SUMMARY:The U. S. Food and Drug Administration on February 3, 2015 granted accelerated approval to IBRANCE® (Palbociclib), for use in combination with FEMARA® (Letrozole), for the treatment of postmenopausal women with Estrogen Receptor (ER)-positive, Human Epidermal growth factor Receptor 2 (HER2) negative advanced Breast Cancer, as initial endocrine-based therapy for their metastatic disease. Approximately 60% of the breast tumors express Estrogen Receptors and these patients are often treated with anti-estrogen therapy as first line treatment.
Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. IBRANCE® is a reversible, oral, small molecule inhibitor of Cyclin Dependent Kinases (CDK) 4/6 and is the first CDK inhibitor approved by the FDA. This agent in pre-clinical studies was noted to reduce cellular proliferation of Estrogen Receptor positive Breast Cancer cell lines by blocking progression of cells from G1 into S phase of the cell cycle and was also noted to be synergistic with anti-estrogens. The approval of IBRANCE® was based on an open-label, randomized, multicenter, phase II study which included postmenopausal women with ER-positive, HER2-negative, advanced (locally advanced or metastatic) Breast Cancer who had not received previous systemic treatment for advanced disease. This trial enrolled and randomly assigned 165 patients, to receive either IBRANCE® 125 mg PO daily for 21 consecutive days, followed by 7 days off treatment) plus FEMARA® (2.5 mg PO daily continuously throughout the 28-day cycle (N=84) or FEMARA® alone (N=81). Among the 165 patients, 43% had received chemotherapy and 33% had received anti-hormonal therapy as a neoadjuvant or adjuvant treatment. Fortynine percent (49%) of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had stage IV disease, 48% had visceral disease and 17% had bone only disease. The primary endpoint was investigator-assessed Progression Free Survival. The median PFS was 20.2 months in the IBRANCE® plus FEMARA® group and 10.2 months in the FEMARA® alone group (HR=0.488, P=0•0004). In patients with measurable disease, the Overall Response rate was higher in the IBRANCE® plus FEMARA® group compared to the FEMARA® alone group (55% versus 39%, P=0.04). The median duration of response for those who had a partial or complete response was 20.3 months with a combination of IBRANCE® plus FEMARA® vs 11.1 months with FEMARA® alone. The most common Grade 3–4 adverse events in the IBRANCE® plus FEMARA® group were neutropenia and leucopenia but without any cases of neutropenic fever. Unlike chemotherapy, the duration of neutropenia was brief with rapid recovery of blood counts. The authors concluded that the addition of IBRANCE® to FEMARA® significantly improved Progression Free Survival in women with advanced Estrogen Receptor positive and HER2-negative breast cancer. This combination may therefore be a reasonable treatment option in this patient group, soon after metastatic disease is diagnosed. Biomarkers expression (cyclinD1 amplification and/or loss of p16) had no impact on outcomes suggesting that the biomarker for IBRANCE® may be the Estrogen Receptor itself, rather than CDK4/6 kinases. Finn RS, Crown JP, Lang I, et al. Lancet Oncol 2015; 16:25-35
Author: RR
Pre- and Post-diagnosis Physical Activity, Television Viewing, and Mortality Among Patients With Colorectal Cancer in the National Institutes of Health–AARP Diet and Health Study
SUMMARY:The American Cancer Society estimates that approximately 137,000 new cases of colorectal cancer were diagnosed in the United States in 2014 and over 50,000 died of the disease. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival and Overall Survival. Reducing risk of death and improving survival even further with leisure time physical activity is the topic of this discussion. The most prevalent sedentary behavior, watching TV, has been associated with poorer survival in the general population. Several studies have suggested protective effects of physical activity on cancer recurrence although this has not been conclusive. Pooled data from other studies have shown that lack of physical activity among survivors of ColoRectal Cancer (CRC) has been associated with higher mortality risk. However, the independent effects of physical activity before and after colorectal cancer diagnosis, has remained unclear and the association between watching TV and mortality in survivors of CRC has not been defined.
