Category: Hem/Onc Updates

Five Year Follow up Data without Adjuvant Chemotherapy, Utilizing Oncotype DX 21-gene Recurrence Score Assay

RR

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 lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for early stage, hormone receptor positive, HER negative breast cancer patients, are often made based on tumor size, grade, immunohistochemical markers such as Ki-67, nodal status and 21-gene Recurrence Score (RS) assay.

The West German Study Group (WSG) PlanB phase III trial, used Recurrence Score assay prospectively, to define a low risk subset of patients with node negative disease with high risk traditional parameters and patients with node positive disease (HR+, HER2 negative), who could be treated with adjuvant endocrine therapy alone, sparing chemotherapy. In this study, patients with a Recurrence Score of 11 or less were defined as having low risk for recurrence, even in those considered to have tumor with high risk features such as large tumor size, high tumor grade and lymph node involvement. Patients were considered to be at intermediate or high risk if they had a Recurrence Score of 12 or more and 25 or more, respectively. Gluz and colleagues had previously reported 3-year follow up results of a planned interim analysis of this study, and were able to show significant difference between tumor grade, Ki-67 and Oncotype DX Recurrence Score.

In this current analysis, the authors reported the 5-year Disease Free Survival (DFS) outcomes of this large prospective trial. This analysis included data from 3,198 patients with early stage hormone receptor positive or HER2 negative breast cancer. The median age was 56 years and 32.5% of the patients had grade 3 tumors and 41% of the patients had node positive disease. Patients with a Recurrence Score of 11 or less received hormonal therapy and adjuvant chemotherapy was omitted. The intermediate and high risk patients were randomized to receive six cycles of TAXOTERE® (Docetaxel)/CYTOXAN® (Cyclophosphamide) or four cycles of ELLENCE® (Epirubicin)/CYTOXAN® followed by four cycles of TAXOTERE®. The primary endpoint was Disease Free Survival (DFS) defined as invasive or noninvasive relapse.

It was noted that the 5-year DFS in the low risk group was 94%, 84% in the high risk group and 94% in the intermediate risk group (P<0.001). It should be noted that approximately 15% of the patients in the clinically determined intermediate or high risk group, with 0-3 lymph node involvement, fell in the low genomic risk group (Recurrence Score of 11 or less) and received hormonal therapy alone.

The authors concluded that West German Study Group (WSG) PlanB study is the first trial that has reported five year survival data using 21-gene Recurrence Score assay, which can identify patients with early breast cancer, who would benefit from hormonal therapy alone and could be spared chemotherapy. Based on these data, 21-gene Recurrence Score has stronger prognostic value compared to immunohistochemical studies such as Ki-67 and hormone-receptor expression and should therefore be routinely incorporated in clinical practice as a decision making tool for this patient population, in addition tumor size, grade and nodal status. Prospective WSG Phase III PlanB trial: Clinical outcome at 5 year follow up and impact of 21 Gene Recurrence Score result, central/local-pathological review of grade, ER, PR and Ki67 in HR+/HER2- high risk node-negative and –positive breast cancer. Gluz O, Nitz U, Christgen M, et al. Abstract 8LBA. Presented at: 10th European Breast Cancer Conference; March 9-11, 2016; Amsterdam.

