tandem mass spectrometry. RESULTS: Stimulation with the meal plus CDCA increased median FGF19 in healthy volunteers from fasting 62 pg/mL [interquartile range (IQR): 41-138] to 99 pg/mL (IQR: 67-147; P = 0.012) after 90 min and peaked after 150 min at 313 pg/mL (IQR: 54-512). This response was impaired in primary bile acid diarrhoea patients [fasting 56 pg/mL (IQR: 42-79); 90 min: 48 pg/mL [IQR: 37-63); 150 min: 57 pg/mL (48-198)]. Receiver operating characteristics (ROCAUC ) for fasting FGF19 was 0.55 (P = 0.75) and at 90 min 0.84 (P = 0.02). The difference in FGF19 from fasting to 90 min after the meal plus CDCA separated the groups (ROCAUC 1.0; P = 0.001). 7α-hydroxy-4-cholesten-3-one was elevated in primary bile acid diarrhoea (P = 0.038) and not significantly affected by stimulation. CONCLUSIONS: The FGF19 response following chenodeoxycholic acid plus meal is impaired in primary bile acid diarrhoea. This may provide a biochemical diagnostic test.

Prognosis of residual axillary disease after neoadjuvant chemotherapy in clinically node-positive breast cancer patients: isolated tumor cells and micrometastases carry a better prognosis than macrometastases.

PURPOSE: The aim of this study was to compare disease-free survival (DFS) and overall survival (OS) between clinically node-positive breast cancer patients, treated with neoadjuvant chemotherapy (NAC), with axillary pathologic complete response (ypN0), residual axillary isolated tumor cells or micrometastases (ypNitc/mi), and residual axillary macrometastases (ypN1-3). METHODS: All patients diagnosed with clinically node-positive primary invasive breast cancer treated with NAC and subsequent axillary lymph node dissection between 2005 and 2008 were retrospectively analyzed. Data were obtained from the Netherlands Cancer Registry. Patients were stratified by final pathological axillary status: ypN0, ypNitc/mi, or ypN1-3. The main outcome measures DFS and OS were analyzed using Kaplan-Meier survival analysis. Uni- and multivariable cox regression analyses were used to determine independent predictors for DFS and OS. RESULTS: A total of 1347 patients were included. Pathologic nodal status was ypN0 in 22.2%, ypNitc/mi in 3.8%, and ypN1-3 in 74.0% of patients. Overall, 5-year DFS was 57.8% and mean OS was 7.4 years. DFS and OS were comparable between ypN0 and ypNitc/mi (HR 1.38 (0.40-4.79, p = 0.613) and HR 0.92 (0.27-3.09, p = 0.889), respectively), but significantly different between ypN0 and ypN1-3 (HR 1.78 (1.06-3.00, p = 0.031) and HR 1.70 (1.07-2.71, p = 0.026), respectively). CONCLUSIONS: Clinically node-positive patients, treated with NAC, with axillary nodal status ypN0 or ypNitc/mi carry similar prognosis regarding DFS and OS. Axillary nodal status ypN1-3 is associated with a less favorable prognosis. Future studies should consider ypN0 and ypNitc/mi as one entity.

Does the TNM classification of solitary internal mammary lymph node metastases in breast cancer still apply?

PURPOSE: TNM classification of solitary internal mammary lymph node metastases (IMLNMs) in breast cancer varies depending on their method of detection: sentinel lymph node biopsy (pN1b) or clinical examination including radiological and/or physical examination (pN2b). This study aimed to evaluate whether there is a difference in prognosis between both groups. METHODS: Data of all patients diagnosed with primary invasive epithelial breast cancer between 2005 and 2008 were obtained from the Netherlands Cancer Registry. Patients with IMLNMs were divided in groups according to their pN1b and pN2b status. The main outcome measures disease-free survival (DFS) after 5 years and overall survival (OS) after 8 years were analyzed using Kaplan-Meier survival analysis. Cox regression analysis was used to determine independent predictors for DFS and OS. RESULTS: A total of 73 patients with pN1b status and 28 patients with pN2b status were included. DFS rate was 74.1% in the pN1b group compared to 85.0% in the pN2b group (p = 0.211). Regarding OS, 20.5% (pN1b) and 25.0% (pN2b) of the patients deceased within 8 years of follow-up (p = 0.589). In multivariable cox regression analysis, nodal status was not statistically significant for DFS (HR 0.29 [95% CI 0.04-2.33], p = 0.244) or OS (HR 1.04 [95% CI 0.37-2.89], p = 0.947). CONCLUSIONS: Although the TNM classification considers pN1b and pN2b to be distinct prognostic entities, we did not observe any prognostic differences between these groups. Therefore, solitary IMLNMs may be regarded as a single category in the future and revision of TNM classification should be considered.