There are several biologic mechanisms that explain the association between sedentary life style, physical activity, and mortality. The adipose tissue in the body in addition to serving as the storage site for energy also releases adipokines, which have pro-inflammatory and anti-inflammatory properties. Physical activity decreases inflammatory adipocytokines and increases anti-inflammatory cytokines and thereby could affect cancer incidence and mortality. Also, physical activity has been shown to increase insulin sensitivity. Several studies have shown increased risk of CRC, increased angiogenesis, tumor growth, and anti-apoptotic activity with higher circulating insulin and insulin-like growth factor-1 and lower insulin-binding protein levels. Physical activity also improves cardiovascular health by lowering blood pressure. The authors in this study explored the impact of lifestyle such as moderate to vigorous intensity physical activity level and TV viewing time (sedentary life style) on ColoRectal Cancer mortality among CRC survivors, with particular attention to pre and post cancer diagnosis contributing factors. Data was collected from a large cohort of patients enrolled in the National Institutes of Health Diet and Health Study and the associations were analyzed between pre CRC diagnosis (N=3797) and post CRC diagnosis (N= 1759) life styles (physical activity and TV watching) and overall and disease-specific mortality. It was noted that patients who had 7 or more hours of weekly leisure physical activity before their diagnosis of CRC had a 20% lower risk of all-cause mortality compared to those who had a sedentary life style and were not engaged in any leisure time activity (HR=0.80; P=0.02). Patients who were engaged in 7 or more hours of weekly leisure physical activity post CRC diagnosis had a 31% lower risk of all-cause mortality compared to those who reported no activity (HR=0.69; P=0.006). This benefit was noted independent of pre-diagnosis activity. Amongst those who reported sedentary lifestyle, patients who spent 5 or more TV hours per day before CRC diagnosis had a 22% increased risk in all-cause mortality compared to those who watched no more than 2 hours of TV per day (HR=1.22; P=0.002). A similar trend of increased risk of all-cause mortality was seen in those who spent more TV hours, post diagnosis although this was not statistically significant. The authors concluded that in patients with CRC, leisure time physical activity was inversely associated with all-cause mortality, whereas more TV hours was associated with increased mortality risk. Health Care providers should therefore proactively promote increasing physical activity and minimizing TV hours, among survivors of ColoRectal Cancer. Arem H, Pfeiffer RM, Engels EA, et al. J Clin Oncol 2015; 33:180-188
Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302) final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study
SUMMARY: Prostate Cancer is the most common cancer in American men and approximately 233,000 new cases were diagnosed in 2014 and close to 30,000 men died of the disease. The primary systemic intervention for patients with advanced prostate cancer is Androgen Deprivation Therapy (ADT). This can be accomplished by either surgical castration (bilateral orchicetomy) or medical castration, using LHRH (GnRH- Gonadotropin-Releasing Hormone) agonists. Majority of these patients will eventually develop progressive disease (Castrate Resistant Prostate cancer – CRPC), due to enhanced autocrine and /or paracrine synthesis of androgens or androgen precursors in the tumor microenvironment. This has lead to the development of novel compounds that decrease androgen synthesis as well as androgen signaling in patients with CRPC.
