Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies.

BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. CONCLUSIONS: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Immediate increase in perceived energy after exercise during the course of chemotherapy treatment for breast cancer.

PURPOSE: Exercise during chemotherapy has beneficial long-term effects on women with breast cancer, but short-term beneficial changes have been less investigated. Though short-term changes may be important as a encouraging factor, this study aimed to investigate immediate changes in self-reported energy, stress, nausea and pain following a single exercise session during chemotherapy. METHODS: Forty-six women who were exercising while undergoing adjuvant chemotherapy for breast cancer were included between October 2016 and April 2018. Self-reported energy and stress were assessed before, immediately after and 3 h after exercise sessions by the Stress-Energy Questionnaire. On the same questionnaire nausea and pain were assessed by a Visual Analog Scale. The measurements were completed at four time points during cycles 2 and 5 of the 6-cycle chemotherapy course. RESULTS: Energy level increased immediately after a single exercise session for three out of four periods during the chemotherapy course (p < 0.01), with a larger increase when energy was lower before the session (p < 0.01). Three hours after the exercise session, the energy was about the same level as before the exercise session. Stress decreased immediately after the session during cycle two (p < 0.01) but not cycle five. There were no changes in nausea or pain. CONCLUSIONS: Patients undergoing chemotherapy should be informed not only about the long-term advantages of exercise, but also immediate benefits in terms of increased energy. The energy increase both while exercise in the beginning and toward the end of the chemotherapy course, this short-term advantageous consequence may strengthen patients' motivation to exercise. Clinicians should also inform patients that exercise does not seem to worsen nausea and pain.

Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women.

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10-8 as genome-wide significant, and p-values < 1 × 10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10-7), which showed genome-wide significant interaction (p-value = 3.8 × 10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.

Oral Contraceptive Use in BRCA1 and BRCA2 Mutation Carriers: Absolute Cancer Risks and Benefits.

BACKGROUND: To help BRCA1 and 2 mutation carriers make informed decisions regarding use of combined-type oral contraceptive preparation (COCP), absolute risk-benefit estimates are needed for COCP-associated cancer. METHODS: For a hypothetical cohort of 10 000 women, we calculated the increased or decreased cumulative incidence of COCP-associated (breast, ovarian, endometrial) cancer, examining 18 scenarios with differences in duration and timing of COCP use, uptake of prophylactic surgeries, and menopausal hormone therapy. RESULTS: COCP use initially increased breast cancer risk and decreased ovarian and endometrial cancer risk long term. For 10 000 BRCA1 mutation carriers, 10 years of COCP use from age 20 to 30 years resulted in 66 additional COCP-associated cancer cases by the age of 35 years, in addition to 625 cases expected for never users. By the age of 70 years such COCP use resulted in 907 fewer cancer cases than the expected 9093 cases in never users. Triple-negative breast cancer estimates resulted in 196 additional COCP-associated cases by age 40 years, in addition to the 1454 expected. For 10 000 BRCA2 mutation carriers using COCP from age 20 to 30 years, 80 excess cancer cases were estimated by age 40 years in addition to 651 expected cases; by the age of 70 years, we calculated 382 fewer cases compared with the 6156 cases expected. The long-term benefit of COCP use diminished after risk-reducing bilateral salpingo-oophorectomy followed by menopausal hormone therapy use. CONCLUSION: Although COCP use in BRCA1 and BRCA2 mutation carriers initially increases breast, ovarian, and endometrial cancer risk, it strongly decreases lifetime cancer risk. Risk-reducing bilateral salpingo-oophorectomy and menopausal hormone therapy use appear to counteract the long-term COCP-benefit.

Genetic testing in women with early-onset breast cancer: a Traceback pilot study.

PURPOSE: In Sweden, a Traceback approach, i.e., a retrospective genetic outreach activity, among cancer patients is not normally used in clinical practice. In this pilot study, we wanted to evaluate a Traceback strategy for possible future clinical implementation and investigate why not all women with early-onset breast cancer underwent genetic testing when they were first diagnosed. METHODS: Out of all women (n = 409) diagnosed with breast cancer at ≤ 35 years in Southern Sweden between 2000 and 2017, 63 had not previously been tested. These women were offered an analysis of the genes BRCA1, BRCA2, PALB2, CHEK2, and ATM through a standardized letter. Subsequently, women with normal test results were informed through a letter and carriers of pathogenic variants were contacted through a telephone call and offered in-person genetic counseling. All tested women were asked to complete a follow-up questionnaire regarding previously not having attended genetic counseling and testing and their experiences of the current retrospective approach. RESULTS: Out of the invited women, 29 (46%) underwent genetic testing and 27 (43%) answered the questionnaire. Pathogenic variants were identified in BRCA1 (n = 2), CHEK2 (n = 1), and ATM (n = 1). The main reason for previously not having undergone genetic testing was not having received any information from their physicians. Most study participants were satisfied with both written pre- and post-test information. CONCLUSION: The process with retrospective identification, written pre-test information, and genetic testing, followed by in-person counseling for carriers of pathogenic variants only, was well accepted. This has implications for future Traceback implementation programs.

