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Purpose Caveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master regulator of membrane transport and cell signaling. Several CAV1 SNPs have been linked to multiple cancers, but the prognostic impact of CAV1 SNPs in breast cancer remains unclear. Here, we investigated CAV1 polymorphisms in relation to clinical outcomes in breast cancer. Methods A cohort of 1017 breast cancer patients (inclusion 2002–2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six CAV1 SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction. CAV1 genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments). Results Only one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The CAV1 rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HRadj) 4.26 (95% CI 1.86–9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HRadj 2.24 (95% CI 1.24–4.04). No other genotypes or haplotypes were associated with clinical outcome. Conclusion CAV1 polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed.

Background Adjuvant treatments with PD-1 and BRAF+MEK inhibitors significantly prolong recurrence-free survival in stage III cutaneous melanoma. Yet, the effect on overall survival is still unclear. Based on recurrence-free survival outcomes, these treatments have been approved and widely implemented. The treatments have significant side effects and costs, and the overall survival effect remains a highly anticipated outcome. Methods Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with stage III melanoma between 2016 and 2020. The patients were divided depending on if they were diagnosed before or from July 2018, based on the timepoint when adjuvant treatment was introduced in Sweden. Patients were followed until the end of 2021. In this cohort study melanoma-specific and overall survival were calculated using the Kaplan-Meier method and Cox-regression analyses. Results There were 1371 patients diagnosed with stage III melanoma in Sweden in 2016-2020. The 2-year overall survival rates, comparing the 634 patients in the pre-cohort and the 737 in the post-cohort, were 84.3% (95% CI 81.4-87.3) and 86.1% (95% CI 83.4-89.0), respectively, with an adjusted HR 0.91 (95% CI 0.70-1.19, P = 0.51). Further, no significant overall or melanoma-specific survival differences were seen when comparing the pre- and the post-cohort in different subgroups for age, sex or tumor characteristics. Conclusions In this nationwide, population and registry-based study, no survival benefit was detected in patients diagnosed before or after the implementation of adjuvant treatment in stage III melanoma. These findings encourage a careful assessment of the current recommendations on adjuvant treatment.

S2. Phospho-kinase antibody array analyses of normoxia (a) or hypoxia (b) level expressed as normalized to reference standard.

S3. Cytotoxicity of T-DM1 catabolites is not altered by hypoxia. Dose response curves showing sensitivity of normoxic or hypoxic SKBR3 and BT474 cells treated with T-DM1 catabolites, DM1 (A, D), MCC-DM1 (B, E), and LMCC-DM1 (C, F) for 72 h. Normoxia (black curves) and hypoxia (red curves). Cell viability was measured by MTS assay and expressed as % cell viability of control. Data shown are from at least three independent experiments, each performed in triplicates. NR, not reached.

Figure S5. Flow chart of the selection process of patients.

S4. Hypoxia induces resistance to Abraxane in SKBR3 cells.

Supplementary Table 1. Patient and tumor characteristics in relation to tumor-specific cytoplasmic intensity of CAV1

S6. CAV1 is expressed in the cytoplasm of invasive tumor cells in primary breast cancer tissue.

S1. Caspase induction in SKBR3 cells pre-incubated for 20 h in normoxia or hypoxia and treated with T-DM1 was measured using the Caspase-Glo 3/7 assay kit and the results are shown as mean luminescence (measured in relative light units [RLU]).

Figure S7. Histology of primary breast cancer tissue.

Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%–38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P < 0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome. Cancer Res; 76(16); 4765–74. ©2016 AACR.