Abiraterone acetate (ZYTIGA®) is a novel, targeted, oral androgen biosynthesis inhibitor that decreases androgen production in the adrenal glands, testes and prostate cancer cells by inhibiting a steroidal enzyme CYP17A. COU-AA-302 trial is a placebo controlled, double-blind, randomized, phase III study and at the interim analyses showed that ZYTIGA® plus Prednisone significantly improved radiographic Progression Free Survival compared with placebo plus Prednisone, in men with chemotherapy-naive CRPC. The authors in this publication provided additional data on the pre-specified final analysis of the trial, which included the effect of ZYTIGA® plus Prednisone on Overall Survival, time to opiate use, and use of other subsequent therapies. In this study which included 1088 chemotherapy-naïve, asymptomatic or mildly symptomatic CRPC patients, 546 patients received ZYTIGA® 1000 mg PO plus Prednisone 5 mg PO twice daily and 542 patients received placebo plus Prednisone. The co-primary endpoints were radiographic Progression Free Survival and Overall Survival. In the final analysis, at a median follow up of 49•2 months, the median Overall Survival was 34.7 months in the ZYTIGA® group vs 30.3 months in the placebo control group (HR = 0.81, P = 0.0033). This benefit was seen across all prespecified subgroups, as well as adjusting for crossover from placebo to ZYTIGA® (HR = 0.79, P = 0.0013). The median time to opiate use for cancer-related pain was significantly prolonged in the ZYTIGA® group compared to the placebo group (33.4 vs 23.4 months, HR = 0.72, P < 0.0001). The most common grade 3 or 4 adverse events of special interest in the ZYTIGA® vs placebo group were cardiac disorders (8% vs 4%), increased ALT (6% vs < 1%), and hypertension (5% vs 3%). The authors concluded that with a median follow up of more than 4 years, treatment with ZYTIGA® in patients with chemotherapy-naive metastatic CRPC, significantly improved Overall Survival compared with Prednisone alone, with favorable toxicities. Ryan CJ, Smith MR, Fizazi K, et al. for the COU-AA-302 Investigators .The Lancet Oncology 2015; 16:152-160
IMBRUVICA® (Ibrutinib)
The FDA on January 29, 2015 approved IMBRUVICA® for the treatment of patients with Waldenstrom’s Macroglobulinemia (WM). IMBRUVICA® was initially approved in November 2013 for the treatment of patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. IMBRUVICA® also received approval in February 2014 for the treatment of Chronic Lymphocytic Leukemia (CLL) in patients who received at least one prior therapy and in July 2014 for the treatment of CLL with 17p deletion. IMBRUVICA® is an oral capsule and is a product of Pharmacyclics, Inc.
Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib
SUMMARY: It is estimated that in the US, approximately 76,000 new cases of melanoma were diagnosed and close to 8000 individuals died of the disease, in 2014. The incidence of melanoma has been on the rise for the past three decades. The FDA granted accelerated approval in January 2014, for a combination of MEKINIST® (Trametinib) and TAFINLAR® (Dabrafenib), to treat patients with advanced melanoma, based on the understanding of the biological pathways of this malignancy. The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6%-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas. In the BREAK-3 randomized phase III trial, TAFINLAR® (Dabrafenib), a selective oral BRAF inhibitor demonstrated a statistically significant improvement in Progression Free Survival (PFS) and Response Rate (RR) compared to Dacarbazine (DTIC), in patients with advanced BRAF V600E/K mutated melanoma. In the BRIM 3 randomized, phase III study, ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF demonstrated significant improvement in Progression Free Survival and Overall Survival compared to Dacarbazine.
Squamous cell carcinoma’s were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. The addition of a MEK inhibitor such as MEKINIST® (Trametinib) to a BRAF inhibitor such as TAFINLAR®, has addressed some of these limitations, in previously published studies, with improvement in Progression Free Survival. MEKINIST® is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway and has been shown to significantly improve Progression Free Survival, Response Rate and Overall Survival, when compared to chemotherapy, in advanced melanoma patients with BRAF V600E/K mutations. The authors in this open label, randomized, phase III trial, evaluated the outcomes, comparing a combination of TAFINLAR® and MEKINIST® with single agent ZELBORAF® , in previously untreated and unresectable Stage IIIC or IV melanoma patients with BRAF V600E or V600K mutations. Eligible patients (N=704) were assigned in a 1:1 ratio to receive either a combination of TAFINLAR® (Dabrafenib), 150 mg PO BID and MEKINIST ® (Trametinib) 2 mg PO QD or ZELBORAF® (Vemurafenib) 960 mg PO BID, as first line therapy. The primary end point of this study was Overall Survival. Secondary end points included Progression Free Survival, Overall Response Rate, duration of response, and safety. At the preplanned interim analysis, the Overall Survival at 12 months was 72% in the combination therapy group and 65% in the single agent ZELBORAF® group (HR=0.69; P=0.005). The median Progression Free Survival was 11.4 months in the combination therapy group and 7.3 months in the ZELBORAF® group (HR=0.56; P<0.001). The objective response rate was 64% with combination therapy and 51% with single agent ZELBORAF® (P<0.001). There was no difference in the rates of severe adverse events and study drug discontinuations between the two groups. Skin cancers such as Squamous cell carcinoma and Keratoacanthoma occurred in 1% of patients in the combination therapy group and 18% of those treated with ZELBORAF® . The authors concluded that a combination of BRAF inhibitor TAFINLAR® and MEK inhibitor MEKINIST® significantly improved Overall Survival as compared with ZELBORAF® monotherapy, with a 31% relative reduction in the risk of death, in previously untreated patients with metastatic melanoma, with BRAF V600E or V600K mutations. This benefit was accomplished without increased overall toxicity. Robert C, Karaszewska B, Schachter J, et al. N Engl J Med 2015; 372:30-39
