A scoping review of statistical methods in studies of biomarker-related treatment heterogeneity for breast cancer.

BACKGROUND: Many scientific papers are published each year and substantial resources are spent to develop biomarker-based tests for precision oncology. However, only a handful of tests is currently used in daily clinical practice, since development is challenging. In this situation, the application of adequate statistical methods is essential, but little is known about the scope of methods used. METHODS: A PubMed search identified clinical studies among women with breast cancer comparing at least two different treatment groups, one of which chemotherapy or endocrine treatment, by levels of at least one biomarker. Studies presenting original data published in 2019 in one of 15 selected journals were eligible for this review. Clinical and statistical characteristics were extracted by three reviewers and a selection of characteristics for each study was reported. RESULTS: Of 164 studies identified by the query, 31 were eligible. Over 70 different biomarkers were evaluated. Twenty-two studies (71%) evaluated multiplicative interaction between treatment and biomarker. Twenty-eight studies (90%) evaluated either the treatment effect in biomarker subgroups or the biomarker effect in treatment subgroups. Eight studies (26%) reported results for one predictive biomarker analysis, while the majority performed multiple evaluations, either for several biomarkers, outcomes and/or subpopulations. Twenty-one studies (68%) claimed to have found significant differences in treatment effects by biomarker level. Fourteen studies (45%) mentioned that the study was not designed to evaluate treatment effect heterogeneity. CONCLUSIONS: Most studies evaluated treatment heterogeneity via separate analyses of biomarker-specific treatment effects and/or multiplicative interaction analysis. There is a need for the application of more efficient statistical methods to evaluate treatment heterogeneity in clinical studies.

Perspectives for personalized therapy for patients with multidrug-resistant tuberculosis.

According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug-resistance is complicating tuberculosis control in many high-burden countries. During the past 5 years, the global number of patients identified with multidrug-resistant tuberculosis (MDR-TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR-TB. The management of MDR-TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug-resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor-made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR-TB. The challenge now is to bring these adances to those patients that need them most.

Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve.

STUDY QUESTION: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? SUMMARY ANSWER: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. WHAT IS KNOWN ALREADY: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. STUDY DESIGN, SIZE, DURATION: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. LIMITATIONS, REASONS FOR CAUTION: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922.

Increased stomach cancer risk following radiotherapy for testicular cancer.

BACKGROUND: Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse. METHODS: In a cohort of 22,269 5-year TC survivors diagnosed during 1959-1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression. RESULTS: Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7-20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend<0.001), with an OR of 20.5 (3.7-114.3) for ⩾50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated ⩾20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR=1.1; 95% CI 0.5-2.5; 14 cases and 23 controls). CONCLUSIONS: Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of ⩾30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients.

Perioperative systemic chemotherapy in peritoneal carcinomatosis of lymph node positive colorectal cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the preferred treatment of peritoneal carcinomatosis (PC) of colorectal carcinoma. Patients with positive lymph node status have worse survival after CRS-HIPEC, which is probably due to higher rates of systemic failure. In this study, we analysed the effect of administration and timing of systemic chemotherapy on the outcome of lymph node positive colorectal carcinoma patients treated with CRS-HIPEC. PATIENTS AND METHODS: A prospective database was reviewed to identify lymph node positive patients with PC treated with CRS-HIPEC within 1 year after primary tumour diagnosis between 2004 and 2012. Medical history of the patients was studied for the administration of perioperative systemic chemotherapy and follow-up. Outcome parameters were progression-free survival (PFS), overall survival (OS) and pattern of recurrence. RESULTS: Seventy-three patients treated with CRS-HIPEC for PC from lymph node positive colorectal carcinoma were identified. Fourteen patients received pre-CRS-HIPEC chemotherapy only, 32 patients underwent post-CRS-HIPEC chemotherapy only, 9 patients received chemotherapy both pre- and post-CRS-HIPEC and 16 patients did not receive any systemic chemotherapy. Of the 47 patients who did not receive pre-CRS-HIPEC chemotherapy, 11 (23%) did not receive any chemotherapy due to major postoperative complications. PFS and OS were significantly higher in patients who received systemic chemotherapy (PFS: median 15 versus 4 months, P = 0.024; OS: median 30 versus 14 months, P = 0.015), although this difference was attenuated after adjustment for major complications. Different chemotherapy timings did not differ significantly in either survival or recurrence patterns. CONCLUSIONS: In patients with PC from lymph node positive colorectal carcinoma, perioperative systemic chemotherapy is associated with increased OS and PFS, although this difference may be partly explained by the occurrence of major postoperative complication; with no evidence of difference in PFS, OS and systemic recurrence rate by timing of systemic chemotherapy.