159930_1_supp_0_t72r9t.jpg from Multiregion Whole-Exome Sequencing Uncovers the Genetic Evolution and Mutational Heterogeneity of Early-Stage Metastatic Melanoma

Overview of the study workflow (S1); Hematoxylin & eosin stainings of samples in the study (S2); FACS ploidy histogram of Mm1702 (S3); Mutation-plots demonstrating the subclonality analysis in different regions of tumor Mm1641 (S4); Mutation-plots demonstrating the subclonality analysis in different regions of tumors Mm1641, Mm1702 and Mm1749 (S5); Mutation-plots demonstrating the subclonality analysis in different regions of tumor Mm1749 (S6); Mutation-plots demonstrating the subclonality analysis in different regions of tumors Mm1749, Mm1765 and Mm1767 (S7); Mutation-plots demonstrating the subclonality analysis in different regions of tumors Mm1767, Mm1772 and Mm1837 (S8); Correlations of trunk and non-trunk mutations to signatures from Alexandrov et al Nature 2013 (S9); Difference in expression levels between tumor regions harboring non-trunk mutations and those missing the corresponding mutations (S10); Correlation plots between DNA and RNA VAF in individual regions in tumors Mm1641 and Mm1702 (S11); Correlation plots between DNA and RNA VAF in individual regions in tumors Mm1702, Mm1742 and Mm1749 (S12); Correlation plots between DNA and RNA VAF in individual regions in tumors Mm1749 and Mm1765 (S13); Correlation plots between DNA and RNA VAF in individual regions in tumors Mm1767 and Mm1772 (S14); Correlation plots between DNA and RNA VAF in individual regions in tumor Mm1837 (S15).

Description of additional methods and procedures used in the study. Also includes Supplementary References.

The prognostic impact of insulin-like growth factor binding protein 7 (IGFBP7) in breast cancer is unclear. Host factors, including lifestyle, anthropometry and metabolic profile, might influence tumor-specific IGFBP7. This study aimed to investigate whether IGFBP7 levels and messenger ribonucleic acid (mRNA) expression are associated with the patient and tumor characteristics and prognosis in breast cancer. Patients with primary breast cancer in Lund, Sweden, were included preoperatively in the study between 2002 and 2012 (n = 1018). Tumor-specific IGFBP7 protein levels were evaluated with immunohistochemistry using tissue microarrays in tumors from 878 patients. IGFBP7 mRNA expression and its corresponding clinical data were obtained from The Cancer Genome Atlas and analyzed for 809 patients. Tumor-specific IGFBP7 protein levels were categorized based on Histo 300 scores into IGFBP7low (6.2%), IGFBP7intermediate (75.7%) and IGFBP7high (18.1%). Both low IGFBP7 protein levels and mRNA expression were associated with less aggressive tumor characteristics. Overall, IGFBP7low conferred low recurrence risk. The prognostic impact of IGFBP7high varied according to any alcohol consumption and tamoxifen treatment. IGFBP7high was associated with low recurrence risk in alcohol consumers but high recurrence risk in alcohol abstainers (Pinteraction= 0.039). Moreover, the combination of IGFBP7high and estrogen receptor-positive tumors was associated with low recurrence risk only in tamoxifen-treated patients (Pinteraction= 0.029). To conclude, IGFBP7low might be a good, independent prognosticator in breast cancer. The prognostic impact of IGFBP7high depends on host factors and treatment. IGFBP7 merits further investigation to confirm whether it could be a suitable biomarker for treatment selection., We investigated the prognostic impact of tumor-specific IGFBP7 levels in breast cancer. Overall, low IGFBP7 conferred good prognosis, while high IGFBP7 in ER+ tumors conferred good prognosis in tamoxifen-treated patients. IGFBP7 merits further investigation as a biomarker for treatment selection., Graphical Abstract

Background The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only. Methods The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/− whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group. Discussion This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM. Results The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden. Trial registration ClinicalTrials.gov, NCT 03116412. Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412

Melanoma of the skin is currently the 19th most common cancer globally. Nearly 290,000 new cases and 61,000 deaths were reported in 2018 and world-wide incidence rates continuously rise with annual...