p16 Protein Expression and Human Papillomavirus Status As Prognostic Biomarkers of Non-Oropharyngeal Head and Neck Squamous Cell Carcinoma
SUMMARY: Squamous Cell Carcinoma of the Head and Neck (HNSCC) accounts for about 3-5% of all cancers in the United States. It is estimated that 55,070 people were diagnosed with Head and Neck cancer in 2014 and 12,000 patients died of the disease. The head and neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma involving the head and neck region (HNSCC) is therefore a heterogeneous disease and the five year survival rate of patients with head and neck cancer depends on several factors and can be variable. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Recent studies have shown that over 70% of the OroPharyngeal Squamous Cell Carcinomas (OPSCC) are caused by HPV with the HPV-16 being the predominant type present in the tumor cells.
The malignant behavior of these tumors is dependent on the expression of viral E6 and E7 oncoproteins that inactivate the tumor suppressor proteins p53 and the retinoblastoma protein (pRB), respectively. HPV positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) is more common among never smokers or light smokers and patients tend to be younger with better performance status. The pathobiology of HPV positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) is different from the HPV negative OroPharyngeal Squamous Cell Carcinoma in that p53 is degraded/inactivated by viral E6 oncoprotein instead of by genetic mutation, pRB pathway is inactivated by viral E7 oncoprotein instead of Cyclin D1 amplification and p16 is overexpressed or upregulated instead of inactivation resulting from reduced negative feedback from pRB. Testing for HPV is based on several methodologies which include detection of HPV DNA by in situ hybridization (ISH) or Polymerase Chain Reaction (PCR), detection of HPV E6/E7 RNA expression by quantitative Reverse Transcriptase–PCR (qRT-PCR) and p16 protein overexpression, a surrogate marker of oncogenic HPV infection, by ImmunoHistoChemistry (IHC) staining. Both p16 overexpression testing by IHC and HPV by ISH can be easily performed on Formalin-Fixed Paraffin Embedded (FFPE) specimen whereas detection of HPV E6/E7 RNA expression, which is indicative of active viral oncogene transcription in tumor cells and is considered to be a gold standard, requires a larger tumor specimen compared with other methodologies.
The concordance rate between HPV by ISH and p16 by IHC is approximately 90% in OPSCC, whereas the prevalence and significance p16 by IHC has remained unclear for HPV infection in non-OPSCC (oral cavity, hypopharynx and larynx). It is well established however that patients with HPV-positive/p16-positive OPSCC have better outcomes compared with those with HPV-negative/p16-negative OPSCC. However, the prognostic significance of p16 overexpression in non-OPSCC patients with or without evidence of HPV infection has not been clear. The authors in this study evaluated p16 protein overexpression by IHC and HPV status by HPV ISH as potential prognostic biomarkers in non-OPSCC tumors of patients enrolled in three prospective Radiation Therapy Oncology Group (RTOG) clinical trials. Of the 1921 patient enrolled in these three trials, 683 patients with non-OPSCC tumors were eligible and 52% (N=356) of these patients were tested for p16 overexpression and overall, 19.3% were p16 positive. When OPSCC and non-OPSCC patients were compared, OPSCC patients whose tumors were p16 positive had better Progression Free Survival and Overall Survival than non-OPSCC patients with p16 positive tumors. However, patients with p16 negative OPSCC and non-OPSCC have similar inferior outcomes. The authors concluded that patients with p16 negative non-OPSCC have worse outcomes than patients with p16 positive non-OPSCC, similar to that seen in patients with OPSCC and therefore HPV infection may influence outcomes in a subset of patients with non-OPSCC as well. Better methodologies for HPV detection and correlation with p16 expression will help identify “true” HPV infection related non-OPSCC and thereby enable tailored and less intense treatment, for this favorable group of patients. Chung CH, Zhang Q, Kong CS, et al. J Clin Oncol 2014; 32:3930-3938
Aspirin for the Prevention of Recurrent Venous Thromboembolism The INSPIRE Collaboration
SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000 – 100,000 deaths. VTE is the third leading cause of cardiovascular mortality with a mortality rate of up to 25% in those with untreated acute pulmonary embolism. Even though the risk of recurrent VTE is high after anticoagulant treatment is discontinued in patients with a first unprovoked venous thromboembolism (10-30% risk of a recurrence within 5 years following cessation of anticoagulation), a significant number of these patients receive therapy for 6-12 months and are not routinely treated with long term anticoagulant therapy. This may be due to bleeding risks, cost of therapy and need for diligent monitoring while on long term anticoagulation. 