Cox proportional hazards regression in small studies of predictive biomarkers.

Predictive biomarkers are essential for personalized medicine since they select the best treatment for a specific patient. However, of all biomarkers that are evaluated, only few are eventually used in clinical practice. Many promising biomarkers may be erroneously abandoned because they are investigated in small studies using standard statistical techniques which can cause small sample bias or lack of power. The standard technique for failure time endpoints is Cox proportional hazards regression with a multiplicative interaction term between binary variables of biomarker and treatment. Properties of this model in small studies have not been evaluated so far, therefore we performed a simulation study to understand its small sample behavior. As a remedy, we applied a Firth correction to the score function of the Cox model and obtained confidence intervals (CI) using a profile likelihood (PL) approach. These methods are generally recommended for small studies of different design. Our results show that a Cox model estimates the biomarker-treatment interaction term and the treatment effect in one of the biomarker subgroups with bias, and overestimates their standard errors. Bias is however reduced and power is increased with Firth correction and PL CIs. Hence, the modified Cox model and PL CI should be used instead of a standard Cox model with Wald based CI in small studies of predictive biomarkers.

Microbiota alterations in patients treated for susceptible or drug-resistant TB.

BACKGROUND: We investigated alterations of human microbiota under anti-TB therapies in relationship to the level of Mycobacterium tuberculosis drug response. METHODS: Stool, sputum, and oral swab samples were analysed from participants with treatment-naïve TB and participants treated for drug-susceptible TB (DS-TB), drug-resistant TB without injectable drugs (DR-TB-inj-), or with injectable drugs (DR-TB-inj+) at 27-42 days of therapy. RESULTS: From September 2018 to December 2019, 5 participants with treatment-naïve TB, 6 participants with DS-TB, 10 participants with DR-TB-inj-, and 4 participants with DR-TB-inj+ were recruited. Reduced alpha diversities in stool samples indicated more profound dysbiosis in participants treated for DR-TB than in participants treated for DS-TB (-12% (non-significant) for DS-TB, -44% (P < 0.001) for DR-TB-inj-, and -60% (P < 0.05) for DR-TB-inj+ compared to treatment-naïve participants). While reduced abundances were observed in numerous taxa, genus Lactobacillus revealed the most substantial abundance increase in sputa of participants treated for DR-TB compared to treatment-naïve ones (P < 0.05 for DR-TB-inj- and DR-TB-inj+). Notably, a group of nosocomial pneumonia-associated taxa was increased in oral swabs of the DR-TB-inj+ compared to the treatment-naïve group (P < 0.05). CONCLUSIONS: Second-line anti-TB therapy in participants with DR-TB results in altered microbiota, including reduced alpha diversity and expansion of phylogenetically diverse taxa, including pathobionts.