Background Over the past decades, many regions have experienced a steady increase in the incidence of cutaneous melanoma. Here, we report on incidence trends for subsequent primary melanoma. Methods In this nationwide population-based study, patients diagnosed with a first primary cutaneous melanoma reported to the Swedish Cancer Registry were followed for up to 10 years for a diagnosis of subsequent primary melanoma. Patients were grouped with patients diagnosed with first melanoma in the same decade (1960s, 1970s, 1980s, 1990s, and 2000s, respectively). Frequencies, incidence rates (IRs), standardized incidence ratios (SIRs), and 95% confidence intervals (CIs) for second melanomas were calculated. All tests of statistical significance were 2-sided. Results Of patients with melanoma, 54 884 were included and 2469 were diagnosed, within 10 years, with subsequent melanomas. Over the 5 decades, there was a statistically significant steady increase in the frequency, IR, and SIR for second primary melanoma. For example, in the 1960s cohort, less than 1% (IR = 1.0, 95% CI = 0.5 to 1.7, and IR = 1.1, 95% CI = 0.5 to 1.9 per 1000 person-years in women and men, respectively) had second primary melanoma, and this rose to 6.4% (IR = 7.5, 95% CI = 6.8 to 8.3, per 1000 person-years) in the women and 7.9% (IR = 10.3, 95% CI = 9.3 to 11.2, per 1000 person-years) in the men in the 2000s cohort. This rise was seen independent of age, sex, invasiveness, or site of the melanoma. Further, in patients diagnosed with a second melanoma, the frequency of those having more than 2 melanomas increased statistically significantly and was 0.0% in the 1960s and rose to 18.0% in the 2000s (P < .001). Conclusions This is the first study to evaluate and report on a rising trend for subsequent primary melanoma. Additional primary melanomas worsen the patients’ survival, and precautions are needed to turn this steep upgoing trend.

Vitamin C may impact the efficiency of radiation therapy (RT) in breast cancer. The effects of RT alone or in combination with vitamin C in SKBR3, MDA-MB-231, and MCF7 cells were compared using clonogenic assay, proliferation assay (MTT), cell cycle analysis, and Western blot. Vitamin C use was assessed in 1803 breast cancer patients 2002-2017 in relation to clinicopathological features and recurrences after RT. Vitamin C combined with RT resulted in non-significant increases in colony formation and minor differences in cell cycle arrest and expression of studied proteins, compared to RT alone. Lower vitamin C doses alone or in combination with RT, resulted in higher proliferation with MTT than higher vitamin C doses in a cell line-dependent manner. Vitamin C use was associated with lower histological grade and BMI but not recurrence risk in RT-treated patients (LogRank

Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug-tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte-specific gene expression and increase of mesenchymal markers. Two crucial transcription factors, microphthalmia-associated transcription factor (MITF) and SRY-box transcription factor 10 (SOX10), important in melanoma development and progression, have been implicated in this process. In this study we describe that loss of MITF is associated with a distinct transcriptional program, MITF promoter hypermethylation, and poor patient survival in metastatic melanoma. From a comprehensive collection of melanoma cell lines, we observed that MITF-methylated cultures were subdivided in 2 distinct subtypes. Examining mRNA levels of neural crest-associated genes, we found that 1 subtype had lost the expression of several lineage genes, including SOX10. Intriguingly, SOX10 loss was associated with SOX10 gene promoter hypermethylation and distinct phenotypic and metastatic properties. Depletion of SOX10 in MITF-methylated melanoma cells using CRISPR/Cas9 supported these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states.

Human epidermal growth factor receptor 2 (HER2) status in breast cancer is routinely determined through immunohistochemistry (IHC) and/or in situ hybridisation (ISH) performed on whole tissue sections (WS). The purpose was to evaluate whether a gene protein assay (GPA) combining IHC with ISH, performed on breast cancer tissue microarray (TMA), is suitable for large-scale retrospective HER2 status evaluation. TMAs from 606 tumours from a Swedish population-based cohort (2005–2012) were stained with GPA. GPA IHC on TMA yielded weaker staining than IHC on WS during routine pathological assessment (86.0% agreement). However, final HER2 status agreement between GPA on TMA and WS based on both IHC and ISH was 97.7%. Only 14 tumours were discordant and one tumour with IHC score 1+ on both TMA and WS was HER2 amplified on TMA. In conclusion, GPA on TMA is suitable for large-scale retrospective evaluation of HER2 status.

