Cardiac function in women receiving dual anti-Her2 antibodies (trastuzumab and pertuzumab) combined with chemotherapy for breast cancer.

BACKGROUND: Chemotherapy regimens containing a combination of anti-Her2 antibodies are effective but can be associated with cardiac toxicity. OBJECTIVES: We evaluate the outcome with a particular focus on the cardiac function of patients with Her2 over-expressed breast cancer receiving Chemotherapy regimens combined with Trastuzumab and Pertuzumab in routine clinical practice settings. DESIGN AND METHODS: The initial cohort of patients who started Chemotherapy regimens in combination with Trastuzumab and Pertuzumab before September 2019 in four cancer units were reviewed retrospectively. All patients had regular measurements of left ventricular ejection fraction by Doppler ultrasound. RESULTS: Sixty-seven patients were identified. Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment were administered in the neoadjuvant and palliative settings in 28 (41.8%) and 39 (58.2%) patients, respectively. All patients underwent left ventricular ejection fraction assessment prior to starting Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment and at 3 and 6 months later. Subsequently, left ventricular ejection fraction was measured at 9, 12, 15, 18, 21, and 24 months as long as patients are still receiving any of the treatment components. Compared to baseline, the mean left ventricular ejection fraction was not significantly different at any of the subsequent time points (range; decrease by 0.936% to increase by 1.087%: T-test P value not statistically significant for all comparisons). Trastuzumab and Pertuzumab administration was withheld temporarily for two patients due to clinically suspected cardiac toxicity which was excluded upon further investigations. In the neoadjuvant cohort, 82.3% of patients were relapse free at 3 years. The median progression-free survival was 20 months, and the median overall survival was 41 months in the palliative cohort. CONCLUSION: In this cohort describing our limited initial experience, dual anti-Her2 antibodies (Trastuzumab and Pertuzumab) combined with chemotherapy is effective and not associated with significant cardiac toxicity when the left ventricular ejection fraction is measured every 3 months. This may suggest that previous concerns about cardiotoxicity may have been overemphasized. Further studies investigating less frequent left ventricular ejection fraction monitoring may be warranted.

Effect of Obesity on Neoadjuvant Systemic Therapy Outcomes in Patients with Early Breast Cancer: A Retrospective Institutional Study.

BACKGROUND: Obesity and overweight are usually considered as poor prognostic factors in early breast cancer. Body mass index (BMI) is a significant predictive factor for lower pathologic complete response (pCR) rates after neo-adjuvant systemic therapy (NST). The relationship between obesity and breast cancer prognosis varies according to patient and tumor characteristics such as menopausal status and tumor subtype, respectively. PATIENTS AND METHODS: Between March 2010 and October 2013, 80 patients with early breast cancer who had received standard NST from KFSH Saudi Arabia were included in this study. For statistical analysis, the study participants were categorized into two groups based on their BMI, as normal (BMI < 25 kg/m2) and obese groups (BMI ≥ 25 kg/m2). pCR was defined as non-invasive cancer in the breast/axillary tissue. RESULTS: The median age of our patients was 48 (range, 38-68) years. Invasive ductal carcinoma (IDC) subtype was identified in 93.8% of the cases. Additionally, 26 (32.5%) and 33 (41.25%) patients were diagnosed with stage II and stage IIIA breast cancer, respectively. Lymphovascular invasion was detected in 32.5%, whereas intermediate and high-grade malignancy were found in 61.25% and 32.5% of the patients, respectively. Forty-four patients (55%) were obese. pCR was achieved in 56 patients (70%), and the comparison between patients with and without pCR revealed that those in the former group had significantly lower tumor grades. Significantly, lower relapse and mortality rates were distinguished in patients who achieved pCR than in those who did not. Additionally, comparison between normal and obese patients revealed that a high number of patients in both groups were post-menopausal (p = 0.001). However, survival analysis indicated the absence of significant differences in disease-free survival between the two groups based on BMI (p = 0.19). Conversely, patients with normal BMI had significantly better overall survival than obese patients (p = 0.029), with a higher mortality rate noted in the obese group (16.7% vs 2.3%, p = 0.037). CONCLUSIONS: In the present study, 58.3% of patients that failed to achieve pCR had BMI above the normal level; they moreover had higher relapse rates and lower survival compared with normal BMI patients. This finding needs to be verified through further prospective studies to determine if BMI is a risk factor for breast cancer.

