Nagi S. El-Saghir

Ratio Between Positive Lymph Nodes and Total Excised Axillary Lymph Nodes as an Independent Prognostic Factor for Overall Survival in Patients with Nonmetastatic Lymph Node-Positive Breast Cancer

Background.The status of the axillary lymph nodes in nonmetastatic lymph node-positive breast cancer (BC) patients remains the single most important determinant of overall survival (OS). Although the absolute number of nodes involved with cancer is important for prognosis, the role of the total number of excised nodes has received less emphasis. Thus, several studies have focused on the utility of the axillary lymph node ratio (ALNR) as an independent prognostic indicator of OS. However, most studies suffered from shortcomings, such as including patients who received neoadjuvant therapy or failing to consider the use of adjuvant therapy and tumor receptor status in their analysis.Methods.We conducted a single-center retrospective review of 669 patients with nonmetastatic lymph nodepositive BC. Data collected included patient demographics; breast cancer risk factors; tumor size, histopathological, receptor, and lymph node status; and treatment modalities used. Patients were subdivided into four groups according to ALNR value (<.25, .25–.49, .50–.74, .75–1.00). Study parameters were compared at the univariate and multivariate levels for their effect on OS.Results.On univariate analysis, both the absolute number of positive lymph nodes and the ALNR were significant predictors of OS. On multivariate analysis, only the ALNR remained an independent predictor of OS, with a 2.5-fold increased risk of dying at an ALNR of ≥.25.Conclusions.Our study demonstrates that ALNR is a stronger factor in predicting OS than the absolute number of positive axillary lymph nodes.

Genetic polymorphisms of CYP2E1, GST, and NAT2 enzymes are not associated with risk of breast cancer in a sample of Lebanese women.

Changes in the activity of drug metabolizing enzymes (DMEs) are potentially associated with cancer risk. This relationship is attributed to their involvement in the bioactivation of multiple procarcinogens or the metabolism of multiple substrates including an array of xenobiotics and environmental carcinogens. 326 Lebanese women of whom 99 were cancer free (controls) and 227 were diagnosed with breast cancer (cases) were included. Blood for DNA was collected and medical charts were reviewed. Three genotyping methods were employed including: (1) restriction fragment length polymorphism (RFLP) for CYP2E1*5B, CYP2E1*6, NAT2*5 and NAT2*6; (2) gel electrophoresis for GSTM1 and GSTT1; and (3) real-time PCR for GSTP1 Ile/Val polymorphism. We analyzed the relationship between genetic susceptibilities in selected xenobiotic metabolizing genes and breast cancer risk. Allele frequencies were fairly similar to previously reported values from neighboring populations with relevant migration routes. There were no statistically significant differences in the distribution of variant carcinogen metabolizing genes between cases and controls even after adjusting for age at diagnosis, menopausal status, smoking, and alcohol intake. Despite its limitations, this is the first study that assesses the role of genetic polymorphisms in DMEs with breast cancer in a sample of Lebanese women. Further studies are needed to determine the genetic predisposition and gene-environment interactions of breast cancer in this population.

Pharmacogenomics Variation in Drug Metabolizing Enzymes and Transporters in Relation to Docetaxel Toxicity in Lebanese Breast Cancer Patients: Paving the Way for OMICs in Low and Middle Income Countries

We investigated the association of genetic polymorphisms in drug metabolizing enzymes (DMEs) and transporters in patients with docetaxel-induced febrile neutropenia, by a new high-throughput DMEs and transporters (DMETPlus) microarray platform, characterizing 1936 single nucleotide polymorphisms (SNPs) in 225 genes. We recruited 100 Lebanese breast cancer patients from a consecutive cohort of 277 patients who received docetaxel either alone, or in combination with trastuzumab. Out of 100 patients, 18 had developed febrile neutropenia (cases). They were age- and treatment- matched with 18 patients who did not develop febrile neutropenia on docetaxel (controls). We found that 12 SNPs in seven genes (ABCC6, ABCG1, ABCG2, CYP1A2, CYP2D6, FMO2, and FMO3) were significantly associated with febrile neutropenia after docetaxel treatment. Many of these SNPs have not been previously reported to be associated with toxicity due to docetaxel treatment. Interestingly, one SNP in the FMO3 gene (rs909530) was significantly associated with three clinical endpoints: febrile neutropenia, reduced absolute neutrophil count, and hemoglobin reduction. To the best of our knowledge, this is the first study that evaluated the effect of a large array of nearly 2000 polymorphisms in DMEs and transporters on docetaxel toxicity in breast cancer patients, and in a previously understudied population. Additionally, it attests to the feasibility of genomics research in low- and middle-income countries (LMICs). In light of the current global epidemic of noncommunicable diseases (NCDs) such as breast cancer impacting LMICs, we suggest pharmacogenomics is considered as an integral part of the global health research agenda for NCDs and personalized therapeutics.

Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial

BACKGROUND In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer. METHODS This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18-59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients. FINDINGS Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigators assessment, median progression-free survival was 23·8 months (95% CI 19·2-not reached) in the ribociclib group compared with 13·0 months (11·0-16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44-0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 [61%] of 335 patients in the ribociclib group and 12 [4%] of 337 in the placebo group) and leucopenia (48 [14%] and four [1%]). Serious adverse events occurred in 60 (18%) of 335 patients in the ribociclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respectively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontinued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five [1%] in the ribociclib group and six [2%] in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast cancer (three [1%] and six [2%]). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient. INTERPRETATION Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients. FUNDING Novartis.