Background Cutaneous melanoma is steadily increasing worldwide. The new AJCC 8th edition was recently launched and introduced several changes in melanoma staging, particularly for stage III. We conducted a population-based registry study with the purpose to evaluate the impact and prognostic accuracy of the new classification in Sweden. Methods Consecutive patients diagnosed with stage III melanoma between January 2005 and September 2017 were identified by the Swedish Melanoma Registry (SMR) and included for analyses. Patients with multiple primary melanomas were excluded. Patients were classified according to the AJCC 7th as well as the 8th edition. Melanoma-specific survival (MSS) was retrieved from the Swedish Cause of Death Registry. Results A total of 2067 eligible patients were identified from the SMR; 1150 patients (57%) changed stage III subgroup when reclassified according to the AJCC 8th edition. The median 5- and 10-year MSS for the whole cohort of stage III melanoma patients was 59% and 51% respectively. The MSS for substage IIIA, B, and C were all improved when patients were reclassified by using to the AJCC 8th edition. The newly defined substage IIID had the worst prognosis with a 10-year MSS of 16%. Conclusions A high proportion of patients diagnosed with stage III melanoma in Sweden between 2005 and 2017 was restaged to another subgroup, when they were reclassified according to the AJCC 8th of staging manual. We established an improved MSS for all substages compared with the former AJCC 7th edition. This may have implications on decisions about adjuvant treatment.

Background: The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age- and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM. Methods: Joinpoint regression models were used to analyse data from the Swedish Cancer Register and the Swedish Melanoma Registry 1997–2018 (N = 35,350 in situ CM, 59,932 CM). Results: The AAPC of CM for women was 4.5 (4.1–5.0, p &lt, 0.001) for the period 1997–2018. For men, the APCC was 4.2 (3.0–5.4, 0.001), with a significantly higher annual percentage change (APC) for the period 2000–2018 (5.0, 4.6–5.4, 0.001) compared to 1997–1999. An increasing annual incidence of CM ≤ 0.6 mm and 0.7 mm Breslow tumour thickness was found for men with a significant incidence shift for the period 2006–2015, respectively. Similarly for women, with a significantly higher APC for CM ≤ 0.6 mm from 2005. The incidence of intermediate thick CM (2.1–4.0 mm) has not increased since 2011. The incidence of CM &gt, 4.0 mm has been increasing among both sexes, with a significantly lower APC among women from 2005. Conclusions: The incidence of in situ and low-risk CM ≤ 1.0 mm in tumour thickness has been rising among both sexes since the 2000s.

Simple summary Patients diagnosed with stage II–III cutaneous melanoma (CM) are at high risk of recurrences, but the CM-specific survival ranges from approximately 40–70%. Here, the cure proportions and survival among uncured stage II–III CM patients were estimated. The 1- and 5-year relative survival ratios, cure proportions and the median survival times of uncured stage II–III CM patients in Sweden (n = 6466) were calculated based on data from the nationwide population-based Swedish Melanoma Register 2005–2013 with a follow-up through 2018. Proportions cured by surgery are low for sub-groups of stage II–III cutaneous melanoma showing that cure analyses can serve as a complement to established survival analyses. Abstract Background: Cure proportion represents the proportion of patients who experience the same mortality rate as the general population and can be estimated together with the survival of the proportion experiencing excess mortality (the uncured). The aim was to estimate the cure proportions and survival among uncured stage II–III cutaneous melanoma (CM) patients. Methods: 1- and 5-year relative survival ratios, cure proportions and the median survival times of uncured stage II–III CM patients in Sweden (n = 6466) were calculated based on data from the nationwide population-based Swedish Melanoma Register 2005–2013 with a follow-up through 2018. Results: Stages IIB and IIC showed significant differences in standardized cure proportions vs. stage IIA CM (0.80 (95% CI 0.77–0.83) stage IIA; 0.62 (95% CI 0.59–0.66) stage IIB; 0.42 (95% CI 0.37–0.46) for stage IIC). Significant differences in standardized cure proportions were found for stages IIIB and IIIC-D CM vs. stage IIIA (0.76 (95% CI 0.68–0.84) stage IIIA; 0.52 (95% CI 0.45–0.59) stage IIIB; 0.35 (95% CI 0.30–0.39) for stage IIIC–D). Conclusions: The results are emphasizing the poor prognosis with low proportions cured by surgery only for sub-groups of stage II–III CM, specifically within stages IIB–C CM.