OPDIVO® Granted Breakthrough Designation by FDA for Head and Neck cancer

RR

SUMMARY: The FDA granted breakthrough therapy designation to Nivolumab (OPDIVO®), as a treatment for patients with recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), following a platinum based therapy. This designation was based on the findings from CheckMate-141 study, which demonstrated an improvement in Overall Survival (OS) with OPDIVO®, compared to investigator’s choice of therapy. The American Cancer Society estimates that 61,760 people will be diagnosed with Head and Neck cancer in 2016 and 13,190 patients will die of the disease. Patients with recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) have a poor prognosis with a median Overall Survival (OS) of about 13 months with first line therapy and about 6 months or less with later lines of therapy. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response. CheckMate-141 is an open-label, phase III trial, in which 361 patients with recurrent or metastatic Squamous Cell Carcinoma of the oral cavity, pharynx, or larynx, were randomly assigned in a 2:1 ratio to receive either OPDIVO® (N= 240) or investigator’s choice of ERBITUX® (Cetuximab), TAXOTERE® (Docetaxel) or Methotrexate (N=121). OPDIVO® was administered intravenously at 3 mg/kg every 2 weeks. ERBITUX® dosing was 400 mg/m2 for the first dose followed by 250 mg/m2 weekly, TAXOTERE® dosing was 30 mg/m2 weekly and Methotrexate dosing was 40 mg/m2 weekly. The median age was 60 years, majority of patients were male, had received 2 or more prior systemic therapies and prior radiation therapy. Patients were stratified based on prior therapy with monoclonal antibody, ERBITUX® and HPV status was known for 50% of the participants. The primary endpoint was Overall Survival and secondary endpoints included Response Rates and Progression Free Survival (PFS).

This study was stopped earlier than scheduled after an independent monitoring panel determined that the primary endpoint for this study was met, with significant superiority of OPDIVO® over the investigator’s choice of therapy. The median Overall Survival with OPDIVO® was 7.5 months, compared to 5.1 months with investigator’s choice of therapy (HR=0.70; P=0.010). The 1-year Overall Survival with OPDIVO® was 36%, which was more than double, compared with investigator’s choice of therapy, which was 16.6%. Patients with PD-L1 expression of 1% or more benefited the most from treatment with OPDIVO®, with a median OS of 8.7 months, compared to 4.6 months in the control group (HR=0.55). For patients with PD-L1 expression less than 1%, median OS was 5.7 with OPDIVO® versus 5.8 months, for the control group (HR=0.89). HPV status also had an impact on outcomes. HPV-positive patients had a median OS of 9.1 months with OPDIVO® compared with 4.4 months with investigator’s choice of therapy (HR=0.56), whereas those who were HPV-negative and receiving OPDIVO®, had a median OS of 7.5 months compared to 5.8 months with investigator’s choice of therapy (HR=0.73). Grade 3 or 4 adverse events were significantly lower with OPDIVO®, compared with investigator’s choice of therapy(13.1% vs 35.1%).

The authors concluded that OPDIVO® is the first agent to demonstrate a significant improvement in Overall Survival, in patients with advanced head and neck cancer following progression on platinum-based chemotherapy, and fulfills an unmet need for this patient group. Gillison ML, Blumenschein G, Fayette J, et al. Nivolumab Versus Investigator’s Choice (IC) for Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (SCCHN): CheckMate-141. Presented at: AACR 2016 Annual Meeting, New Orleans; April 16-20, 2016. Abstract CT099.

Left Sided Colon Cancer Patients Have Better Outcomes than Those with Right Sided Tumors

RR

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die of the disease. Even though prognosis for patients with Colon Cancer has improved over the past two to three decades, it has remained unclear if improvement in survival was greater for Left sided Colon Cancer versus cancer originating in the Right hemicolon. To address this question, the authors in this study used the Geneva population-based registry and collected the data on all Colon Cancer patients from 1980-2006. They then compared outcomes ided Tumorsin 3396 patients with proximal (Right-sided) and distal (Left-sided) Colon Cancer. In the study population, 1,334 patients (39%) had Right-sided tumors and 2,062 (61%) had Left-sided tumors. Colon Cancer specific survival was then determined and compared, taking into consideration tumor and treatment characteristics of Left and Right sided tumors, as well as putative confounding variables. The authors also compared changes in survival between Colon Cancer location in early and late years of this observation study.

At the beginning of the study period (1980s), the 5-year specific survival was identical for Right and Left sided Colon Cancers (49% versus 48%). However, over the course of the study period, there was a marked improvement in survival, for patients with Left-sided cancers (HR=0.42; P<0.001), but this benefit was not noted in Right-sided Colon Cancer patients (HR=0.76; P=0.69). As such, distal Colon Cancer (Left sided) had a better prognosis than patients with proximal or Right sided Colon Cancer (Hazard Ratio for Left versus Right Colon Cancer = 0.81; P<0.001).