Modified resistance to chemotherapy and trastuzumab by bevacizumab in locally recurrent breast cancer

Antiangiogenic therapy is a valuable new approach in the treatment of breast cancer. Response rates ranging from 6.7% to 54% were reported using Bevacizumab (Avastin), anti-vascular endothelial growth factor, with chemotherapy. We report the first case of a patient, with a highly vascular breast cancer that recurred locally while on treatment with paclitaxel and trastuzumab combination, but showed complete clinical and pathological regression upon the addition of bevacizumab therapy to the same combination.

Axillary Lymph Node Ratio Revisited

examining the superiority of the lymph node ratio (LNR) to theabsolute number of positive lymph nodes (pN) as a prognostic indi-catorinpatientswithlymphnode–positivebreastcancer.Theauthorsconclude that LNR cut-offs (0.2 and 0.65) provide better patientseparation into low, intermediate, and high risk groups than pN. Thiswas mostly evident as patients with pN2 (four to nine positive nodes)and pN3 ( 10 positive nodes) involvement showed an imbalance inprognostic separation, with survival curves crossing after 15 years.Although the authors described several limitations to their work, theystill failed to mention some very pertinent shortcomings.The study did not take into consideration or document if anypatients received neoadjuvant chemotherapy. There was no mentionin the methodology section if such patients were excluded from theanalysis. This is relevant as neoadjuvant systemic treatments maymodify the nodal yield in an axillary dissection.

Long-term outcome of adult acute lymphoblastic leukemia in Lebanon: a single institution experience from the American University of Beirut

BACKGROUND AND OBJECTIVES The most important studies about outcome of acute leukemia come from developed countries, whereas most of the patients with this disease are in developing countries. We report predictive and prognostic factors in patients with acute lymphoblastic leukemia (ALL) in a tertiary care center in a developing country. PATIENTS AND METHODS We retrospectively reviewed the records of adult patients with acute leukemia who were referred to the American University of Beirut Medical Center between 1996 and early 2006. RESULTS Of 105 patients, 36 (34%) patients were diagnosed with ALL, and included 19 (53%) males and 17 (47%) females with a median age of 34 years (range, 14-79 years). Induction chemotherapy with curative intent was administered to 34 (94%) patients. Twenty-seven patients received intrathecal chemotherapy as prophylaxis (n=24) or as treatment for CNS disease (n=3). Twenty-eight patients (82%) achieved complete remission (CR) after induction chemotherapy. The median overall survival (OS) time was 22 months and the five-year OS for ALL patients was 38%. The median disease-free survival (DFS) time was 12 months, while the five-year DFS was 38%. Multivariate analysis showed that age <40 years, WBC <30 X 109/L, achievement of CR after first induction, and CNS prophylaxis were predictive factors for OS and DFS. CONCLUSION Despite limitations and the relatively low socioeconomic status of the Lebanese population, OS (38%) and DFS (38%) are quite similar to international data. Trends toward a higher CR and DFS in adults are due to intensified consolidation chemotherapy, the use of stem cell transplantation, and improvements in supportive care.

A clinical phase II study of a non-anthracycline sequential combination of cisplatin-vinorelbine followed by docetaxel as first-line treatment in metastatic breast cancer.

Background: We tested a sequential combination regimen using cisplatin and vinorelbine (PVn) followed by docetaxel as first-line chemotherapy in a phase II clinical trial in metastatic breast cancer (MBC). Patients and Methods: Thirty-five patients were enrolled. Cisplatin 80 mg/m2 was given on day 1 and vinorelbine 30 mg/m2 on days 1 and 8 every 3 weeks for 4 cycles. Responding patients received docetaxel 75 mg/m2 every 21 days for a maximum of 4 cycles. Three patients were excluded from analysis because of death unrelated to treatment. Results: After a median follow-up of 14 months, 32 patients completed the study. The overall response rate was 53.1%. Complete remission was seen in 5 patients (15.6%), partial response in 12 (37.5%), stable disease in 6 (18.75%), and progressive disease in 9 patients (28.1%). Median time to disease progression was 8 months (range 1–24). At 24 months, 12 (37.5%) patients were alive. A total of 183 cycles were administered. Febrile neutropenia was observed in 4 patients (2.2%). Grade II nephrotoxicity occurred in 12 cycles (6.5%) and grade III vomiting in 31/183 cycles (16.9%). Discussion: PVn is a feasible non-anthracycline option as first-line chemotherapy in patients with metastatic breast cancer and has acceptable toxicity. The sequential addition of 4 cycles of docetaxel following 4 cycles of PVn did not improve the overall response rate and results.

Tailoring Treatment Decision-making in Metastatic Breast Cancer

Advanced breast cancer (BC) includes locally advanced and metastatic disease and constitutes about 6–10% of cases of BC at presentation in industrialised nations and up to 60–80% in developing countries with limited or basic resources, as defined in the Breast Health Global Initiative Guidelines.1–3 A significant number of patients with primary early BC at presentation continue to relapse and present with metastatic disease. Median survival of patients with metastatic BC (MBC) is between two and three years.4 Recent data using modern systemic chemotherapy and hormone and targeted therapy give better but still modest results.5