Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P<10−77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Breast cancer is a major health care problem that affects more than one million women yearly. While it is traditionally thought of as a disease of the industrialized world, around 45% of breast cancer cases and 55% of breast cancer deaths occur in low and middle income countries. Managing breast cancer in low income countries poses a different set of challenges including access to screening, stage at presentation, adequacy of management and availability of therapeutic interventions. In this paper, we will review the challenges faced in the management of breast cancer in low and middle income countries.

Purpose: Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. The polymorphic cytochrome P450 2D6 (CYP2D6) strongly determines an individual’s capacity for endoxifen formation, however, CYP2D6 phenotype assignments inferred from genotype widely differ between studies. Thus, we modeled plasma endoxifen predictability depending on variable CYP2D6 genotype groupings.Methods: CYP2D6 diplotype and metabolite plasma concentrations were assessed in 908 pre- and post-menopausal estrogen receptor (ER)-positive, TAM treated early breast cancer patients of Caucasian (N = 678), Middle-Eastern Arab (N = 77), and Asian (N = 153) origin. Robust coefficients of determination (R2) were estimated for endoxifen (E) or metabolic ratio endoxifen/desmethyl-TAM (E/DMT) as dependent and different CYP2D6 phenotype assignments as independent variables. Allele activity scores (ASs) were modified with respect to a reduced ∗10 allele activity. Predictability of endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL was investigated by receiver operating characteristic (ROC) analysis.Results: CYP2D6 diplotypes (N = 898) were strongly associated with E and E/DMT independent of age (P < 10-15). Across all ethnicities, 68–82% inter-patient variability of E/DMT was explained by CYP2D6 diplotype, while plasma endoxifen was predictable by 39–58%. The previously used codeine specific phenotype classification showed worse prediction for both endpoints particularly in Asians (median R2< 20%; P < 10-9). Downgrading of ∗10 activity slightly improved the explanatory value of metabolizer phenotype (P < 0.002). Endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL were achieved in 82.3% of patients and were predictable (96% sensitivity, 57% specificity) by CYP2D6 diplotypes with AS > 0.5, i.e., omitting PM/PM and PM/IM patients.Conclusion: The CYP2D6 explanatory power for active drug level assessment is maximized by TAM-specific phenotype assignments while a genotype cutoff that separates PM/PM and PM/IM from the remaining patients may improve clinical benefit via increased endoxifen concentrations.

Key Words. Breast cancer x Young age x Family history x BRCA mutations x Haplotype x Lebanon x Arab countries ABSTRACT Purpose. Breast cancer is the most common malignancy among women in Lebanon and in Arab countries, with 50% of cases presenting before the age of 50 years. Methods. Between 2009 and 2012, 250 Lebanese women with breastcancer who were considered to be at high riskof carrying BRCA1 or BRCA2 mutations because of presentation at young age and/or positive family history (FH) of breast or ovarian cancer were recruited. Clinical data were analyzed statistically. Coding exons and intron-exon boundaries of BRCA1 and BRCA2 were sequenced from peripheral blood DNA. All patients were tested for BRCA1 rearrangements using multiplex ligationdependent probe amplification (MLPA). BRCA2 MLPA was done in selected cases. Results. Overall, 14 of 250 patients (5.6%) carried a deleterious BRCA mutation (7 BRCA1, 7 BRCA2) and 31 (12.4%) carried a variant of uncertain significance. Eight of 74 patients (10.8%) aged #40 years with positive FH and only 1 of 74 patients (1.4%) aged #40 years without FH had a mutated BRCA. Four of 75 patients (5.3%) aged 41-50 years with FH had a deleterious mutation. Only 1 of 27 patients aged .50 years at diagnosis had a BRCA mutation. All seven patients with BRCA1 mutations had grade 3 infiltrating ductal carcinoma and triple-negative breast cancer. Nine BRCA1 and 17 BRCA2 common haplotypes were observed. Conclusion. Prevalence ofdeleterious BRCA mutations is lower than expected and does not support the hypothesis that BRCA mutations alone cause the observed high percentage of breast cancer in young women of Lebanese and Arab descent. Studies to search for other genetic mutations are recommended. The Oncologist 2015;20:357-364Implications for Practice: This study provides new data to support discussion and referral of patients of Lebanese and Arab ancestry with high-genetic-risk breast cancer for BRCA counseling and testing.The probability of carrying a deleterious BRCA mutation in this population seems low at 5.6%.The absence of family history in patients aged #40 years reduces the possibility of BRCA mutations to only 1.4%. Young age combined with a positive family history raises the prevalence to 10.8% and increases the yield of testing. Further clarification of the 12.4% of cases with variants of uncertain significance and searches for alternative gene mutations are needed. This study adds missing information to the international BRCA population maps.