The authors concluded from this study that survival of patients with Right Colon Cancer did not improve since 1980, and tend to have the worse prognosis of all Colon Cancer patients. Therefore, change in treatment strategy is warranted for this patient subgroup. Right colon cancer: left behind. Gervaza P, Usel M, Rapiti E, et al. European Journal of Surgical Oncology 2016;doi:10.1016/j.ejso.2016.04.002

Impact of Treatment Delay on Clinical Outcomes in Breast Cancer Patients

RR

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 lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy and this is even more so true for HER positive and triple negative (ER, PR and HER negative) breast cancer patients, who are at an increased risk to develop recurrent disease. Even though majority of the patients start their adjuvant chemotherapy within 4-6 weeks following surgery, the impact of delay in the initiation of adjuvant therapy on outcomes, has remained unclear. Preclinical models have suggested that there is phase of increased angiogenesis and accelerated growth of micrometastases, as well as development of drug resistant clones, following removal of the primary tumor. Previously published data from a large meta-analysis had suggested that a four week delay in the initiation of adjuvant chemotherapy resulted in a 6% increase in the risk of death and an 8% increase in the risk of relapse. Nonetheless, over the past 2 decades, there has been increasing delay for both surgery and adjuvant chemotherapy treatment intervention, following diagnosis of breast cancer. These delays have been attributed to the increasing use of prognostic tools prior to treatment intervention, in order to optimize breast cancer care, germ-line genetic testing to plan appropriate surgical intervention, as well as patients seeking immediate reconstructive surgical options. Two studies addressed the impact of delay in treatment intervention following diagnosis of breast cancer, by investigating outcomes, in a very large group of patients with breast cancer.

In the study by Bleicher, et al., the relationship between the time from diagnosis to breast cancer surgery and survival was investigated, by collecting data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database and the National Cancer Database (NCDB). The SEER-Medicare cohort had 94,544 patients 66 years or older, diagnosed between 1992 and 2009 and the NCDB cohort included 115,790 patients 18 years or older, diagnosed between 2003 and 2005. Patients included in this analysis underwent surgery as initial treatment and had a diagnosis of non-inflammatory, non-metastatic, invasive breast cancer. The primary outcome was Overall and Disease-Specific Survival, as a function of time between diagnosis and surgery, measured in 30 day increments. They noted that with each interval of treatment delay increase, Overall Survival was lower (HR=1.09; P<0.001 in the SEER-Medicare cohort and HR=1.10; P<0.001 in the NCDB cohort). This relationship was statistically significant only in stages I and II breast cancer. The authors in this study concluded that longer time to surgery is associated with lower Overall and Disease-Specific Survival.

Chavez-MacGregor et al. analyzed the outcomes of 24, 843 patients in the California Cancer Registry with stage I-III invasive breast cancer, diagnosed between January 2005 and December 2010, and treated with adjuvant chemotherapy. Time to chemotherapy was defined as the number of days between surgery and the first dose of chemotherapy, and delayed treatment was defined as 91 or more days from surgery to the first dose of adjuvant chemotherapy. Median age at the time of diagnosis was 53 years, and median time to adjuvant chemotherapy was 46 days. Patients were evaluated for Overall Survival and Breast Cancer-Specific Survival. They noted that patients receiving adjuvant chemotherapy 91 or more days following surgery experienced worse Overall Survival (HR=1.34) and worse Breast Cancer-Specific Survival (HR=1.27) compared with patients receiving adjuvant chemotherapy within 31 days from surgery and these adverse outcomes were even more so, among patients with triple negative breast cancer (HR=1.53). Factors associated with adjuvant therapy delays included, low socioeconomic status, breast reconstruction, non-private insurance, and Hispanic or African American ethnicity. The authors in this study concluded that delaying initiation of adjuvant chemotherapy 91 days or more, results in adverse outcomes and this may be even more detrimental, in patients with triple negative breast cancer.