Aspirin is a non-selective, irreversible inhibitor of both COX-1 and COX-2 (Cyclooxygenases 1 and 2). It inhibits the production of Prostaglandins and Thromboxane A2 and there by decreases platelet aggregation. Both ASPIRE and WARFASA trials support the role of aspirin for the prevention of recurrent VTE in patients with an unprovoked VTE, after 6-18 months of anticoagulation therapy. These trials however were not individually powered to detect benefits of treatment for particular outcomes or subgroups of patients. The INSPIRE Collaboration involved further analysis of these trials to detect outcomes in pre-specified subgroups of patients. The intent-to-treat analysis included 1,224 patients and at a median follow up of 30.4 months, daily Aspirin given at a dose of 100mg reduced recurrent VTE events by 32% (HR=0.68; P=0.008) and this included reduction in recurrent Deep Vein Thrombosis by 34% (HR=0.66; P=0.01) and Pulmonary Embolism by 34% (HR=0.66; P=0.08), compared to Placebo. After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR=0.58; P=0.005). Subgroup analyses indicated similar relative, but larger absolute, risk reductions in men and older patients. Aspirin also reduced major vascular events by 44% (HR=0.66; P=0.002). The major bleeding rate was low at 0.5%/year for Aspirin and 0.4%/year for Placebo. The authors concluded that aspirin reduces the risk of recurrent VTE. Even though the efficacy of aspirin is inferior to that of Warfarin or the new oral anticoagulants, this data suggests that Aspirin should be strongly considered in patients with unprovoked VTE for whom long-term anticoagulation therapy with Warfarin or one of the new oral anticoagulants has to be discontinued or is not an appropriate option. Aspirin however, should not be considered a replacement option for conventional anticoagulation. Simes J, Becattini C, Agnelli G, et al. Circulation. 2014; 130:1062-1071
Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma
SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 24,050 new cases were diagnosed in 2014 and 11,090 died of the disease. KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone proteasome inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. KYPROLIS® monotherapy is presently approved in the United States for use in patients with relapsed and refractory Multiple Myeloma following a phase 2b single arm study which showed a 24% overall response rate in this patient group. REVLIMID® (Lenalidomide) given along with weekly Dexamethasone, was associated with significantly improved Progression Free Survival (PFS) when administered until disease progression, in patients with newly diagnosed Multiple Myeloma. The combination of REVLIMID® and weekly Dexamethasone is considered a reference regimen for both newly diagnosed and relapsed multiple myeloma. VELCADE® in combination with REVLIMID® and Dexamethasone showed an overall response rate of 64% and a median PFS of 9.5 months in patients with relapsed and refractory Multiple Myeloma. Based on this background the authors conducted this randomized, open label, multicenter, phase III study in which the safety and efficacy of a combination of KYPROLIS® (Carfilzomib), REVLIMID® and weekly Dexamethasone (KYPROLIS® group) was compared with a combination of REVLIMID® and weekly Dexamethasone (control group), in patients with relapsed Multiple Myeloma. Seven hundred and ninety two (N=792) patients were randomly assigned in a 1:1 ratio to KYPROLIS® group (N=396) and control group (N=396). Eligible patients included those with Multiple Myeloma who had received one to three prior treatments which included VELCADE® or REVLIMID and Dexamethasone combination, provided that they did not have disease progression during treatment with these agents. The 28 day treatment cycle consisted of KYPROLIS® IV given on days 1, 2, 8, 9, 15, and 16 (starting dose, 20 mg/m2 on days 1 and 2 of cycle 1 with a target dose of 27 mg/m2 thereafter) during cycles 1 through 12 and on days 1, 2, 15, and 16 during cycles 13 through 18, following which KYPROLIS® was discontinued. REVLIMID® 25 mg PO was given on days 1 through 21 and Dexamethasone 40 mg PO was