CONTEXTE: Nous avons étudié les altérations du microbiote humain sous traitements anti-TB en lien avec le niveau de réponse médicamenteuse de Mycobacterium tuberculosis. METHODES: Des échantillons de selles, d'expectorations et d'écouvillons buccaux ont été examinés chez des participants n'ayant jamais reçu de traitement contre la TB et des participants traités pour une TB sensible aux médicaments (DS-TB), une TB résistante aux médicaments sans médicaments injectables (DR-TB-inj­), ou avec des médicaments injectables (DR-TB-inj+) après 27 à 42 jours de traitement. RESULTATS: De septembre 2018 à décembre 2019, 5 participants atteints de TB naïve, 6 participants atteints de DS-TB, 10 participants atteints de DR-TB-inj­ et 4 participants atteints de DR-TB-inj+ ont été sélectionnés. La diminution des diversités alpha dans les échantillons de selles indique une dysbiose plus profonde chez les participants traités pour la DR-TB que chez les participants traités pour la DS-TB (­12% (non significatif) pour la DS-TB, ­44% (P < 0,001) pour la DR-TB-inj­, et -60% (P < 0,05) pour la DR-TB-inj+ par rapport aux participants n'ayant jamais reçu de traitement). Bien que des abondances réduites aient été observées dans de nombreux taxons, le genre Lactobacillus a montré la plus forte augmentation d'abondance dans les expectorations des participants traités pour la DR-TB par rapport aux participants non traités (P < 0,05 pour DR-TB-inj­ et DR-TB-inj+). En particulier, un groupe de taxons associés à la pneumonie nosocomiale était plus abondant dans les écouvillons oraux du groupe DR-TB-inj+ par rapport au groupe non traité (P < 0,05). CONCLUSIONS: Le traitement anti-TB de deuxième ligne chez les participants atteints de DR-TB entraîne des changements dans le microbiote, notamment une diminution de la diversité alpha et une expansion de taxons phylogénétiquement diversifiés, y compris les pathobiontes.

Finite-Sample Bias of the Linear Excess Relative Risk in Cohort Studies of Computed Tomography-Related Radiation Exposure and Cancer.

The linear excess relative risk (ERR) is the most commonly reported measure of association in radiation epidemiological studies, when individual dose estimates are available. While the asymptotic properties of the ERR estimator are well understood, there is evidence of small sample bias in case-control studies of treatment-related radiation exposure and second cancer risk. Cohort studies of cancer risk after exposure to low doses of radiation from diagnostic procedures, e.g., computed tomography (CT) examinations, typically have small numbers of cases and risks are small. Therefore, understanding the properties of the estimated ERR is essential for interpretation and analysis of such studies. We present results of a simulation study that evaluates the finite-sample bias of the ERR estimated by time-to-event analyses and its confidence interval using simulated data, resembling a retrospective cohort study of radiation-related leukemia risk after CT examinations in childhood and adolescence. Furthermore, we evaluate how the Firth-corrected estimator reduces the finite-sample bias of the classical estimator. We show that the ERR is overestimated by about 30% for a cohort of about 150,000 individuals, with 42 leukemia cases observed on average. The bias is reduced for higher baseline incidence rates and for higher values of the true ERR. As the number of cases increases, the ERR is approximately unbiased. The Firth correction reduces the bias for all cohort sizes to generally around or under 5%. Epidemiological studies showing an association between radiation exposure from pediatric CT and cancer risk, unless very large, may overestimate the magnitude of the relationship, while there is no evidence of an increased chance for false-positive results. Conducting large studies, perhaps by pooling individual studies to increase the number of cases, should be a priority. If this is not possible, Firth correction should be applied to reduce small-sample bias.

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

CYP2C19 2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment.

Estrogen catabolism is a major function of CYP2C19. The effect of CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by a variation in tamoxifen metabolite levels but also by an effect on breast cancer risk and molecular subtype due to variation in lifelong exposure to estrogens. We determined the association between these polymorphisms and tamoxifen sensitivity in the context of a randomized trial, which allows for the discernment of prognosis from prediction. We isolated primary tumor DNA from 535 estrogen receptor-positive, stages I-III, postmenopausal breast cancer patients who had been randomized to tamoxifen (1-3 years) or no adjuvant therapy. Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of CYP2C19 2 and CYP2C19 17. Hazard ratios and interaction terms were calculated using multivariate Cox proportional hazard models, stratified for nodal status. Tamoxifen benefit was not significantly affected by CYP2C19 17. Patients with at least one CYP2C19 2 allele derived significantly more benefit from tamoxifen (HR 0.26; p = 0.001) than patients without a CYP2C19 2 allele (HR 0.68; p = 0.18) (p for interaction 0.04). In control patients, CYP2C19 2 was an adverse prognostic factor. In conclusion, breast cancer patients carrying at least one CYP2C19 2 allele have an adverse prognosis in the absence of adjuvant systemic treatment, which can be substantially improved by adjuvant tamoxifen treatment.

