Ultra-radical upfront surgery does not improve survival in women with advanced epithelial ovarian cancer; a natural experiment in a complete population.

OBJECTIVE: Ultra-radical surgery to achieve complete resection in advanced epithelial ovarian cancer (EOC) has been widely accepted without strong supporting data. Our objective was to assess overall survival after a structured shift to an ultra-radical upfront surgical treatment algorithm and to investigate changes in the distribution of primary treatments after this shift. PATIENTS AND METHODS: In this population-based cohort study, all women with suspected EOC in the Stockholm-Gotland region of Sweden reported to the Swedish Quality Registry for Gynecologic Cancer (SQRGC) and National Cancer Registry (NCR) were selected in two 3-year cohorts, based on year of diagnosis (before (cohort1) or after (cohort 2) change in surgical treatment algorithm) and followed for at least three years. 5-year overall survival (OS) in non-surgically and surgically treated women was analyzed. Moreover, proportional distribution of primary treatment was evaluated. RESULTS: 752 women were included in the final analysis (n = 364 and 388 in cohort 1 and 2 respectively) with a median follow-up of 29 and 27 months. The complete resection rate increased from 37 to 67% (p ≤ 0.001) as well as proportion non-surgically treated women, 24 to 33%. No improvement in OS was observed in non-surgically (HR 0.76 (95% CI, 0.58-1.01); p = 0.06) or surgically treated (HR 0.94 (95% CI, 0.75-1.18); p = 0.59) women, even when complete resection was achieved (HR 1.31 (95% CI, 0.89-1.92); p = 0.17). CONCLUSION: A shift to ultra-radical upfront surgery in EOC did not improve survival despite a significant increase in complete resection rate. Identifying the limitations of surgical treatment remains a challenge.

Validation of data quality in the Swedish National Register for Breast Cancer.

BACKGROUND: The National Breast Cancer Register (NBCR) of Sweden was launched in 2008 and is used for quality assurance, benchmarking, and research. Its three reporting forms encompass Notification, Adjuvant therapy and Follow-up. Target levels are set by national and international guidelines. This national validation assessed data quality of the register. METHODS: Data recorded through the Notification form were evaluated for completeness, timeliness, comparability and validity. Completeness was assessed by cross-linkage to the Swedish Cancer Register (SCR). Comparability was analyzed by comparing registration routines in NBCR with national and international guidelines. Timeliness was defined as the difference between the earliest date of diagnosis and the reporting date to NBCR. Validity was assessed by re-abstraction of medical chart data for 800 randomly selected patients diagnosed in 2013. RESULTS: The completeness of the NBCR was high with a coverage across regions and years (2010-2014) of 99.9%. Of all incident cases reported to the NBCR in 2013 (N = 8654), 98.5% were included within 12 months and differences between health regions were essentially negligible. Coding procedures followed guidelines and were uniformly adhered to. The proportion of missing values was < 5% for most variables and reported information generally had high exact agreement (> 90%). CONCLUSIONS: Completeness of data, comparability and agreement in the NBCR was high. For clinical quality purposes and benchmarking, improved timeliness is warranted. Assessment of validity has resulted in a thorough review of all variables included in the Notification form with clarifications and revision of selected variables.

Safety of fertility preservation in breast cancer patients in a register-based matched cohort study.

PURPOSE: To determine if women with breast cancer that undergo fertility preservation (FP), with or without hormonal stimulation, present with an increased risk of breast cancer recurrence. METHODS: A matched cohort study on women with breast cancer attempting to ensure FP in Stockholm from 1999 to 2013 [exposed women (n = 188), age-matched unexposed controls (n = 378)] was designed using the Stockholm regional data from the Swedish National Breast Cancer Quality Register. Breast cancer relapse rates [incidence rate ratio (IRR)] and 95% confidence interval (CI) were estimated using Cox regression and adjusted for potential confounding factors. Completeness of the registry at the time of the study was close to 99%. RESULTS: Most women attempted FP by hormonal stimulation treatment (n = 148, 79%) with the objective of freezing their eggs or embryos. A smaller group elected FP methods without hormone stimulation (n = 40, 21%). Women who received hormone stimulation did not present with a higher relapse rate than unexposed control women in a model adjusted for age and calendar period of diagnosis (IRR 0.59, 95% CI 0.34-1.04). The results remained virtually unchanged after adjustment for tumor size, estrogen receptor status, affected lymph nodes, and chemotherapy treatment (IRR 0.66, 95% CI 0.37-1.17). CONCLUSION: Evidence was not found that fertility preservation, with or without hormonal stimulation, was associated with an increased risk of breast cancer recurrence. The high coverage rate of this population-based study supports the safe practice of fertility preservation in young women with breast cancer.