BackgroundBreast cancer patients are increasingly seeking Complementary and Alternative Medicine (CAM) therapies with the hope of alleviating the burden of the disease and improving their quality of life (QOL). The objective of this study was to assess the prevalence, types, socio-demographic and disease-related correlates as well as characteristics of CAM use (including disclosure to treating physicians) among breast cancer patients in Beirut, Lebanon. A secondary objective was to evaluate the association between CAM use and QOL.MethodsA cross-sectional survey was conducted on breast cancer patients recruited from two major referral centers in Beirut: a philanthropic hospital and a private academic medical center. In face-to-face interviews, participants completed a questionnaire of three sections: socio-demographic and lifestyle characteristics, breast cancer condition, and CAM use. Three to four weeks following these interviews, the secondary QOL assessment was carried out via telephone using the Arabic version of the Functional Assessment of Cancer Therapy-Breast questionnaire. The main outcome in this study, CAM use, was defined as using CAM at least once after breast cancer diagnosis.ResultsA total of 180 breast cancer patients completed the survey (response rate: 94.6 %). Prevalence of CAM use was 40 %. Using multivariate logistic regression, CAM use was negatively associated with age (OR: 0.96, CI: 0.92-0.99), treatment at the philanthropic hospital (OR: 0.13, CI: 0.05-0.35) and was positively associated with an advanced stage of the disease (OR: 4.20, CI: 1.65-10.69). Among study participants recruited from both sites, the most commonly used CAM was ‘special food’ followed by ‘herbal teas’, ‘diet supplements’ and ‘Spiritual healing’. Only 4 % of CAM users cited health professionals as influencing their choice of CAM and only one in four patients disclosed CAM use to their treating physician. There was no significant association between CAM use and QOL.ConclusionsThe findings of this study revealed a prevalent CAM use among Lebanese breast cancer patients. Furthermore, physicians’ role in orienting CAM use was found to be marginal as patients relied mainly on family and media for their choice of CAM and were less likely to disclose CAM use to their treating physicians.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-015-0969-9) contains supplementary material, which is available to authorized users.

Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady‐state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on CSS,min ENDX using nonlinear mixed‐effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1–13.8‐fold higher risk for subtarget CSS,min ENDX compared with elderly low‐weight patients. Considering ever‐rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing.

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents the most frequently diagnosed subtype of this morbid malignancy. NSCLC is causally linked to tobacco consumption with more than 500 million smokers worldwide at high risk for this fatal malignancy. We are currently lagging in our knowledge of the early molecular (e.g., genomic) effects of smoking in NSCLC pathogenesis that would constitute ideal markers for early detection. This limitation is further amplified when considering the variable etiologic factors in NSCLC pathogenesis among different regions around the globe. In this review, we present our current knowledge of genomic alterations arising during early stages of smoking-induced lung cancer initiation and progression, including discussing the premalignant airway field of injury induced by smoking. The review also underscores the wider spectra and higher age-adjusted rates of tobacco (e.g., water-pipe smoke) consumption, along with elevated environmental carcinogenic exposures and relatively poorer socioeconomic status, in low-middle income countries (LMICs), with Lebanon as an exemplar. This “cocktail” of carcinogenic exposures warrants the pressing need to understand the complex etiology of lung malignancies developing in LMICs such as Lebanon.

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