Bioenergy therapies as a complementary treatment: a systematic review to evaluate the efficacy of bioenergy therapies in relieving treatment toxicities in patients with cancer.

PURPOSE: Bioenergy therapies are among the popular alternative treatment options for many diseases, including cancer. Many studies deal with the advantages and disadvantages of bioenergy therapies as an addition to established treatments such as chemotherapy, surgery, and radiation in the treatment of cancer. However, a systematic overview of this evidence is thus far lacking. For this reason, the available evidence should be reviewed and critically examined to determine what benefits the treatments have for patients. METHODS: In June 2022, a systematic search was conducted searching five electronic databases (Embase, Cochrane, PsychInfo, CINAHL and Medline) to find studies concerning the use, effectiveness and potential harm of bioenergy therapies including Reiki, Therapeutic Touch, Healing Touch and Polarity Therapy on cancer patients. RESULTS: From all 2477 search results, 21 publications with 1375 patients were included in this systematic review. The patients treated with bioenergy therapies were mainly diagnosed with breast cancer. The main outcomes measured were anxiety, depression, mood, fatigue, quality of life (QoL), comfort, well-being, neurotoxicity, pain, and nausea. The studies were predominantly of moderate quality and for the most part found no effect. In terms of QoL, pain and nausea, there were improved short-term effects of the interventions, but no long-term differences were detectable. The risk of side effects from bioenergy therapies appears to be relatively small. CONCLUSION: Considering the methodical limitations of the included studies, studies with high study quality could not find any difference between bioenergy therapies and active (placebo, massage, RRT, yoga, meditation, relaxation training, companionship, friendly visit) and passive control groups (usual care, resting, education). Only studies with a low study quality were able to show significant effects.

A multimarker QPCR-based platform for the detection of circulating tumour cells in patients with early-stage breast cancer.

BACKGROUND: The detection of circulating tumour cells (CTCs) has been linked with poor prognosis in advanced breast cancer. Relatively few studies have been undertaken to study the clinical relevance of CTCs in early-stage breast cancer. METHODS: In a prospective study, we evaluated CTCs in the peripheral blood of 82 early-stage breast cancer patients. Control groups consisted of 16 advanced breast cancer patients and 45 healthy volunteers. The CTC detection was performed using ErbB2/EpCAM immunomagnetic tumour cell enrichment followed by multimarker quantitative PCR (QPCR). The CTC status and common clinicopathological factors were correlated to relapse-free, breast cancer-related and overall survival. RESULTS: Circulating tumour cells were detected in 16 of 82 (20%) patients with early-stage breast cancer and in 13 out of 16 (81%) with advanced breast cancer. The specificity was 100%. The median follow-up time was 51 months (range: 17-60). The CTC positivity in early-stage breast cancer patients resulted in significantly poorer relapse-free survival (log rank test: P=0.003) and was an independent predictor of relapse-free survival (multivariate hazard ratio=5.13, P=0.006, 95% CI: 1.62-16.31). CONCLUSION: The detection of CTCs in peripheral blood of early-stage breast cancer patients provided prognostic information for relapse-free survival.

An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients.

BACKGROUND: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-like(CGH) classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. PATIENTS AND METHODS: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup). RESULTS: We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-like(CGH) tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04-0.43] compared with patients with non-BRCA1-like(CGH) tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50-1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-like(CGH) tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12). CONCLUSION: BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.

Phosphorylation of the oestrogen receptor alpha at serine 305 and prediction of tamoxifen resistance in breast cancer.

