SUMMARY: The MyeloDysplastic Syndromes (MDS) are disorders of hematopoietic stem cells, characterized by one or more peripheral blood cytopenias. These syndromes may arise de novo or can be secondary, following treatment with chemotherapy and/or radiation therapy for other malignancies. It can also manifest after environmental exposures. The International Prognostic Scoring System (IPSS), based on the score, divides patients with MDS into Lower Risk (IPSS low and intermediate-1 scores) and Higher Risk (IPSS intermediate-2 and high scores) groups. This classification remains arbitrary because of the heterogeneity in the Lower Risk group and poor outcomes in certain Lower Risk subset of patients. DACOGEN® (Decitabine) exerts its antineoplastic effects by inhibitng DNA methyltransferase, resulting in hypomethylation of DNA and apoptosis. The authors in this Phase II study evaluated the outcomes in patients with Low or Intermediate-1 risk MDS using lower doses of DACOGEN® given subcutaneously on two different treatment schedules. Of the 67 randomized patients, 43 patients received DACOGEN® 20mg/m2 SC QD for three consecutive days every 28 days (Schedule A) or 20mg/m2 SC given on days 1, 8 and 15, of a 28 day cycle (Schedule B). Treatment was planned for up to one year. Primary endpoint was Overall Improvement Rate (OIR) and this included Complete Remission (CR), Partial Remission (PR), marrow CR or Hematologic Improvement (HI). Secondary end points included HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Taken as a group, there was no difference in the OIR (23%), HI, transfusion independence or cytogenetic response between schedule A and schedule B. However, patients on schedule A had more CR's making this a protocol defined superior schedule. Median OS was not reached. Transfusion independency was noted in 67% of the patient's on schedule A and 59% of the patient's on schedule B. Further, approximately 70% of the patients were alive at 500 days. The most frequent adverse events in schedule A and B were anemia (23% vs 18%), neutropenia (28% vs 36%) and thrombocytopenia (16% vs 32%). Based on these promising results, the authors recommended DACOGEN® given on three consecutive days SC every 28 days as per Schedule A, for patients with Low or Intermediate-1 risk MDS. Garcia-Manero G, Jabbour E, Borthakur G, et al. J Clin Oncol 2013;31:2548-2553
Category: Hem/Onc Updates
Effect of NPM1 and FLT3 Mutations on the Outcomes of Elderly Patients With Acute Myeloid Leukemia Receiving Standard Chemotherapy
SUMMARY: Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, cytogenetics stratify patients based on risk and helps manage them accordingly. Even though normal karyotype is the most common cytogenetic finding, approximately 10%-15% of AML patients have a monosomal karyotype (presence of at least 2 autosomal monosomies or a single autosomal monosomy in combination with at least one structural abnormality). These patients have a poor prognosis and alterations in the TP53 gene has been implicated in majority of these patients. AML patients with a normal karyotype should be tested for NPM1 (Nucleophosmin), FLT3 (Fms-related tyrosine kinase 3) and CEBPA (CCAAT/Enhancer Binding Protein Alpha) mutations, in addition to cytogenetics, as this may have therapeutic implications. CEBPA is a transcription factor and plays an important role in myeloid differentiation. Mutations in the CEBPA gene have been described in approximately 10% of patients with AML. Patients can have one or two mutations in this gene. It appears that favorable outcomes may be limited to those patients who have double CEBPA mutations rather than those with single CEBPA mutations. AML patients without FLT3 mutations or NPM1 mutation with CEBPA-double mutations have a favorable outcome. In this retrospective review, the authors analyzed the clinical impact of NPM1 and FLT3 mutations in AML patients, 65 years of age or older, treated with cytotoxic chemotherapy. A total of 557 patients were retrospectively reviewed. They noted that the outcomes were significantly better amongst patients with NPM1-mut/FLT3-wild type genotype compared to any other NPM1/FLT3 genotypes. The median survival was 21.5 months vs. 9.0 months and estimated 2-year survival rates were 51% vs. 38%, respectively (P = .003). The authors concluded that elderly AML patients with NPM1-mut/FLT3-wild type genotype have significantly improved outcomes when treated with cytotoxic chemotherapy. This subset of patients have a good prognosis with outcomes similar to those with favorable cytogenetics such as Inversion 16 and t(8:21). The discovery of molecular mutations is providing valuable information to facilitate risk-adapted therapy. Daver N, Liu Dumlao T, Ravandi F, et al. Clinical Lymphoma Myeloma and Leukemia 2013;13:435-440
Validation of the 12-Gene Colon Cancer Recurrence Score in NSABP C-07 As a Predictor of Recurrence in Patients With Stage II and III Colon Cancer Treated With Fluorouracil and Leucovorin (FU/LV) and FU/LV Plus Oxaliplatin
SUMMARY: The beneficial role of adjuvant chemotherapy is established in Stage III colon Cancer. This however is less convincing in patients with stage II colon cancer. The conventional clinical and pathological features such as Tumor stage, Grade, Lymphovascular invasion and number of lymph nodes evaluated, may be of some prognostic significance in Stage II colon cancer, but have not been validated. Nonetheless, a majority of these patients receive ELOXATIN® (Oxaliplatin) based adjuvant chemotherapy, with very little benefit and significant toxicity. The 12-gene Colon Cancer Recurrence Score assay was developed after it was validated in multiple studies in over 3000 patients. This assay is not recommended for Stage II MMR (MisMatchRepair) Deficient patients, as these patients have a better survival and their tumors are resistant to 5-Fluorouracil and may actually do worse with adjuvant chemotherapy following surgery. The recurrent score corresponds to the likelihood of