These two studies strongly suggest that treatment delays should be avoided in patients with early stage breast cancer and if surgery is to be delayed, neoadjuvant treatment approach may be reasonable, to avoid adverse outcomes.

Time to Surgery and Breast Cancer Survival in the United States. Bleicher RJ, Ruth K, Sigurdson ER, et al. JAMA Oncol. 2016;2:330-339.

Delayed Initiation of Adjuvant Chemotherapy Among Patients With Breast Cancer. Chavez-MacGregor M, Clarke CA, Lichtensztajn DY, et al. JAMA Oncol. 2016;2:322-329.

Liquid Biopsy Can Rapidly Detect EGFR Mutations and KRAS mutations with High Specificity

RR

SUMMARY: It has been well established that treatment with EGFR TKIs results in superior outcomes, for patients with tumors harboring exon 19 deletions and exon 21 mutations. The application of precision medicine with targeted therapy, requires detection of molecular abnormalities in a tumor specimen, following progression or recurrence. Archived biopsy specimens may not be helpful as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping cell free DNA in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The purpose of this study was to prospectively validate plasma droplet digital PCR (ddPCR) for the rapid detection of common Epidermal Growth Factor Receptor (EGFR) and KRAS mutations, as well as the EGFR T790M acquired resistance mutation. The authors prospectively evaluated the feasibility and accuracy of this assay in patients with newly diagnosed advanced non-squamous Non Small Cell Lung Cancer (NSCLC) who either were newly diagnosed and initial therapy was planned (N=120) or had developed acquired resistance to an EGFR kinase inhibitor and rebiopsy was planned (N=60). The median age was 62 years and 62% were females.

Following initial blood sampling of all patients, plasma droplet digital Polymerase Chain Reaction (ddPCR) for EGFR and KRAS mutations, including EGFR exon 19 deletion, EGFR L858R, KRAS G12X and EGFR T790M acquired resistance mutation, was performed. All patients underwent biopsy for tissue genotyping, and this was used as a reference standard for comparison with the liquid biopsy results. Important study outcomes included sensitivity and specificity of plasma ddPCR assay, as well as test turnaround time, which was defined as the number of business days between blood sampling and test reporting.

Tumor genotypes identified included 80 EGFR exon 19 or L858R mutations, 35 EGFR T790M mutations, and 25 KRAS G12X mutations. The ddPCR assay median turnaround time was 3 days compared with 12 days for tissue genotyping and 27 days for patients with acquired resistance. Plasma ddPCR exhibited a positive predictive value of 100% for EGFR 19 del, 100% for EGFR L858R mutation and 100% for KRAS. The positive predictive value for EGFR T790M was lower at 79%. The sensitivity of plasma ddPCR assay was 82% for EGFR exon19 del, 74% for EGFR L858R mutation, and 77% for EGFR T790M acquired resistance mutation, but lower for KRAS at 64%. Sensitivity for EGFR or KRAS was higher in patients with multiple metastatic sites (P=0.001), specifically in those with bone and hepatic metastases.

The authors concluded that in this first prospective study, plasma ddPCR assay can rapidly detect EGFR and KRAS mutations with high specificity, allowing treatment selection, without repeat biopsies. Additionally, this assay may also detect EGFR T790M mutation, missed by tissue genotyping, due to tumor heterogeneity in resistant disease. Prospective Validation of Rapid Plasma Genotyping for the Detection of EGFR and KRAS Mutations in Advanced Lung Cancer. Sacher AG, Paweletz C, Dahlberg SE, et al. JAMA Oncol. Published online April 07, 2016. doi:10.1001/jamaoncol.2016.0173

FDA Approves VENCLEXTA®, a BCL2 Inhibitor for the Treatment of Chronic Lymphocytic Leukemia