Phosphorylation of oestrogen receptor alpha at serine 305 (ERalphaS305-P) induces tamoxifen resistance in experimental studies, but does not influence response to other endocrine agents, such as fulvestrant. We evaluated ERalphaS305-P using immunohistochemistry in 377 breast carcinomas from premenopausal participants of a randomized trial (n=248) and patients with advanced disease (n=129). Among the premenopausal patients, adjuvant tamoxifen improved recurrence-free survival (RFS) for ERalphaS305-P-negative tumours (multivariate HR=0.53, 95% CI 0.32-0.86, p=0.010), but not for ERalphaS305-P-positive tumours (multivariate HR=1.01, 95% CI 0.33-3.05, p=0.99) (interaction p=0.131). Notably, ERalphaS305-P was not significantly associated with RFS in patients not treated with tamoxifen (multivariate HR=0.64, 95% CI 0.30-1.37, p=0.248), indicating that ERalphaS305-P is a marker for treatment outcome rather than tumour progression. Given the direct experimental link between ERalphaS305-P and tamoxifen resistance and these first clinical data suggesting that premenopausal patients with ERalphaS305-P-positive breast cancer are resistant to adjuvant tamoxifen, further research is encouraged to study whether alternative endocrine treatment should be considered for this subgroup.

Refinement of breast cancer classification by molecular characterization of histological special types.

Most invasive breast cancers are classified as invasive ductal carcinoma not otherwise specified (IDC NOS), whereas about 25% are defined as histological 'special types'. These special-type breast cancers are categorized into at least 17 discrete pathological entities; however, whether these also constitute discrete molecular entities remains to be determined. Current therapy decision-making is increasingly governed by the molecular classification of breast cancer (luminal, basal-like, HER2+). The molecular classification is derived from mainly IDC NOS and it is unknown whether this classification applies to all histological subtypes. We aimed to refine the breast cancer classification systems by analysing a series of 11 histological special types [invasive lobular carcinoma (ILC), tubular, mucinous A, mucinous B, neuroendocrine, apocrine, IDC with osteoclastic giant cells, micropapillary, adenoid cystic, metaplastic, and medullary carcinoma] using immunohistochemistry and genome-wide gene expression profiling. Hierarchical clustering analysis confirmed that some histological special types constitute discrete entities, such as micropapillary carcinoma, but also revealed that others, including tubular and lobular carcinoma, are very similar at the transcriptome level. When classified by expression profiling, IDC NOS and ILC contain all molecular breast cancer types (ie luminal, basal-like, HER2+), whereas histological special-type cancers, apart from apocrine carcinoma, are homogeneous and only belong to one molecular subtype. Our analysis also revealed that some special types associated with a good prognosis, such as medullary and adenoid cystic carcinomas, display a poor prognosis basal-like transcriptome, providing strong circumstantial evidence that basal-like cancers constitute a heterogeneous group. Taken together, our results imply that the correct classification of breast cancers of special histological type will allow a more accurate prognostication of breast cancer patients and facilitate the identification of optimal therapeutic strategies.

Human individual radiation sensitivity and prospects for prediction.

In the past few decades, it has become increasingly evident that sensitivity to ionising radiation is variable. This is true for tissue reactions (deterministic effects) after high doses of radiation, for stochastic effects following moderate and possibly low doses, and conceivably also for non-cancer effects such as cardiovascular disease, the causal pathway(s) of which are not yet fully understood. A high sensitivity to deterministic effects is not necessarily correlated with a high sensitivity to stochastic effects. The concept of individual sensitivity to high and low doses of radiation has long been supported by data from patients with certain rare hereditary conditions. However, these syndromes only affect a small proportion of the general population. More relevant to the majority of the population is the notion that some part of the genetic contribution defining radiation sensitivity may follow a polygenic model, which predicts elevated risk resulting from the inheritance of many low-penetrance risk-modulating alleles. Can the different forms of individual radiation sensitivities be inferred from the reaction of cells exposed ex vivo to ionising radiation? Can they be inferred from analyses of individual genotypes? This paper reviews current evidence from studies of late adverse tissue reactions after radiotherapy in potentially sensitive groups, including data from functional assays, candidate gene approaches, and genome-wide association studies. It focuses on studies published in 2013 or later because a comprehensive review of earlier studies was published previously in a report by the UK Advisory Group on Ionising Radiation.