Breast-conserving therapy versus mastectomy in T1-2N2 stage breast cancer: a population-based study on 10-year overall, relative, and distant metastasis-free survival in 3071 patients.

PURPOSE: Our previous study demonstrated breast-conserving surgery with radiation therapy (BCT) to be at least equivalent to mastectomy in T1-2N0-1 breast cancer. Yet, 10-year survival rates after BCT and mastectomy with radiation therapy (MAST) in T1-2N2 breast cancer specifically have not been examined. Our study aimed to determine 10-year overall (OS), relative (RS), and distant metastasis-free survival (DMFS) in T1-2N2 breast cancer after BCT and MAST, stratified for T category. METHODS: All women diagnosed with primary invasive T1-2N2 breast cancer in 2000-2004, treated with BCT or MAST, both with axillary dissection and RT, were selected from the Netherlands Cancer Registry. Ten-year OS and DMFS were estimated using multivariable Cox regression. Excess mortality ratios (EMR) were calculated to estimate RS, using life tables of the general population. OS and RS were determined on the whole cohort, and DMFS on the 2003 cohort with completed follow-up. Missing data were imputed. RESULTS: Of 3071 patients, 1055 (34.4 %) received BCT and 2016 (65.7 %) MAST. BCT and MAST showed equal 10-year OS and RS. After stratification, BCT was significantly associated with improved 10-year OS [HRadjusted 0.82 (95 % CI 0.71-0.96)] and RS (EMRadjusted 0.81 (95 % CI 0.67-0.97]) in T2N2, but not in T1N2. Ten-year DMFS was equal for both treatments [HRadjusted 0.87 (95 % CI 0.64-1.18)] in the 2003 cohort (n = 594), which was representative for the full cohort. CONCLUSION: BCT showed at least equal 10-year OS, RS, and DMFS compared to MAST. These results confirm that BCT is a good treatment option in T1-2N2 breast cancer.

Population based study on sentinel node biopsy before or after neoadjuvant chemotherapy in clinically node negative breast cancer patients: Identification rate and influence on axillary treatment.

The timing of the sentinel lymph node biopsy (SNB) is controversial in clinically node negative patients receiving neoadjuvant chemotherapy (NAC). We studied variation in the timing of axillary staging in breast cancer patients who received NAC and the subsequent axillary treatment in The Netherlands. Patients diagnosed with clinically node negative primary breast cancer between 1st January 2010 and 30th June 2013 who received NAC and SNB were selected from the Netherlands Cancer Registry. Data on patient and tumour characteristics, axillary staging and treatment were analysed. Two groups were defined: (1) patients with SNB before NAC (N=980) and (2) patients with SNB after NAC (N=203). Eighty-three percent of patients underwent SNB before NAC, with large regional variation (35-99%). The SN identification rate differed for SNBs conducted before and after NAC (98% versus 95%; p=0.032). A lower proportion of patients had a negative SNB when assessed before NAC compared to after (54% versus 67%; p=0.001). The proportion of patients receiving any axillary treatment was higher for those with SNB before NAC than after (45% versus 33%; p=0.006). In conclusion, variation exists in the timing of SNB in clinical practice in The Netherlands for clinically node negative breast cancer patients receiving NAC. The post-NAC SN procedure is, despite some lower SN identification rate, associated with a significantly less frequent axillary treatment and thus with less expected morbidity. The effect on recurrence rate is not yet clear. Patients in this registry will be followed prospectively for long-term outcome.

Quality improvement by implementing an integrated oncological care pathway for breast cancer patients.