Background The incidence of cutaneous malignant melanoma (CMM) continues to increase in most countries worldwide and the majority are diagnosed with thin tumours (Funding Agencies|M. Paulsson Fund; Gorthon Foundation; S. Paulsson Fund; LMK Foundation; Welander Finsen Foundation

Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.

The antibody–drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. We find that hypoxia fosters relative resistance to T-DM1 in HER2+ cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking. Implications: Together, our data for the first time identify hypoxic regulation of caveolin-1 as a resistance mechanism to T-DM1 with potential implications for individualized treatment of breast cancer.

Purpose To investigate the prognostic impact of body size changes during the first postoperative year in breast cancer. Methods A cohort of 1,317 primary breast cancer patients included in Sweden (2002–2014) underwent body size measurements at the preoperative and 1-year visits (n = 1,178). Landmark survival analyses were used to investigate how postoperative weight gain or loss (> 5%) or change in waist–hip ratio (WHR) categories (≤ 0.85 or > 0.85) impact prognosis. Results Median age at inclusion was 61 years and body mass index 25.1 kg/m2. After a median follow-up of 5.0 years from inclusion, 165 recurrences and 77 deaths occurred. Weight gain (17.0%) conferred over twofold recurrence risk only in patients Pinteraction = 0.033). Weight loss (8.6%) was only associated with a poor prognosis in patients ≥ 70 years, but not after restriction analysis. Weight change did not impact prognosis in patients 50 to Pinteraction = 0.007), with higher recurrence risk in patients with ER+ tumors and lower recurrence risk with ER− tumors. Conclusion Both changes in terms of weight and WHR category yielded independent prognostic information. Further research is imperative before recommending weight loss for all overweight breast cancer patients.

This study investigated how a history of menopausal hormone therapy (MHT) impacts clinical outcomes overall and in different subgroups of breast cancer patients. The study included 814 primary breast cancer patients aged ≥50 years in Sweden (2002–2012) with follow-up until 2016. Associations between patient- and tumor characteristics, recurrences, and overall survival were analyzed in relation to MHT. After a median follow-up of 7 years, 119 recurrences, and 111 deaths occurred. Ever MHT (n = 433, 53.2%) was associated with a lower BMI, frequency of alcohol abstinence, and histological grade, higher frequency of oral contraceptive use, and lobular cancer. Overall, MHT was not associated with prognosis, but there were significant effect modifications by estrogen receptor (ER) status, node status, main histological type, and aromatase inhibitor (AI) treatment on recurrence-risk (all Pinteractions≤ 0.017). MHT conferred an increased recurrence-risk in patients with ER- tumors, adjusted Hazard Ratio (HRadj) 3.99 (95% Confidence Interval (CI) 1.40–11.33), in node-negative patients HRadj 1.88 (95% CI 1.11–3.17), and in non-AI-treated patients HRadj 1.81 (95% CI 1.01–3.24), but decreased recurrence-risk in AI-treated patients HRadj 0.46 (95% CI 0.25–0.84) and in patients with lobular cancer HRadj 0.15 (95% CI 0.04–0.64). MHT was associated with lower risk of death in node-positive patients HRadj of 0.48 (95% CI 0.27–0.86) and in AI-treated patients HRadj of 0.41 (95% CI 0.22–0.77), but not in other patients (both Pinteractions≤ 0.027). A history of MHT may have prognostic value for certain subgroups of breast cancer patients such as AI-treated or node-negative patients.