Outcomes at 3 years posttransplant in imlifidase-desensitized kidney transplant patients.

Imlifidase is a cysteine proteinase which specifically cleaves IgG, inhibiting Fc-mediated effector function within hours of administration. Imlifidase converts a positive crossmatch to a potential donor (T cell, B cell, or both), to negative, enabling transplantation to occur between previously HLA incompatible donor-recipient pairs. To date, 39 crossmatch positive patients received imlifidase prior to a kidney transplant in four single-arm, open-label, phase 2 studies. At 3 years, for patients who were AMR+ compared to AMR-, death-censored allograft survival was 93% vs 77%, patient survival was 85% vs 94%, and mean eGFR was 49 ml/min/1.73 m2 vs 61 ml/min/1.73 m2 , respectively. The incidence of AMR was 38% with most episodes occurring within the first month post-transplantation. Sub-analysis of patients deemed highly sensitized with cPRA ≥ 99.9%, and unlikely to be transplanted who received crossmatch-positive, deceased donor transplants had similar rates of patient survival, graft survival, and eGFR but a higher rate of AMR. These data demonstrate that outcomes and safety up to 3 years in recipients of imlifidase-enabled allografts is comparable to outcomes in other highly sensitized patients undergoing HLA-incompatible transplantation. Thus, imlifidase is a potent option to facilitate transplantation among patients who have a significant immunologic barrier to successful kidney transplantation. Clinical Trial: ClinicalTrials.gov (NCT02790437), EudraCT Number: 2016-002064-13.

The Human Melanoma Proteome Atlas-Complementing the melanoma transcriptome.

The MM500 meta-study aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative mass-spectrometry-based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 well-annotated melanoma tumor samples, is defined based on almost 16 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13 176 protein-coding genes, represented by 366 172 peptides, in addition to 52 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease.

The human melanoma proteome atlas-Defining the molecular pathology.

The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients.

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma.

BRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

BACKGROUND: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. METHODS: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. RESULTS: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. CONCLUSIONS: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.

Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients.

Up to 10% of pediatric cancer patients harbor pathogenic germline variants in one or more cancer susceptibility genes. A recent study from the US reported pathogenic variants in 22 out of 60 analyzed autosomal dominant cancer susceptibility genes, implicating 8.5% of pediatric cancer patients. Here we aimed to assess the prevalence of germline pathogenic variants in these 22 genes in a population-based Swedish cohort and to compare the results to those described in other populations. We found pathogenic variants in 10 of the 22 genes covering 3.8% of these patients. The prevalence of TP53 mutations was significantly lower than described in previous studies, which can largely be attributed to differences in tumor diagnosis distributions across the three cohorts. Matched family history for relatives allowed assessment of familial cancer incidence, however, no significant difference in cancer incidence was found in families of children carrying pathogenic variants compared to those who did not.

Improved survival in several cancers with use of H1-antihistamines desloratadine and loratadine.

BACKGROUND: We have previously shown an association with substantially improved survival in breast cancer and melanoma for desloratadine and loratadine users, and set out to find whether an improved survival can be seen in tumors with and without a known response to immune checkpoint therapy, such as anti-CTLA-4 or anti-PD-1. METHODS: We investigated survival and use of six common H1-antihistamines (cetirizine, clemastine, desloratadine, ebastine, fexofenadine and loratadine) in a nation-wide cohort of all 429,198 Swedish patients with ten types of immunogenic (gastric, colorectal/anal, pancreatic, lung, breast, prostate, kidney, and bladder cancer, melanoma and Hodgkin lymphoma) and six non-immunogenic (liver, uterine, ovarian, brain/CNS, and thyroid cancer and non-Hodgkin lymphoma) tumors diagnosed 2006-2017. Follow-up was until 2019-02-24. FINDINGS: Desloratadine use was associated with an improved survival for all immunogenic tumors, but not for the non-immunogenic ones. Loratadine use was associated with improved survival for some tumors. Use of the other antihistamines could not be shown to be consistently associated with improved survival to a statistically significant degree. INTERPRETATION: Our hypothesis is that our findings result from immune checkpoint inhibition, and we believe both desloratadine and loratadine should be tested in randomized clinical trials as treatment of immunogenic tumors, with priority given to trials of desloratadine as treatment of tumors with few therapy options and dismal prognoses, such as pancreatic cancer. If our results can be confirmed in a clinical setting, new, potentially curative, therapies could result for several tumors, including ones with dire prognoses and limited treatment options.

Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study.

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.

Common Susceptibility Loci for Male Breast Cancer.

BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

Multiple Primary Melanoma Incidence Trends Over Five Decades: A Nationwide Population-Based Study.

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.

Increased Cancer Risk in Families with Pediatric Cancer Is Associated with Gender, Age, Diagnosis, and Degree of Relation to the Child.

BACKGROUND: Studies of cancer risk among relatives of children with cancer beyond parents and siblings are limited. We have investigated the cancer risk up to the third degree of relation in families with pediatric cancer to reveal patterns of inheritance. METHODS: A single-center cohort of 757 patients with pediatric cancer was linked to the Swedish National Population Register, resulting in 16,137 relatives up to the third degree of relation. All relatives were matched to the Swedish Cancer Register, and standard incidence ratios (SIR) were calculated to define relatives at risk. RESULTS: Children and adults up to the third degree of relation had increased cancer risk, with SIRs of 1.48 (P = 0.01) and 1.07 (P < 0.01), respectively. The SIRs for first- and third-degree adult relatives were 1.22 and 1.10, respectively, but no increased risk was observed in second-degree relatives. Male relatives had a higher risk than females, especially when related to a girl and when the child had leukemia. The risk was mainly increased for lung, prostate, and gastrointestinal cancer. When excluding 29 families of children with known pathogenic germline variants, the increased risk remained. CONCLUSIONS: Relatives to children with cancer up to third degree of relation have an increased cancer risk. Known pathogenic germline variants do not explain this increased risk. IMPACT: The overall increased cancer risk among relatives of children with cancer in this population-based cohort strengthens the importance of surveillance programs for families with pediatric cancer.

Variations in the Referral Pattern for Genetic Counseling of Patients with Early-Onset Breast Cancer: A Population-Based Study in Southern Sweden.

Swedish national breast cancer guidelines recommend that all women diagnosed with breast cancer (BC) at the age of 35 years or younger should be referred to their regional oncogenetic clinic for genetic counseling and testing, regardless of family history of cancer. The main objective of this study was to evaluate whether place of residence at BC diagnosis and treating hospital were associated with the fact that not all BC patients diagnosed at ≤35 years in the southern part of Sweden have attended genetic counseling and testing. Between 2000 and 2013, 279 women in the South Swedish Health Care Region were diagnosed with BC at ≤35 years. Information regarding place of residence at BC diagnosis, treating hospital, time of registration and first meeting at the Oncogenetic Clinic in Lund, and genetic testing was collected. With a follow-up period until August 2018, 64% were registered at the clinic (60% underwent genetic testing) and 36% were not. BC patients from 2 counties and from rural settings with a population of <10,000 inhabitants were significantly less likely to be registered at the clinic. Our results suggest that place of residence at BC diagnosis and treating hospital were associated with the probability of referral for genetic counseling and testing for women diagnosed with BC at ≤35 years in the South Swedish Health Care Region. We propose, as a generalizable finding, that further educational and outreach activities within the health care system and the community may be needed to ensure that all women diagnosed with early-onset BC receive proper genetic counseling.

Desloratadine and loratadine stand out among common H1-antihistamines for association with improved breast cancer survival.

BACKGROUND: As tumors maintain an inflammatory microenvironment, anti-inflammatory medication can be useful in cancer therapy. We have previously shown an association with improved survival in melanoma for use of the H1-antihistamines desloratadine and loratadine, and here we examine use of H1-antihistamines and breast cancer mortality. MATERIAL AND METHODS: We investigated use of the six major H1-antihistamines (cetirizine, clemastine, desloratadine, ebastine, fexofenadine and loratadine) and breast cancer-specific and overall mortality in a nation-wide register-based study of all 61,627 Swedish women diagnosed with breast cancer 2006-2013. Both peri- and post-diagnostic antihistamine use was analyzed using Cox regression models. Analyses were stratified for age and subgroup analyses based on estrogen receptor status and menopausal status were performed. RESULTS: We found a consistently improved survival of desloratadine users (HR = 0.67; 95% CI 0.55-0.81, p < .001), as well as of loratadine users (HR = 0.80; 95% CI 0.67-0.95, p = .012), relative to nonusers, regardless of patient age, menopause, estrogen receptor status or stage of the tumor, or whether breast cancer-specific or overall survival was analyzed. The survival of users of other antihistamines varied relative to non-users. CONCLUSION: Based on their safety and current use within the patient population, together with our observations, we suggest the initiation of trials of desloratadine and loratadine as treatment of breast cancer as well as studies of the mechanism behind their possible effect. Further studies on any effects of other H1-antihistamines may also be merited, as well as of H1-antihistamine use and survival in other malignancies.

Author Correction: Tertiary lymphoid structures improve immunotherapy and survival in melanoma.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.