BACKGROUND AND AIM: In cancer care, more and more systemized approaches such as care pathways are used to reduce variation, reduce waiting- and throughput times and to improve quality of care. The aim of this study was to determine whether the implementation of a multidisciplinary breast cancer pathway in three hospitals has improved the care for breast cancer patients. METHODS: Retrospectively almost 800 patients with breast cancer were selected from the Netherlands Cancer Registry (NCR). The patients were divided in two groups: before implementation of the pathway in 2006-07 (baseline measurement) and those after implementation in 2009 (post measurement). Fourteen quality indicators were compared before and after the implementation of the care pathway. To estimate the impact of the care pathway relative to evidence based guidelines and profession-based norms, involved project leaders were interviewed. RESULTS: Seven out of eight indicators with medical information and four out of five indicators with information about waiting- and throughput times improved. With the multidisciplinary meeting as key in the breast cancer care, more compliance to national guidelines was observed. E.g. for more patients a HER2neu test was performed after implementation of the pathway (from 92% to 96%, ⤳ = 0.016) and more patients started with their first chemotherapy (from 33% to 45%) or their first radiotherapy (from 55% to 59%) within 4 weeks after surgery. CONCLUSION: Implementing a multidisciplinary breast cancer pathway leads to better compliance with the national guidelines and can improve breast cancer care.

Limited human epidermal growth factor receptor 2 discordance in metastatic breast cancer patients treated with trastuzumab, a population based study.

BACKGROUND: Accurate assessment of the human epidermal growth factor receptor 2 (HER2) in breast cancer is essential for proper treatment decisions. HER2 positivity confirmation rates in breast cancer trials by central testing pathology laboratories were reported to be approximately 85%. The aim of our study was to assess in a population based sample concordance of HER2 status in metastatic breast cancer (MBC) patients locally tested HER2 positive and treated with trastuzumab. Moreover cost-effectiveness of in situ hybridisation (ISH) in patients with an immunohistochemical score 3+ (IHC3+) was explored. METHODS: MBC patients treated between 2005 and 2009 with trastuzumab-based therapy in North East Netherlands were identified by a survey of hospital pharmacies. Primary tumour samples were retested centrally for HER2 status using 1 immunohistochemical (IHC) method and two methods using ISH on tissue micro-arrays. Potential discordant patients were retested on whole tumour slides. HER2 positivity was defined as: (1) ISH amplification (according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice Guideline Update) and (2) when ISH failed an IHC score of 3+. Cost-effectiveness was estimated using potential ISH and treatment costs. RESULTS: HER2 status could be retested in 174 of 194 (90%) patients. The HER2 concordance rate was 87%. The 21 discordant patients were in the 67% due to primary HER2 testing with only IHC. Overall survival of HER2 discordant and concordant patients was not significantly different (18 versus 25months, p=0.131). Structural ISH in the case of IHC3+ has an estimated potential saving of €87,710 per 100 patients. CONCLUSION: HER2 concordance in a population based study is comparable to those described in selected populations. Discordance is mostly due to testing with only IHC. ISH in the case of IHC3+ is cost-effective.

Impact of primary local treatment on the development of distant metastases or death through locoregional recurrence in young breast cancer patients.

In this study, we tested the hypothesis whether breast conserving therapy (BCT) compared with mastectomy is associated with a negative outcome in terms of distant metastases or death (DMD) and investigated the relation between locoregional recurrence (LRR) and DMD in young breast cancer (BC) patients. This study included a consecutive series of 536 patients ≤40 years of age at diagnosis with pathological T1N0-3M0 BC, treated between 1989 and 2005. A multistate survival model was used to evaluate the influences of local treatment and LRR on DMD, adjusted for potential prognostic factors. Patients were treated with mastectomy (N = 213) or BCT (N = 323). Median age at diagnosis was 36.3 years, with a median follow-up of 9.0 years. The 10-year actuarial cumulative incidence of DMD was 30.6 % after mastectomy and 26.3 % after BCT (P = 0.04). In total, 81 (15 %) LRRs were observed. After BCT, patients had a threefold higher risk of LRR than after mastectomy (HR 2.9; 95 % CI 1.6-5.3). Patients with LRR had a higher risk of DMD compared with patients without LRR (HR 5.5; 95 % CI 2.1-14.5). However, BCT was not negatively associated with DMD-after-LRR (HR 0.47; 95 % CI 0.2-1.1, BCT vs mastectomy). In conclusion, although LRR significantly affected DMD, the increased risk of LRR after BCT compared with mastectomy did not lead to a worse DMD outcome in BC patients ≤40 years of age.