administered on days 1, 8, 15, and 22. Patients in both treatment groups received only REVLIMID® and Dexamethasone after cycle 18 until disease progression. Antiviral and antithrombotic prophylaxis was administered to patients in both treatment groups. The primary end point was Progression Free Survival and secondary end points included Overall Survival, the rate of overall response (partial response or better), response duration, health-related quality of life, and safety. The rate of clinical benefit (minimal response or better) was an exploratory end point. The study met its primary endpoint at the time of the pre-specified interim analysis with a significant improvement in the median Progression Free Survival for those patients in the KYPROLIS® group compared to the control group (26.3 months versus 17.6 months; HR=0.69; P=0.0001). This benefit in the PFS was demonstrated across all predefined subgroups. The median overall survival was not reached in either group and the 24 month overall survival rates were 73.3% and 65.0% in the KYPROLIS® and control groups, respectively (HR=0.79; P=0.04). The overall response rates (partial response or better) were 87.1% and 66.7% in the KYPROLIS® and control groups, respectively (P<0.001). Amongst the responders, 31.8% and 9.3% of patients in the respective groups had a complete response or better and 14.1% and 4.3% had a stringent complete response. Further, patients in the KYPROLIS® group reported superior health-related quality of life. Grade 3 or higher adverse events were reported in 83.7% and 80.7% of patients in the KYPROLIS® and control groups respectively. The authors concluded that the addition of KYPROLIS® to REVLIMID® and Dexamethasone resulted in significant improvement in PFS as compared with REVLIMID® and Dexamethasone alone, in patients with relapsed Multiple Myeloma. Additional benefits in the KYPROLIS® group included higher and deep response rates, improved health-related quality of life, a favorable risk–benefit profile and a trend towards improved Overall Survival. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. N Engl J Med 2015; 372:142-152
Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their life time. Approximately, 233,000 new cases of invasive breast cancer were diagnosed in 2014 and 40,000 women died of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15%-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2.
HERCEPTIN® binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). HERCEPTIN® in combination with chemotherapy has been proven to significantly improve Progression Free Survival and Overall Survival in patients with advanced breast cancer. Adjuvant chemotherapy in combination with HERCEPTIN® has been shown to reduce the relative risk of relapse by 52% and relative risk of death by 33%. The National Comprehensive Cancer Network (NCCN) has recommended adjuvant chemotherapy with HERCEPTIN® for patients with small, HER positive, node-negative tumors, including those with T1bN0 tumors, even though there are little or no data supporting this recommendation, because these patients are generally not included in adjuvant therapy studies. Further, the chemotherapy regimens often recommended (ACTH, TCH) along with HERCEPTIN® are relatively toxic. The authors in this study chose a less toxic chemotherapy regimen than the regimens often recommended for those patients with high risk disease. In this multicenter, investigator initiated study, 406 patients with tumors measuring up to 3 cm in greatest dimension received weekly treatment with TAXOL® (Paclitaxel) and HERCEPTIN (Trastuzumab) for 12 weeks, followed by 9 months of HERCEPTIN® monotherapy. Close to 50% of the patients had tumors 1 cm in diameter or less, about 40% of the patients had tumors 1-2 cm in diameter and majority of the tumors (56%) were high grade. Treatment regimen consisted of TAXOL® 80 mg/m2 IV weekly, for 12 weeks and HERCEPTIN® 4 mg/kg loading dose IV on day 1, followed by 2 mg/kg weekly, for a total of 12 doses followed by HERCEPTIN® 6 mg/kg every 3 weeks for an additional 40 weeks, for a total of 52 weeks of treatment with HERCEPTIN®. Patients who underwent lumpectomy