RR

SUMMARY: The FDA on April 11, 2016, granted an accelerated approval to Venetoclax (VENCLEXTA®) for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. The FDA also approved Vysis CLL FISH probe kit, as a companion diagnostic to VENCLEXTA®, for detection of the del(17p). There are two main types of lymphocytes, B and T lymphocytes. B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton's Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. PI3K (PhosphoInositide 3-Kinase) delta signaling, is hyperactive in B-cell malignancies and is important for the activation, proliferation, homing of malignant B cells in the lymphoid tissues and their survival. The delta isoform of PI3K enzyme is predominantly expressed in leukocytes. Targeting proteins in key pathways of B-cell biology has fundamentally changed the management and outcomes of CLL, over the past 5 years. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. ZYDELIG® (Idelalisib) is a highly selective oral inhibitor of the enzyme PI3K and specifically blocks the delta isoform of PI3K enzyme and its signaling pathway. The pro-survival (anti-apoptotic) protein BCL2, is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs are in development that mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death).

VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. VENCLEXTA® causes markedly less thrombocytopenia but more neutropenia compared to its first generation predecessor, Navitoclax. In the phase I study by Roberts, et al. (N Engl J Med 2016;374:311-322), high response rates of 71 to 79% were observed in CLL patients with poor prognostic features, when treated with VENCLEXTA®, with a 15-month Progression Free Survival (PFS) of 69%.

Based on this phase I data, a pivotal phase II, single-arm, multicenter study was conducted, to evaluate the efficacy of VENCLEXTA® monotherapy in patients with Relapsed/Refractory del(17p) CLL. This study included 106 patients with a median age of 67 years and patients had received a median of 2 prior chemotherapy regimens. More than a third of the patients were refractory to prior therapy with Fludarabine and Bendamustine. Treatment consisted of VENCLEXTA® tablets given once daily with a weekly dose ramp-up schedule (20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg and then the recommended daily dose of 400 mg), over a period of 5 weeks, given along with Tumor Lysis Syndrome (TLS) prophylaxis. Patients were treated with the daily 400 mg dosing until disease progression or unacceptable toxicity. The primary endpoint was Overall Response Rate (ORR). Secondary endpoints included Complete Response (CR), Partial Response (PR) rates, Time to first response, Duration of Response (DoR), Progression Free Survival (PFS), Overall Survival (OS), the proportion of patients proceeding to allogeneic Stem Cell Transplant (allo-SCT) and Safety.

The ORR was 79.4% with 8% Complete Response (including 2% Complete Response with incomplete marrow recovery-CRi). Minimal Residual Disease (MRD) was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with VENCLEXTA®. Forty five (N=45) patients were evaluated for MRD and 18 attained MRD-negative status in their peripheral blood. The median time to first response was 0.8 months (range: 0.1 to 8.1 months) and median time to CR/CRi was 8.2 months. With a median follow up of 12 months, the median Duration of Response (DoR) has not been reached (2.9-19.0 months).

The most common adverse reactions of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Patients should be closely monitored and should receive prophylaxis for Tumor Lysis Syndrome, which can occur as a result of rapid reduction in tumor volume.

The authors concluded that monotherapy with VENCLEXTA® resulted in a high ORR and sustained remissions, in high risk patients with CLL. Undetectable Minimal Residual Disease was noted in more than 20% of responders, with more than 10% of all patients achieving a deep response. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase II study. Stilgenbauer S, Eichhorst BF, Schetelig JS, et al. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA6.

Clinical Guidelines for the Evaluation of Hematuria as a Marker of Occult Urinary Tract Cancer

RR

SUMMARY: Hematuria is a common finding in clinical practice and millions of patients have routine urine evaluation. However, the magnitude of the risk for an underlying malignancy can vary significantly. Screening healthy, asymptomatic patients with urinalysis for malignancy is not currently recommended by any major health organization. This article describes the indications for the evaluation of hematuria, as a marker of occult urinary tract cancer, and is meant to help Health Care Providers make appropriate referral of patients, for urologic evaluation. The information in this article was gathered following a review of published clinical guidelines that addressed the evaluation of hematuria as a marker of occult urinary tract cancer, as well as other relevant studies, from the peer-reviewed literature. The American College of Physicians' High Value Care Task Force put this information together, with the intent to increase awareness and provide practical advice, based on the best available evidence.