Optimal adjuvant endocrine treatment of ER+/HER2+ breast cancer patients by age at diagnosis: A population-based cohort study.

BACKGROUND: Prior randomised controlled trials on adjuvant hormonal therapy included HER2any patients; however, a differential effect of aromatase inhibitors (AIs) versus tamoxifen (TAM) may have been missed in ER+/HER2+ patients that comprise 7-15% of all breast cancer patients. In addition, a woman's hormonal microenvironment may influence sensitivity to TAM and AIs in the adjuvant setting, which changes during menopausal transition, a process that takes years. We studied the efficacy of AIs versus TAM in ER+/HER2+ breast cancer patients grouped by age at diagnosis as a proxy for menopausal status using treatment and outcome data from the nationwide population-based Netherlands Cancer Registry (NCR). PATIENTS AND METHODS: All women diagnosed between 2005 and 2007 with endocrine-treated, TanyNanyM0, ER+/HER2+ breast cancer were identified through the NCR (n = 1155). Patients were divided by age at diagnosis: premenopausal (≤45 years; n = 326), perimenopausal (4555 years; n = 525). A time-dependent variable, indicating whether AI or TAM was received for >50% of endocrine treatment duration, was applied to subdivide groups by predominant treatment received. Recurrence-free survival (RFS) and overall survival (OS) were assessed using Kaplan-Meier survival estimation and Cox regression. Hazard ratios (HRs) were adjusted for chemotherapy, trastuzumab, age at diagnosis, N-status, grade, pT-stage and ovarian ablation. RESULTS: During follow-up, 237 recurrences and 182 deaths occurred. Perimenopausal women derived significant RFS and OS benefit from AI compared with TAM, HR 0.47 (95% CI 0.25-0.91; P = 0.03) and HR 0.37 (95% CI 0.18-0.79; P = 0.01), respectively, whereas premenopausal women derived no benefit from AI compared with TAM. Treatment effects differed significantly between these age groups (interaction P = 0.03 and P = 0.02, respectively). Among postmenopausal women a small but non-significant AI benefit was observed. CONCLUSION: AI treatment, preferably without any TAM treatment, was associated with the best RFS and OS outcome in ER+/HER2+ perimenopausal breast cancer patients.

A critical evaluation of lymph node ratio in head and neck cancer.

In head and neck squamous cell carcinoma (HNSCC), the search for better prognostic factors beyond TNM-stage is ongoing. Lymph node ratio (LNR) (positive lymph nodes/total lymph nodes) is gaining interest in view of its potential prognostic significance. All HNSCC patients at the Netherlands Cancer Institute undergoing neck dissection for lymph node metastases in the neck region between 2002 and 2012 (n = 176) were included. Based on a protocol change in specimen processing, the cohort was subdivided in two distinct consecutive periods (pre and post 2007). The prognostic value of LNR, N-stage, and number of positive lymph nodes for overall survival was assessed. The mean number of examined lymph nodes after 2007 was significantly higher (42.3) than before (35.8) (p = 0.024). The higher number concerned mostly lymph nodes in level V. The mean number of positive lymph nodes before 2007 was 3.3 vs. 3.6 after 2007 (p = 0.745). By multivariate analysis of both pre- and post-2007 cohort data, two factors remained associated with an increased hazard of dying: N2 [HR 2.1 (1.1-4.1) and 2.4 (1.0-5.8)] and >3 positive lymph nodes [HR 2.0 (1.1-3.5) and 3.1 (1.4-6.9)]. Hazard ratio for LNR >7 % was not significantly different: pre 2007 at 2.2 (1.3-3.8) and post 2007 at 2.1 (1.0-4.8, p = 0.053). In this study, changes in specimen processing influenced LNR values, but not the total number of tumor positive nodes found. Therefore, in HNSCC, the number of positive nodes seems a more reliable parameter than LNR, provided a minimum number of lymph nodes are examined.