Adjuvant Chemotherapy for Patients with Breast Cancer Based on Clinical and Evolving Oncotype DX Criteria.

INTRODUCTION: Oncotype DX assay recurrence score (ODX-RS) cut-off values have recently changed after the publication of the TAILOR-X trial results. We aim to explore decisions for adjuvant chemotherapy (ACT) based on physicians' clinical assessment and the evolving ODX-RS. METHODOLOGY: Patients who underwent ODX testing after curative surgical resection of estrogen receptor positive (ER+), Her2 non-overexpressed (Her2-) and lymph node-negative (LN-) breast cancer (BC) were eligible. Management of these patients was guided by the results of the old ODX-RS-1 (<18, 18-30, and ≥31) risk grouping. For the purpose of this study, treatment decisions were also assumed according to TAILOR-X results (ODX-RS-2). Decisions of 3 medical oncologists on ACT were solicited by blinding them to the RS to investigate concordance with ODXA RS-1 and 2 recommendations. RESULTS: Sixty-six consecutive patients were included. Median age was 50.5 (range: 21-73) years. There was 1 male patient, and 37/65 females (56.9%) were premenopausal. Among the 3 oncologists, recommendations for ACT based on clinical assessment were discrepant in 29 (43.9%) patients. Based on majority consensus (≥2 oncologists), ACT would have been recommended to 22/41 (53.7%) and 22/46 (47.82%) patients with low-risk tumors according to ODX-RS-1 and ODX-RS-2, respectively. Compared to ODX-RS-1, ODX-RS-2 identifies 12% (46 vs. 41) more low-risk patients and 66% (20 vs. 12 patients) more high-risk patients. CONCLUSION: Overtreatment and discrepancies in the management of patients with ER+/Her2-/LN- early BC can be minimized by the implementation of ODX genomic assay. Some differences in ACT recommendations exist between ODX-RS-1 and ODX-RS-2.

Effect of KRAS mutational status on disease behavior and treatment outcome in patients with metastatic colorectal cancer: intratumor heterogeneity and mutational status.

BACKGROUND: Nowadays, the outcomes of metastatic colorectal cancer (mCRC) have considerably improved. Genetic studies evaluating KRAS mutational status are important in the personalized therapy era to understand disease heterogeneity, disease behaviors, and treatment outcomes. METHODS: This multicenter retrospective study evaluated 360 patients with mCRC treated at three oncology centers in Saudi Arabia and Egypt between February 2011 and December 2015. Patients were treated with bevacizumab and cetuximab according to guidelines. Therapy outcome, time to progression, and disease-associated death were assessed. KRAS mutational status was evaluated by testing exons 12 and 13. RESULTS: Approximately 220 (61.1%) cases were of wild-type KRAS, whereas KRAS mutation was noted in 38.9%. KRAS mutation was common in the descending colon, whereas a low incidence of the KRAS mutation was observed in the ascending colon (P<0.001). Among patients with KRAS mutation, 64.3% initially presented as emergency cases with obstruction/perforation (P=0.002), and 62.9% had hepatic or pulmonary metastasis. The progression-free survival (PFS) was 10.7 months. Cases without KRAS mutation showed a higher PFS than did those with KRAS mutation (mean PFS: 11.5 vs. 9.6 months, P=0.001). The overall survival was 23.2 months. The survival varied considerably according to KRAS type: patients without mutation survived for 25.0 months and those with mutation survived for 19.6 months (P<0.001). Disease-related death occurred in 132 (36.7%) cases, approximately 57.1% of them (80 cases) had KRAS mutations (P=0.001). CONCLUSIONS: A major association between KRAS mutational status and both disease behavior and treatment outcomes was found in this study. Patients with KRAS mutation show advanced disease presentation, with lower PFS and overall survival.

A Multicenter Study of the Impact of Body Mass Index (BMI) on the incidence of Pathologic Complete Response (pCR) Among Saudi Patients with locally advanced Breast cancer (LABC) post Neoadjuvant Chemotherapy (NAC).