High-Value Care Advice 1: Clinicians should include gross hematuria in their routine review of systems and specifically ask all patients with microscopic hematuria about any history of gross hematuria.

High-Value Care Advice 2: Clinicians should not use screening urinalysis for cancer detection in asymptomatic adults.

High-Value Care Advice 3: Clinicians should confirm heme-positive results of dipstick testing with microscopic urinalysis that demonstrates 3 or more erythrocytes per high-powered field before initiating further evaluation in all asymptomatic adults.

High-Value Care Advice 4: Clinicians should refer all adults with gross hematuria, even if self-limited, for further urologic evaluation.

High-Value Care Advice 5: Clinicians should consider urology referral for cystoscopy and imaging in adults with microscopically confirmed hematuria, in the absence of some demonstrable benign cause.

High-Value Care Advice 6: Clinicians should pursue evaluation of hematuria even if the patient is receiving antiplatelet or anticoagulant therapy.

High-Value Care Advice 7: Clinicians should not obtain urinary cytology or other urine-based molecular markers for bladder cancer detection in the initial evaluation of hematuria.

Hematuria as a Marker of Occult Urinary Tract Cancer: Advice for High-Value Care from the American College of Physicians. Nielsen M, Qaseem A, for the High Value Care Task Force of the American College of Physicians. Ann Intern Med. 2016;164:488-497.

Aromatase Inhibitors-Induced Carpal Tunnel Syndrome

RR

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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol, in extragonadal/peripheral tissues. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. The use of Aromatase Inhibitors (AIs) has been long associated with musculoskeletal symptoms, as well as accelerated bone loss, leading to a decrease in Bone Mineral Density (BMD). Approximately 25% of the patients on AIs are non-compliant during the first year of therapy and this has been attributed to musculoskeletal symptoms. Increased risk of Carpal Tunnel Syndrome (CTS) has also been reported with AIs.

Carpal tunnel syndrome (CTS), also called median nerve compression, is the most common entrapment neuropathy and results from compression of the median nerve, as it runs from the forearm into the palm of the hand, through the carpal tunnel. The carpal tunnel is a narrow and rigid passage at the base of the hand and houses the median nerve and tendons. In most cases, CTS is due to a congenital predisposition, with the carpal tunnel being simply smaller in some individuals than others. Secondary CTS is caused by any condition that further narrows this osteofibrous passage such as arthritis, acromegaly and mechanical problems in the wrist joint or effects the contents of this passage such as tenosynovitis, synovial hypertrophy, hypothyroidism, fluid retention during pregnancy or menopause, or the development of a cyst or tumor in the passage. Bilateral oophorectomy and use of the combined oral contraceptive have also been identified as risk factors for CTS. Patients often experience nocturnal paraesthesias in median nerve distribution (thumb, index and middle fingers), such as burning sensation, tingling, or heaviness, with the pain radiating to the forearm or elbow. It has been postulated that estrogen has antinociceptive properties and estrogen deprivation with AIs decreases the threshold for pain stimuli. Estrogen deprivation may also impact the metabolism of transverse carpal ligament on which estrogen and progesterone receptors are expressed and lack of estrogen may additionally result in morphological changes in the contents of carpal tunnel including, thickening of the tendon sheaths and fluid accumulation. This may directly induce CTS.

To address the risk factors and incidence of CTS in women taking AIs, the authors conducted an exploratory analysis of the International Breast Cancer Intervention Study II, a double-blind randomized clinical trial, in which women at increased risk of breast cancer were randomly assigned to receive ARIMIDEX® or placebo for 5 years. In this study, a total of 3,864 women were randomly assigned to receive either ARIMIDEX® (N=1920) or placebo (N=1944). The median age was 60 years and majority of the women (69%) had a BMI of greater than 25 kg/m2.