Sentinel lymph node biopsy (SLNB) is an important staging tool for the management of melanoma. A multicentre study was done to validate previous findings that the timing of lymphoscintigraphy influences the accuracy of SLNB and patient outcomes, particularly survival.Data were reviewed on patients undergoing SLNB for melanoma at three centres in the UK and Sweden, examining the effect of timing of SLNB after nuclear medicine scanning. Kaplan-Meier survival analysis was used to assess overall (OS), disease-specific (DSS) and progression-free (PFS) survival, stratified by timing of lymphoscintigraphy. Independent risk factors for survival were identified by Cox multivariable regression analysis.A total of 2270 patients were identified. Median follow-up was 56 months. Univariable analysis showed a 4·2 per cent absolute and 35·5 per cent relative benefit in DSS (hazard ratio 1·36, 95 per cent c.i. 1·05 to 1·74; P = 0·018) for 863 patients whose SLNB was performed up to 12 h after lymphoscintigraphy compared with 1407 patients who had surgery after more than 12 h. There were similar OS and PFS benefits (P = 0·036 and P = 0·022 respectively). Multivariable analysis identified timing of lymphoscintigraphy as an independent predictor of OS (P = 0·017) and DSS (P = 0·030). There was an excess of nodal recurrences as first site of recurrence in the group with delayed surgery (4·5 versus 2·5 per cent; P = 0·008).Delaying SLNB beyond 12 h after lymphoscintigraphy withLa biopsia de ganglio centinela (sentinel lymph node biopsy, SLNB) es una técnica importante para la estadificación y tratamiento del melanoma. Se realizó un estudio multicéntrico para validar hallazgos previos según los cuales el momento de la linfogammagrafía (lymphoscintigraphy, LS) influye en la precisión de la SLNB y en los resultados de los pacientes, especialmente en la supervivencia. MÉTODOS: Se revisaron los datos de los pacientes a los que se realizó una SLNB por melanoma en 3 centros en el Reino Unido y Suecia, con especial atención al efecto del período entre la inyección el material radioactivo y la SLNB. Se realizó un análisis de supervivencia mediante el método de Kaplan-Meier para la supervivencia específica de la enfermedad (disease-specific survival, DSS), supervivencia global (overall survival, OS) y supervivencia libre de progresión (progression-free survival, PFS), todas ellas estratificadas por el momento de la LS. Los factores de riesgo independientes para la supervivencia se determinaron mediante un análisis de regresión multivariable de Cox.Se incluyeron 2.270 pacientes. La mediana de seguimiento fue de 49 meses. El análisis univariado mostró un beneficio absoluto del 4,2% y relativo del 35,5% (cociente de riesgos instantáneos, hazard ratio, HR: 1,36 (i.c. del 95% 1,05-1,74, P = 0.02)) en la DDS para los pacientes a los que la SLNB se realizó 12 horas después de la LS (n = 863) en comparación con aquellos realizados 12 horas (n = 1407). Se detectaron beneficios similares para la OS y la PFS (P = 0,04 y P = 0,02, respectivamente). El análisis multivariable identificó el tiempo entre la LS y la SLNB como un factor independiente de OS (P = 0,017) y DSS (P = 0,03). Hubo un aumento en las recidivas ganglionares como primer sitio de recidiva en el grupo de 12 horas (2,5% versus 4,5%; P = 0,008). CONCLUSIÓN: Estos datos validan nuestra investigación previa y tienen implicaciones significativas para las unidades de melanoma, en el sentido de que retrasar la SLNB más allá de las 12 horas después de realizar la LS con nanocoloides marcados con Tc99 tiene un impacto negativo significativo en la supervivencia de los pacientes y debe evitarse. Se presenta la hipótesis de que la causa subyacente es la migración temporal del trazador que determina una SLNB incorrecta. .