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.

Tertiary lymphoid structures improve immunotherapy and survival in melanoma.

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.

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.

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.

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.

Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations.

BACKGROUND: Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated. METHODS: CDKN2A mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic CDKN2A mutation were analysed for association with tumour mutational load. RESULTS: Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic CDKN2A mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without CDKN2A mutation (Wilcoxon test, p<0.001). CONCLUSION: Patients with CDKN2A mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.

A Targeted Mass Spectrometry Strategy for Developing Proteomic Biomarkers: A Case Study of Epithelial Ovarian Cancer.

Protein biomarkers for epithelial ovarian cancer are critical for the early detection of the cancer to improve patient prognosis and for the clinical management of the disease to monitor treatment response and to detect recurrences. Unfortunately, the discovery of protein biomarkers is hampered by the limited availability of reliable and sensitive assays needed for the reproducible quantification of proteins in complex biological matrices such as blood plasma. In recent years, targeted mass spectrometry, exemplified by selected reaction monitoring (SRM) has emerged as a method, capable of overcoming this limitation. Here, we present a comprehensive SRM-based strategy for developing plasma-based protein biomarkers for epithelial ovarian cancer and illustrate how the SRM platform, when combined with rigorous experimental design and statistical analysis, can result in detection of predictive analytes.Our biomarker development strategy first involved a discovery-driven proteomic effort to derive potential N-glycoprotein biomarker candidates for plasma-based detection of human ovarian cancer from a genetically engineered mouse model of endometrioid ovarian cancer, which accurately recapitulates the human disease. Next, 65 candidate markers selected from proteins of different abundance in the discovery dataset were reproducibly quantified with SRM assays across a large cohort of over 200 plasma samples from ovarian cancer patients and healthy controls. Finally, these measurements were used to derive a 5-protein signature for distinguishing individuals with epithelial ovarian cancer from healthy controls. The sensitivity of the candidate biomarker signature in combination with CA125 ELISA-based measurements currently used in clinic, exceeded that of CA125 ELISA-based measurements alone. The SRM-based strategy in this study is broadly applicable. It can be used in any study that requires accurate and reproducible quantification of selected proteins in a high-throughput and multiplexed fashion.

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.

Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.

BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.

Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.

After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed.

Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk.

A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large-scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse-variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin-like growth factor receptor 1 and other membrane receptors (OR: 0.82-1.18, p values: 6.96 × 10-4 -3.28 × 10-8 ), are linked to insulin resistance and estrogen receptor signaling pathways. Proteins identified at other loci include those involved in biological processes such as alcohol and lipid metabolism, proteolysis, apoptosis, immune regulation and cell motility and proliferation. Consistent associations were observed for 22 proteins in the UK Biobank data (p < 0.05). The study identifies potential novel biomarkers for breast cancer, but further investigation is needed to replicate our findings.

Novel functional proteins coded by the human genome discovered in metastases of melanoma patients.

In the advanced stages, malignant melanoma (MM) has a very poor prognosis. Due to tremendous efforts in cancer research over the last 10 years, and the introduction of novel therapies such as targeted therapies and immunomodulators, the rather dark horizon of the median survival has dramatically changed from under 1 year to several years. With the advent of proteomics, deep-mining studies can reach low-abundant expression levels. The complexity of the proteome, however, still surpasses the dynamic range capabilities of current analytical techniques. Consequently, many predicted protein products with potential biological functions have not yet been verified in experimental proteomic data. This category of 'missing proteins' (MP) is comprised of all proteins that have been predicted but are currently unverified. As part of the initiative launched in 2016 in the USA, the European Cancer Moonshot Center has performed numerous deep proteomics analyses on samples from MM patients. In this study, nine MPs were clearly identified by mass spectrometry in MM metastases. Some MPs significantly correlated with proteins that possess identical PFAM structural domains; and other MPs were significantly associated with cancer-related proteins. This is the first study to our knowledge, where unknown and novel proteins have been annotated in metastatic melanoma tumour tissue.

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.

Participation in a Prospective Cohort Study on Melanoma did not Affect the Incidence and Mortality of the Studied Disease.

Prospective observational studies have shown previously that study participants have lower morbidity and mortality than non-participants. The aim of the current study was to determine whether participants in a prospective cohort study on melanoma have a different incidence and mortality of melanoma compared with non-participants and the background population. Information was collected from Swedish National Registers on participants (n = 30,501) and non-participants (n = 10,499) in the "Melanoma In Southern Sweden" (MISS) study and the background population (n = 243,032). Hazard ratios were calculated for overall incidence of cancer and melanoma, and all-cause and melanoma-specific mortality, using Cox regression. Participants had a lower overall incidence of cancer and all-cause mortality than non-participants and the background population. There was no difference in incidence of melanoma or melanoma-specific characteristics between participants and the background population. In conclusion, participants in the MISS study have a slightly better general health, but are a representative sample of the population with regard to studies of melanoma risk factors.

Women with a predisposition for diabetes have an increased risk of pregnancy complications, especially in combination with pregestational overweight.