Role of intravenous dosage regimens of bisphosphonates in relation to other aetiological factors in the development of osteonecrosis of the jaws in patients with myeloma.

The aim of this case-control study was to identify possible explanatory risk factors for the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ) by estimating the effects of intravenous dosage regimens of bisphosphonates, coexisting diseases, and other drugs on 201 patients with multiple myeloma, with or without BRONJ. We compared sex, treatment with bisphosphonates, incidence of diabetes, and the taking of drugs such as corticosteroids and chemotherapy in patients who had BRONJ (n=44) and patients who did not (n=157). Among the bisphosphonates given intravenously zoledronic acid showed a stronger correlation with BRONJ than pamidronic acid. The risk of developing BRONJ increased dramatically at cumulative intravenous doses of more than 78 mg of zoledronic acid or 600 mg of pamidronic acid, which corresponds to treatment for 18 months or longer. Diabetes mellitus correlated significantly with the development of BRONJ (p=0.01) while there was no correlation with sex, simultaneous treatment with corticosteroids, or chemotherapy. In conclusion, treatment with zoledronic acid, high doses of pamidronic acid, and the coexistence of diabetes mellitus seem to be associated with the development of BRONJ.

Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer.

About one-third of oestrogen receptor alpha-positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen.

Interobserver variability of histopathological prognostic parameters in cutaneous malignant melanoma: impact on patient management.

Clinical management of primary cutaneous melanomas is based on histopathological staging of the tumour. The aim of this study was to investigate, in a non-selected population in clinical practice, the agreement rate between general pathologists and pathologists experienced in melanoma in terms of the evaluation of histopathological prognostic parameters in cutaneous malignant melanomas, and to what extent the putative variability affected clinical management. A total of 234 cases of invasive cutaneous malignant melanoma were included in the study from the Stockholm-Gotland Healthcare Region in Sweden. Overall interobserver variability between a general pathologist and an expert review was 68.8-84.8%. Approximately 15.5% of melanomas ≤1 mm were re-classified either as melanoma in situ or melanomas >1 mm after review. In conclusion, review by a pathologist experienced in melanoma resulted in a change in recommendations about surgical excision margins and/or sentinel node biopsy in subgroups of T1 melanomas.

Difference in hormone receptor content in breast cancers from Vietnamese and Swedish women.

BACKGROUND: The aim of the present study was to compare both estrogen (ER) and progesterone receptor (PgR) content in operable breast cancers from Vietnamese and Swedish patients. MATERIAL AND METHODS: Primary breast cancer tissues were randomly selected from 249 Vietnamese patients treated in Hanoi, Vietnam between 2002 and 2004 and 1 257 Swedish patients treated in Stockholm, Sweden between 2002 and 2003. Clinical information was available for all patients in the study. The hormone receptor content in tumors from Vietnam was analyzed by immunohistochemistry using an automated slide stainer (Bench MarkXT, Ventana) in combination with anti-ER (SP1 250), and anti-PgR (clone 1E2) rabbit monoclonal antibody. Tumors with ≥ 10% stained nuclei were considered as receptor positive. Tumors from Swedish patients were analyzed with an enzyme immunoassay with a cut-off point of ≥ 0.10 fmol/µg DNA as positive. The hormone receptor frequencies between populations were compared according to clincopathology features. RESULTS: The ER positive rate was higher in premenopausal and lower in postmenopausal Vietnamese patients as compared to Swedish patients with similar menopausal status (71% versus 58%, OR 1.75, p = 0.007; 44% versus 72%, OR 0.32, p < 0.001, respectively). PgR positive tumors were found in 58% and 25% of pre- and postmenopausal Vietnamese patients, respectively. The corresponding figures for Swedish patients were 73% and 66%, respectively. CONCLUSIONS: There were significant differences in the frequency of ER/PgR positivity between Vietnam and Swedish breast cancer patients. These differences were independent on menopausal status and age of patients at diagnosis can not be explained by these factors and they can be contributed to knowledge about both basic biology features and prognoses.