After a median follow up of 6.4 years, 96 patients had symptoms of Carpal Tunnel Syndrome (CTS). Patients receiving ARIMIDEX® were more likely to have CTS related symptoms than those receiving placebo (3.4% versus 1.6%; P<0.001). Eight of the 10 participants reported as having severe CTS were taking ARIMIDEX® (P =0.08). Eighteen women (0.9%) in the ARIMIDEX® group required surgical intervention for CTS compared to six women (0.3%) in the placebo group and this was significantly different (P=0.018). Participants experiencing CTS symptoms did so early in the course of treatment and only 6 women discontinued the allocated treatment. In addition to taking AIs, high Body Mass Index and prior complaints of musculoskeletal symptoms, were the only other risk factors for developing CTS.

The authors concluded that the use of ARIMIDEX® was associated with a higher incidence of Carpal Tunnel Syndrome (CTS), although few participants required surgery. Given the association between CTS and other musculoskeletal symptoms induced by AIs (Aromatase Inhibitors), the authors suggested that these findings induced by AIs, may share the same pathobiology. Anastrozole-Induced Carpal Tunnel Syndrome: Results from the International Breast Cancer Intervention Study II Prevention Trial. Spagnolo F, Sestak I, Howell A, et al. J Clin Oncol 2016;34:139-143

Caplacizumab, a Novel Anti-vWF targeted Nanobody, for Acquired TTP

RR

SUMMARY: Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS) and Atypical Hemolytic Uremic Syndrome (aHUS) are life-threatening Thrombotic MicroAngiopathies (TMAs) associated with systemic microvascular thrombosis, MicroAngiopathic Hemolytic Anemia (MAHA), thrombocytopenia and organ failure. Even though their clinical presentation has some similarities, they are distinct entities with different pathophysiology and hence managed differently. Patients with TTP have either severe deficiency of ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) secondary to anti-ADAMTS13 autoantibodies or rarely due to ADAMTS13 gene mutations. The physiological role of ADAMTS13 is to prevent intravascular platelet thrombosis. ADAMTS13 accomplishes this by cleaving ultralarge von Willebrand Factor multimers (which bind to platelets and induce aggregation), thereby mitigating the tendency of von Willebrand Factor (vWF) and platelets to form aggregates in normal microcirculation. Deficiency of ADAMTS13 causes vWF-platelet aggregation in the arterioles and capillaries, characteristic of TTP, resulting in tissue ischemia from microthrombi and end organ damage. Thus the microthrombi in TTP are platelets bound to vWF and not to fibrinogen. Rapid initiation of Plasma Exchange, the frontline therapy in patients with TTP, removes the anti-ADAMTS13 autoantibodies and ultra large vWF multimers and replenishes ADAMTS13. Immunosuppressive therapy with glucocorticoids and RITUXAN® (Rituximab) inhibits anti-ADAMTS13 autoantibody formation, by targeting the B lymphocytes. These interventions have significantly improved the survival rate among patients with TTP. Despite these advances with the use of Plasma Exchange, approximately 10-20% of the patients with TTP will succumb to their disease.

Caplacizumab is an anti-von Willebrand Factor, humanized, single-variable-domain immunoglobulin (Nanobody), directed against the A1 domain of von Willebrand Factor and prevents the interaction of vWF with the platelet glycoprotein Ib-IX receptor. TITAN is an international, multicenter, phase II, randomized, placebo-controlled study, designed to assess the efficacy and safety of Caplacizumab given as an adjunct to Plasma Exchange, in patients with acquired TTP. Seventy five patients (N=75) were randomized in a 1:1 ratio to receive Plasma Exchange plus either Caplacizumab 10 mg subcutaneous or placebo, daily. The mean age was 42 years and the mean platelet count was 24,600 per cubic millimeter. Majority of the patients in both groups received concomitant glucocorticoids and 23% of the patients in the placebo group received RITUXAN® during daily Plasma Exchange compared 6% in the Caplacizumab group. The primary end point was the time to response, defined as normalization of the platelet count (150,000 per cubic millimeter or higher) and a Lactate DeHydrogenase (LDH) level that was no more than twice the upper limit of the normal range. Secondary end points included TTP exacerbations and relapses.