PURPOSE: Obesity was reported to be a poor prognostic factor for breast cancer. There is a growing evidence of increasing prevalence of obesity among Saudi women across all age groups (44%). Since the prognostic significance of obesity was not studied in Saudi patients with breast cancer, the aim of this study was to evaluate the impact of BMI on pCR in LABC patients post NAC. PATIENTS AND METHODS: This is a retrospective study between May 2005 to July 2010; 246 consecutive female patients who were diagnosed of LABC (Stage II & III) and underwent surgery in three tertiary care centers, representative of the Kingdom of Saudi Arabia (King Saud Medical City, Riyadh; King Abdullah Hospital, Mecca and King Fahad Specialist Hospital, Dammam) were included in this study. All included patients have received NAC (Anthracycline/Taxane based combination chemotherapy and ± Herceptin). Patients who were diagnosed to have stage IV breast cancer due to presence of distant metastasis were excluded. Patients were categorized as normal (BMI <25 kg/m2), overweight (BMI of 25 to <30 kg/m2) and obese (BMI >30 kg/m2). pCR was defined as no invasive cancer in the breast or axillary tissue. Univariate and multivariate analysis were used to evaluate the statistical associations between pCR and BMI with respect to the other previously established prognostic factors, namely age, tumor grade, stage, ER/ PR /Her-2neu status, molecular subtypes, and lympho-vascular invasion (LVI). RESULTS: The median age was 50 years (range 24-68). Molecular subtypes were as follows: luminal A; 23.2%, luminal B; 45.1%, triple negative; 16.7% and Her-2 neu positive; 15%. Infiltrating ductal carcinoma represents the majority of our cohort (92.7%). Eighty-six (35%) were stage II and 160 (65%) were stage III. Intermediate and high-grade malignancies were found in 52% and 44.3% of the patients respectively. Positive lymph vascular invasion was detected in 41.5%. Obese patients constitute 55.7% of our cohort. Pathologic complete response was achieved in 62 patients (25.2%). In Univariate analysis LVI and overweight /obesity were negatively correlated with pCR (P= 0.037 and 0.000 respectively) while tumor grade was positively correlated with pCR (P= 0.008). In multivariate analysis, Overweight/ obesity was the only significant independent factor correlating with pCR (P=0.000). No impact of BMI has been demonstrated on both disease-free survival (DFS) and overall survival (OS) (P=0.93, 0.18 respectively). CONCLUSION: In this study, Overweight/Obesity (which represent more than half of the patients =81.3 %) had a negative impact on pCR in Saudi patients with LABC treated with NAC. This poorer outcome in patients with abnormal weight (Overweight/Obesity) necessitates further prospective studies of this risk factor in order to optimize the care of this group of patients.

Efficacy and safety of crizotinib in patients with anaplastic lymphoma kinase-positive advanced-stage non-small-cell lung cancer.

INTRODUCTION: Lung cancer is the leading cause of cancer mortality worldwide, despite advances in management, especially with targeted agents and immunotherapy. Numerous oncogenes have been identified that control the growth of these malignancies. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that develops distorted functioning as a result of chromosomal rearrangement. Crizotinib, a tyrosine kinase inhibitor (TKI), was approved by the Food and Drug Administration (FDA) in 2011 for the treatment of advanced ALK-positive non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this chart review, we compiled data from two cancer hospitals in Kuwait and Saudi Arabia which were collected from patients with advanced NSCLC treated between January 2013 and September 2017 with crizotinib after diagnosed with ALK-positive disease. Crizotinib 250 mg BID was given orally with/without food intake. We assessed overall survival (OS), objective response rate (ORR), progression-free survival (PFS), duration of the response, and dose reduction/cessation. RESULTS: De-identified data from 38 subjects were compiled. Their median age was 53 years, 65.8% were male, the 1-year OS was 88%, and the PFS was 16.5 months. Two cases (5.3%) had a complete response (CR), while 17 (44.7%) had a partial response (PR). Side effects of grade III/IV occurred, including elevated transaminase levels, diarrhea, and prolonged QT intervals, in 8% patients, with dose reduction in six patients (15.8%). CONCLUSION: In NSCLC, crizotinib is a viable treatment option with good response and tolerable toxicity for patients with ALK-positive advanced disease.

Chemotherapy-Induced Febrile Neutropenia in Solid Tumours.