Azathioprine and mercaptopurine in the management of patients with chronic, active microscopic colitis.

BACKGROUND: Microscopic colitis (MC) is a common chronic diarrhoeal disease, and remission can be induced with budesonide. However, diarrhoea relapses frequently when budesonide is tapered and a few patients become budesonide intolerant. AIM: To examine retrospectively the effect of azathioprine (AZA) and mercaptopurine (MP) in patients with chronic, active MC. METHODS/PATIENTS: Data on all MC patients who received AZA or MP in the years 1997-2011 at three centres representing three countries were pooled for analysis. The indications for thiopurine therapy were frequent relapses after short-term treatment (N = 26), budesonide dependency on 6 mg (N = 15) and budesonide intolerance (N = 5). The response to thiopurine treatment was defined as clinical remission, intolerance or nonresponse. RESULTS: Forty-six MC patients (32 CC and 14 LC), 32 female; median age 59 years (range: 36-83) with a median disease duration of 3 years (range: 0.5-18) were included. Thirteen patients (28%) achieved long-term clinical remission on AZA therapy. AZA failed in 31 patients (67%) due to intolerance and in 2 patients (4%) because of nonresponse. Thirteen of 31 AZA-intolerant patients were switched to MP and 6 patients (46%) obtained clinical remission. Thus, the overall response rate to thiopurines was 19/46 (41%). The main side effects were nausea/vomiting and abnormally elevated liver enzymes. CONCLUSIONS: In this retrospective case series, the majority of chronic, active MC patients were intolerant to AZA leading to cessation of treatment. However, further studies are needed to explore the efficacy, acceptance, tolerance and safety of MP in patients with chronic, active MC refractory to budesonide.

A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer, Fallopian tube or primary peritoneal carcinomas: the DoCaCel study.

BACKGROUND: In ovarian cancer, cyclooxygenase-2 (COX-2) overexpression is prognostic for poor survival. We investigated the efficacy of celecoxib (C), a selective COX-2 inhibitor, added to docetaxel (Taxotere)/carboplatin (DC) in advanced ovarian cancer. PATIENTS AND METHODS: In a phase II, randomized study, 400 mg celecoxib b.i.d. was added to first-line DC treatment (DCC). Celecoxib was to be continued after DC termination up to 3 years. Study end points were tolerability, progression-free survival (PFS) and overall survival (OS). RESULTS: 151 of 196 eligible patients were diagnosed with stage IIIC/IV disease. Median follow-up for patients alive was 32.3 months. Celecoxib was used during a mean of 8.5 months. Twenty-three of 97 DCC patients stopped celecoxib prematurely, mainly due to skin reactions. Complete biochemical response was achieved in 51/78 DC patients (65%) versus 57/78 DCC patients (75%, not significant). In both study arms, median PFS was 14.3 months and median OS 34 months. COX-2 was expressed in 82% of 120 tumor samples retrospectively recovered. The PFS and OS of patients with intermediate/high COX-2 expression were similar to that in the other patients. CONCLUSION: Celecoxib did not influence PFS and OS, but interpretation of results is hampered by premature celecoxib discontinuation.

Microscopic colitis: Current status, present and future challenges: statements of the European Microscopic Colitis Group.

Microscopic colitis (MC) is an inflammatory bowel disease presenting with chronic, non-bloody watery diarrhoea and few or no endoscopic abnormalities. The histological examination reveals mainly two subtypes of MC, lymphocytic or collagenous colitis. Despite the fact that the incidence in MC has been rising over the last decades, research has been sparse and our knowledge about MC remains limited. Specialists in the field have initiated the European Microscopic Colitis Group (EMCG) with the primary goal to create awareness on MC. The EMCG is furthermore a forum with the intention to promote clinical and basic research. In this article statements and comments are given that all members of the EMCG have considered being of importance for a better understanding of MC. The paper focuses on the newest updates in epidemiology, symptoms and diagnostic criteria, pathophysiology and highlights some unsolved problems. Moreover, a new treatment algorithm is proposed on the basis of new evidence from well-designed, randomized control trials.