HER2 status in operable breast cancers from Vietnamese women: Analysis by immunohistochemistry (IHC) and automated silver enhanced in situ hybridization (SISH).

BACKGROUND: HER2 amplification has been reported to occur in 19-30% of breast cancers in women from Western countries. Little is known about the HER2 status in breast cancers from Vietnamese women. The aim of this study was to assess the HER2 status in Vietnamese women with operable breast cancer using immunohistochemistry and silver in situ hybridization techniques. MATERIAL AND METHOD: Tissue blocks from 242 Vietnamese women with invasive primary breast carcinoma were stained by immunohistochemistry (IHC) and a dual silver in situ hybridization (SISH) for assessing HER2 status. The analysis followed international recommendations with a semi-quantitative grading of the reaction in four levels, "0", "1+", "2+" and "3+". The HER2 gene amplification was assessed by calculating the ratio of HER2/chromosome 17 in 20 tumor cell nuclei. A ratio of <1.8 was classified as non-amplification and a ratio >2.2 indicated tumors with gene amplification. A ratio between 1.8 and 2.2 was equivocal. RESULTS: Using IHC, 39% of the tumors strongly expressed "3+" the HER2 protein. An intermediate level "2+" of the protein was found in 11% while 50% showed no or low "0/1+" levels of protein expression. Gene amplification was found in 95% and 46% of the tumors with high "3+" and intermediate "2+" levels of protein expression, respectively. Thus, 41% of the patients had tumors with HER2 amplification. The concordance between IHC and SISH was 87%. Gene amplification was more frequent in ER negative than in ER positive tumors, 57% versus 33%, respectively. Additionally, tumors from postmenopausal women were amplified in 55% as compared to 36% in premenopausal women. CONCLUSIONS: HER2 gene amplification was found in 41% of Vietnamese breast cancers; this level is considerably higher than that previously found in a series of Swedish breast cancer women. The HER2-positive tumors were more often found in post-menopausal women than in ER negative tumors.

Eleven-year follow-up of a randomized study of pectoral fascia preservation after mastectomy for early breast cancer.

BACKGROUND: The present study reports results of a randomized trial in which breast cancer patients operated with preserved pectoral fascia compared to removal of the pectoral fascia showed a trend toward an increased risk for chest wall recurrence The aim of the study was to assess whether the different procedural modes had any impact on survival or local control in breast cancer patients followed in the long term. METHOD: The trial included 247 patients with breast cancer who underwent modified radical mastectomy in five Swedish hospitals between 1993 and 1997. The median follow-up time was 11 years. The patients were randomized between removal (n = 122) versus preservation (n = 125) of the pectoral fascia. RESULTS: The breast-cancer-specific survival at 10 years was 73%. Removal or preservation of the pectoral fascia had no significant impact on chest-wall recurrence rate or breast-cancer-specific survival. A total of 18 patients with chest-wall recurrence were seen in the group allocated to pectoral fascia preservation versus a total of 10 in patients allocated to pectoral fascia removal (hazard ratio = 1.8, 95% confidence interval = 0.8-4.0). The majority of the chest-wall recurrences were detected 0-5 years postoperatively. The cumulative chest-wall recurrence rates at 5 and at 10 years were 13 and 15%, respectively, in patients allocated to pectoral fascia preservation and 8 and 9% in patients allocated to pectoral fascia removal. CONCLUSIONS: With long-term follow-up neither the chest wall recurrence rate nor the breast-cancer-specific survival was significantly influenced by the preservation of the pectoral fascia. A trend toward an increased risk for chest wall recurrence was observed in patients with preserved pectoral fascia. A hazard ratio of 1.8 for a chest-wall recurrence in patients with preserved fascia indicates that fascia-sparing mastectomy may negatively affect prognosis.