BACKGROUND: Overweight and gestational diabetes are risk factors for pregnancy complications. We hypothesized that the metabolic impact of overweight on pregnancy outcome, would be different if it was combined with a predisposition for diabetes. The aim of this study was to compare the outcome of pregnancies in women with diabetes diagnosed later in life, to the outcome of pregnancies of women who did not develop diabetes. METHODS: Women in a population-based cohort who also were registered in the Swedish Medical Birth Registry (n = 4738) were included. A predisposition for diabetes (GDM or diabetes after pregnancy) was found in 455 pregnancies. The number of pregnancies with maternal BMI ≥ 25 kg/m2 and without diabetes were 2466, and in 10,405 pregnancies the mother had a BMI < 25 kg/m2 without diabetes at any time. Maternal BMI, gestational length, gestational weight gain, frequency of caesarean section, infant birth weight, frequency of large for gestational age (LGA) and Apgar score were retrospectively compared. RESULTS: Pregnancies with normal maternal BMI ≤25 kg/m2, with predisposition for diabetes had a higher frequency of LGA (11.6% vs. 2.9%; p < 0.001), a higher frequency of macrosomia (28.6% vs. 17.6%; p < 0.001), and a shorter gestational length (39.7 vs. 40 weeks; p = 0.08) when compared to pregnancies in women without a predisposition for diabetes. In addition, pregnancies with both maternal predisposition for diabetes and BMI ≥ 25 kg/m2 there was a higher frequency of LGA (23.3% vs. 7.1%; p < 0.001), caesarean section (24.0% vs. 14.9%, p = 0.031) compared to pregnancies in women who were only overweight. A predisposition for diabetes significantly increases the risk of macrosomia (OR1.5; 95% CI 1.07-2.15; p = 0.02). CONCLUSIONS: In pregnancy, there is an increased frequency of LGA, macrosomia and caesarean section if the woman has a predisposition for diabetes. The frequency of overweight young women is increasing, and it is urgent to identify pregnant women with a predisposition to diabetes. How to distinguish the women with the highest risk for adverse pregnancy outcome and the highest risk of future disease, remains to be studied.

Correction to: Women with a predisposition for diabetes have an increased risk of pregnancy complications, especially in combination with pregestational overweight.

Following publication of the original article [1], we have been notified by the author that the age of women from the Result section was incorrectly tagged as references.

Statin use and breast cancer survival - a Swedish nationwide study.

BACKGROUND: A sizeable body of evidence suggests that statins can cease breast cancer progression and prevent breast cancer recurrence. The latest studies have, however, not been supportive of such clinically beneficial effects. These discrepancies may be explained by insufficient power. This considerably sized study investigates the association between both pre- and post-diagnostic statin use and breast cancer outcome. METHODS: A Swedish nation-wide retrospective cohort study of 20,559 Swedish women diagnosed with breast cancer (July 1st, 2005 through 2008). Dispensed statin medication was identified through the Swedish Prescription Registry. Breast cancer related death information was obtained from the national cause-of-death registry until December 31st, 2012. Cox regression models yielded hazard ratios (HR) and 95% confidence intervals (CI) regarding associations between statin use and breast cancer-specific and overall mortality. RESULTS: During a median follow-up time of 61.6 months, a total of 4678 patients died, of which 2669 were considered breast cancer related deaths. Compared to non- or irregular use, regular pre-diagnostic statin use was associated with lower risk of breast cancer related deaths (HR = 0.77; 95% CI 0.63-0.95, P = 0.014). Similarly, post-diagnostic statin use compared to non-use was associated with lower risk of breast cancer related deaths (HR = 0.83; 95% CI 0.75-0.93, P = 0.001). CONCLUSION: This study supports the notion that statin use is protective regarding breast cancer related mortality in agreement with previous Scandinavian studies, although less so with studies in other populations. These disparities should be further investigated to pave the way for future randomized clinical trials investigating the role of statins in breast cancer.

A single exercise session improves side-effects of chemotherapy in women with breast cancer: an observational study.

BACKGROUND: To measure changes in four common chemotherapy related side-effects (low energy, stress, nausea and pain) immediately after a single exercise session within the first week after treatment. METHODS: Thirty-eight patients with chemotherapy-treated breast cancer, participating in a multi-centre randomised controlled study, the Physical Training and Cancer study (Phys-Can) were included in this sub-study. The Phys-Can intervention included endurance and resistance training. Before and after a single training session (endurance or resistance) within the first week of chemotherapy, energy and stress were measured with the Stress-Energy Questionnaire during Leisure Time, and nausea and pain were assessed using a Visual Analog Scale 0-10. Paired t-tests were performed to analyse the changes, and linear regression was used to analyse associations with potential predictors. RESULTS: Thirty-eight participants performed 26 endurance training sessions and 31 resistance training sessions in the first week after chemotherapy. Energy and nausea improved significantly after endurance training, and energy, stress and nausea improved significantly after resistance training. Energy increased (p = 0.03 and 0.001) and nausea decreased (p = 0.006 and 0.034) immediately after a single session of endurance or resistance training, and stress decreased (p = 0.014) after resistance exercise. CONCLUSIONS: Both endurance and resistance training were followed by an immediate improvement of common chemotherapy-related side-effects in patients with breast cancer. Patients should be encouraged to exercise even if they suffer from fatigue or nausea during chemotherapy. TRIAL REGISTRATION: NCT02473003, June 16, 2015.

Clinical protein science in translational medicine targeting malignant melanoma.

Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry-based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular functions underlying disease progression. In parallel to a streamlined, patient-centric, clinical proteomic pipeline, mass spectrometry-based imaging can aid in interrogating the spatial distribution of drugs and drug metabolites within tissues at single-cell resolution. These developments are an important advancement in studying drug action and efficacy in vivo and will aid in the development of more effective and safer strategies for the treatment of melanoma. A collaborative effort of gargantuan proportions between academia and healthcare professionals has led to the initiation, establishment and development of a cutting-edge cancer research centre with a specialisation in melanoma and lung cancer. The primary research focus of the European Cancer Moonshot Lund Center is to understand the impact that drugs have on cancer at an individualised and personalised level. Simultaneously, the centre increases awareness of the relentless battle against cancer and attracts global interest in the exceptional research performed at the centre.