It was noted that the median time to a response was significantly reduced with Caplacizumab as compared with placebo (39% reduction in median time, P=0.005). The mean number of Plasma Exchange days was lower with Caplacizumab (5.9 versus 7.9 days), the mean volume of Plasma administered was lower with Caplacizumab (19.9L versus 28.3L), normalization of LDH and creatinine occurred more rapidly with Caplacizumab and Complete Remissions after initial course of Plasma Exchange was more common in the Caplacizumab group (81% versus 46%), when compared to the placebo group. Mild to moderate bleeding was more common with Caplacizumab than with placebo (54% versus 38%).

The authors concluded that the addition of Caplacizumab to Plasma Exchange induces a faster resolution of acute TTP compared with placebo and Caplacizumab maintained a platelet-protective effect during the treatment period. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. Peyvandi F, Scully M, Hovinga JK, et al. for the TITAN Investigators. N Engl J Med 2016; 374:511-522

EGFR Inhibition may not be Effective Immediately after VEGF blockade in Metastatic ColoRectal Cancer

RR

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die 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 (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now becoming clear that even among the KRAS Wild Type patients, about 15% to 20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Therefore, pan RAS (expanded RAS) testing is now recommended.

The CALGB/SWOG 80405 study reported that either ERBITUX® or AVASTIN® in combination with chemotherapy have equivalent Overall Survival benefit, when given as first line therapy, for patients with metastatic ColoRectal Cancer (mCRC), whose tumors are KRAS Wild Type. Consequently, the optimal first-line therapy for patients with KRAS Wild Type metastatic CRC still remains unclear. ERBITUX® has a similar activity across all treatment lines whereas AVASTIN® appears to lose its efficacy along the course of treatment lines. Although FOLFOX and FOLFIRI are equally effective as first line treatment for patients with metastatic CRC, FOLFOX might be more effective as second line treatment. Preclinical studies have suggested that a prior anti VEGF therapy, may lower sensitivity to a subsequent anti EGFR treatment.

The authors in a phase III randomized multicenter trial addressed these issues by comparing two different sequences of ERBITUX® and FOLFOX chemotherapy in KRAS Wild Type metastatic CRC patients, refractory to first line FOLFIRI chemotherapy and AVASTIN®. Patients with mCRC (N=110) were randomly assigned in a 1:1 ratio to receive CAMPTOSAR® (Irinotecan)/ERBITUX® as second line followed by FOLFOX-4 chemotherapy as third line (Arm A) or the reverse sequence (FOLFOX-4 chemotherapy second line followed by CAMPTOSAR®/ERBITUX® as third line – Arm B). The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS) and toxicity. It was noted that the median PFS in Arm A was 9.9 months compared to 11.3 months in Arm B (HR=0.85; P=0.42) and the median OS was 12.3 months in Arm A and 18.6 months in Arm B (HR=0.79; P=0.28). The Objective Response Rate in Arm A was 37% and in Arm B was 57% (P=0.05). Treatment was well tolerated with a low incidence of serious adverse events.

It was concluded that EGFR inhibition is not active immediately after VEGF blockade and therefore ERBITUX® is less effective immediately after AVASTIN®. The sequence of biological agents appears to be more important than the first-line chemotherapy choice. In RAS Wild Type metastatic CRC patients progressing after a first line AVASTIN® based therapy, ERBITUX® should be given in the third line setting or should be considered in first line treatment regimen. Efficacy of cetuximab immediately after bevacizumab: A phase III multicenter trial comparing two different sequences of cetuximab and FOLFOX in K-Ras WT metastatic colorectal cancer patients refractory FOLFIRI/bevacizumab. Cascinu S, Zaniboni A, Lonardi S, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 632)