received either partial breast radiation before the initiation of the therapy, or radiation of the whole breast, following completion of treatment with TAXOL®. Treatment with HERCEPTIN® was continued during the time patient was receiving radiation therapy. Adjuvant hormonal therapy was recommended for women with hormone-receptor positive tumors after the completion of TAXOL® treatment. The primary end point was survival free from invasive disease. The median follow up period was 4 years. The 3-year rate of survival free from invasive disease was 98.7%. Treatment was very well tolerated with a low incidence of heart failure (0.5%) and neuropathy. The authors concluded that a less toxic regimen such as HERCEPTIN® given along with weekly TAXOL® has significant efficacy, decreasing the risk of recurrence in this patient group, most notable during the first three years after diagnosis. They also point out that the risk of recurrence of breast cancer is greatest during the first 3-5 years after diagnosis and it would seem unlikely that a different chemotherapy regimen administered with HERCEPTIN® would impact the risk of late recurrences. Tolaney SM, Barry WT, Dang CT, et al. N Engl J Med 2015;372:134-141
Hereditary Hemochromatosis Missed Diagnosis or Misdiagnosis?
SUMMARY: It is estimated that 1-6 individuals per 100 in the United States have Iron overload syndrome as measured by random elevated Iron Saturation level. Hereditary Hemochromatosis (HH) is an inherited, Autosomal Recessive, iron storage disease and in the US usually occurs as a result of HFE gene mutations. This is more prevalent among persons of European origin and the HFE gene is located on the short arm of chromosome 6 and modulates iron uptake. Two mutations on the HFE gene, C282Y and H63D, account for the majority of the cases of Hereditary Hemochromatosis, in the United States.
The authors in this provocative study reviewed the electronic medical records of patients seen at a tertiary referral center, to evaluate the accuracy of diagnosis of Hereditary Hemochromatosis (HH). HFE genotyping helps differentiate HH from secondary causes of Iron overload syndromes. This differentiation is relevant because of the lack of established guidelines with regards to management of individuals with abnormal iron studies, secondary to liver disease. It is however well known that HH and iron overload related to transfusions, can cause organ damage and this could be prevented by removing the excess iron. In this study, the authors investigated the diagnostic approach, when elevated iron studies were noted, interpretation of HFE genotyping results by physicians in order to accurately diagnose HH and factors contributing to misdiagnosis. Their review conducted between January 2002 and May 2012, demonstrated that of the 601 patients with disorders of iron metabolism, only 62% were genotyped for mutations in the HFE gene. Of those genotyped, 54% had genotypes consistent with HH (Homozygotes – C282Y/C282Y or Compound Heterozygotes – C282Y/H63D) and the rest of the 46% had non-hereditary hemochromatosis genotypes (C282Y heterozygotes, H63D homozygotes and heterozygotes, etc). One half of these non-hereditary hemochromatosis genotype patients were misdiagnosed as Hereditary Hemochromatosis and a third of these patients underwent phlebotomy. Of those who were not genotyped for mutations in the HFE gene, a third of these patients were diagnosed to have Hereditary Hemochromatosis and majority of these patients underwent phlebotomy. More than two third of the patients misdiagnosed to have Hereditary Hemochromatosis in fact had liver disease and 5% had other hematological conditions. The authors concluded that C282Y heterozygotes as well as H63D homozygotes and heterozygotes do not have Hereditary Hemochromatosis and a majority of patients with iron overload are misdiagnosed to have Hereditary Hemochromatosis. Aggressive phlebotomy in the absence of an appropriate Hereditary Hemochromatosis genotype, is not indicated and can be potentially harmful, delaying more appropriate therapy. Cherfane CE, Hollenbeck RD, Go J, et al. The American Journal of Medicine 2013;126:1010-1015.