Febrile neutropaenia (FN) is defined as an oral temperature of >38.3°C or two consecutive readings of >38.0°C for 2 hours and an absolute neutrophil count (ANC) of <0.5 × 109/l, or expected to fall below 0.5 × 109/l. Fever is one of the characteristic symptoms of FN and is usually associated with the presence of an infection caused by various microorganisms. The incidence and epidemiology of FN are variable based on different factors: (type of cancer, the age/sex of the patient, chemotherapy type /number of cycles). FN remains one of the most common and risky complications of chemotherapy which occurred within 6-8 days with standard chemotherapy and it is occurred as about 7-8/1000 patients receiving treatment with chemotherapeutic agents. There is a clear relationship between the severity of neutropaenia (which directly influences the incidence of FN) and the intensity of chemotherapy. Currently, the different regimens are classified as producing a high risk (>20%), an intermediate risk (10%-20%) or a low risk (<10%) of FN. The causative organisms including either bacteria, fungi or viruses. The bacteria Gram-positive (currently dominating) and Gram-negative (Dominant in the 1970s), are usually the main microorganisms responsible for FN and cause complicated infections. Although the morbidity and mortality rates of FN have decreased over the years due to use of proper antibiotic treatment, preventive measures and use the standardrisk management plan as per guidelines but it is still one of oncological emergency. FN is responsible for considerable morbidity as 20%-30% of patient's present complications that require in-hospital management, with an overall in-hospital mortality of ~10%.

Paroxysmal Nocturnal Hemoglobinuria: From Bench to Bed.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia with highly variable clinical symptoms making the diagnosis and prediction of its outcome difficult. It is caused by the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene that results in deficiency of the glycosylphosphatidylinositol anchor structure responsible for fixing a wide spectrum of proteins particularly CD55 and CD59. The clinical features of this disease arise as a result of complement-mediated hemolysis in unprotected red cells, leukocytes, and platelets as well as the release of free hemoglobin. Patients may present with a variety of clinical manifestations, such as anemia, thrombosis, kidney disease, smooth muscle dystonias, abdominal pain, dyspnea, and extreme fatigue. PNH is an outstanding example of how an increased understanding of pathophysiology may directly improve clinical symptoms and treat disease-associated complications when we inhibit the terminal complement cascade. This topic will discuss PNH overview to assist specialists looking after PNH patients.

Predictive Value of IHC4 Score for Pathological Response to Neoadjuvant Chemotherapy in Hormone Receptor-Positive Breast Cancer.

PURPOSE: This study aimed to explore the value of IHC4 in predicting pathological response after neoadjuvant chemotherapy in patients with hormonal receptor (HR)-positive breast cancer (BC). MATERIALS AND METHODS: In this retrospective exploratory study, data for 68 HR-positive BC patients who received neoadjuvant chemotherapy were recorded. IHC4 scores were calculated based on estrogen receptors/progesterone receptors, Ki-67 and HER2 status. Logistic and ordinal regression analyses in addition to likelihood ratio test were used to explore associations of IHC4 scores and other clinico-pathological parameters with pathological complete response (pCR) and pathological stage. RESULTS: Taking the 25th percentile as the cut-off, a lower IHC4 score was associated with an increased probability of pCR (low; 52.9% vs. High; 21.6%, OR=4.1, 95% CI= 1.28-13.16, p=0.018) and a lower pathological stage (OR =3.9, 95% CI=1.34-11.33, p=0.012). When the IHC4 score was treated as a continuous variable, a lower score was again associated with an increased probability of pCR (OR=1.010, 95% CI=1.001-1.018, p=0.025) and lower pathological stage (OR=1.009, 95% CI= 1.002-1.017, P=0.008). Lower clinical stage was associated with a better pCR rate that was of borderline significance (P=0.056). When clinical stage and IHC4 score were incorporated together in a logistic model, the likelihood ratio test gave a P-value of 0.004 after removal of the IHC4 score and 0.011 after removal of the stage, indicating a more significant predictive value of the IHC4 score for pCR. CONCLUSIONS: This study suggests that the IHC4 score can predict pathological response to neoadjuvant chemotherapy in HR-positive BC patients. This finding now needs to be validated in a larger cohort of patients.