colon cancer recurrence 3 years after surgery, with a higher score suggesting a higher risk of recurrence. The authors in this analysis conducted a prospectively designed, clinical validation study of Recurrence Score, in 892 fixed Paraffin embedded tumor specimens from patients with stage II and III colon cancer, randomly assigned to Fluorouracil (FU) or FU plus ELOXATIN® in the National Surgical Adjuvant Breast and Bowel Project C-07. The primary objective of this study was to retrospectively determine the relationship between the recurrent score and the recurrent risk in stage II/III patients treated with 5-FU or 5-FU/ELOXATIN®. Secondary objectives were to determine if recurrence score provided significant information beyond T stage, tumor grade, MMR status and number of lymph nodes examined. From this analysis, the authors reported that recurrent score performs similarly in both Stage II and Stage III colon cancer patients and predicts recurrence risk beyond T and N stage, Grade, MMR status, number of lymph nodes examined and treatment. Amongst Stage II patients, T4 tumors that are MMR proficient fall in the high risk category and chemotherapy should be considered regardless of the recurrent score whereas T3 tumors that are MMR proficient fall in the standard/intermediate risk category and recurrent score assay may assist in the decision making process. In this group, a recurrence score of 41 or more puts these patients at a recurrence risk that is similar to those who have T4 tumors that is MMR proficient and will therefore benefit from adjuvant chemotherapy. In certain stage IIIA/B patients, a low recurrence score of less than 30 is associated with low absolute benefit with ELOXATIN® and therefore is not recommended. The authors concluded that the 12- Gene Colon Cancer Recurrent Score results can help guide adjuvant therapy decisions for patients with Stage II colon cancer and certain patients with Stage III colon cancer. Yothers G, O’Connell MJ, Lee M, et al. J Clin Oncol 2013;31:4512-4519.
Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations
SUMMARY: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 site and is detected in approximately 50% of melanomas. In the BREAK-3 randomized phase III trial, TAFINLAR®, 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 mutated melanoma. Squamous cell carcinoma’s were seen in 6% of the patients. In the METRIC phase III study, MEKINIST®, a potent and selective inhibitor of MEK gene (which is downstream from RAF in the MAPK pathway) was compared with either Dacarbazine or TAXOL® (Paclitaxel) in advanced melanoma patients with BRAF V600E/K mutations. Patients in the MEKINIST® group had a significantly improved PFS, RR and Overall Survival. Based on the understanding of the biological pathways of the disease and different mechanisms of action (MOA) of these two agents, a phase I and II trial was conducted combining TAFINLAR® and MEKINIST®. In this study, 162 treatment naïve patients with unresectable or metastatic melanoma, with BRAF V600E or V600K mutations received either TAFINLAR® 150 mg plus MEKINIST® 1 or 2 mg or TAFINLAR® alone. Treatment was given until disease progression or side effects were intolerable. The primary end points were the incidence of Cutaneous Squamous-cell carcinoma, PFS and RR. Secondary end points included Overall Survival and pharmacokinetic activity. The combination treatment resulted in a lower incidence of Cutaneous Squamous-cell carcinoma (7% vs 19% in those receiving monotherapy, P=0.09), improved median PFS (9.4 months vs 5.8 months in the monotherapy group, HR=0.39, P<0.001) and superior complete or partial responses (76% compared with 54% with monotherapy (P=0.03). Pyrexia was however more common in the combination group than in the monotherapy group (71% vs. 26%). The authors concluded that by combining two agents with different MOA’s targeting two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway, PFS was significantly improved. Further, development of resistance can be overcome in BRAF mutation positive melanoma patients and the incidence of secondary skin cancers found with BRAF inhibitor monotherapy can be reduced as well. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med 2012;367:1694-1703
Multiple Myeloma International Staging System “Staging” or Simply “Aging” System?
SUMMARY: In this provocative perspective, the authors suggest revising the present Multiple Myeloma (MM) International Staging System, to incorporate more relevant information related to the biology of the disease. The MM International Staging System (MM-ISS) takes into account Beta-2 Microglobulin (B2M) along with Serum Albumin (SA) levels to determine the prognosis in MM patients. 
Although B2M and SA may act as surrogates for the extent of the disease, the evidence is insufficient to rely on these two entities to prognosticate MM. Even though B2M can correlate with MM tumor bulk as well as act as a biomarker of renal failure related to MM, the authors cite multiple studies suggesting that elevated serum B2M can be seen independent of MM history, in healthy elderly patients, infections, autoimmune disorders and chronic renal insufficiency. Further elevated B2M can be a marker of frailty in elderly patients and can predict disability and mortality in this patient group. With regards to Serum Albumin (SA) in MM, SA is inhibited by IL6, a MM cell growth factor and thus is able to indirectly reflect MM tumor bulk. However, low SA levels can also be seen in frail and elderly patients independent of MM history. The authors point out that the stage of the disease in the MM-ISS increases with age, independent of MM tumor bulk, due to the these nonspecific factors and does not necessarily correlate with other more specific prognostic markers such as cytogenetics, particularly in elderly patients. The authors conclude that combining the MM-ISS with tumor cytogenetics will more accurately predict prognosis in MM patients. Bataille R, Annweiler C, Beauchet O. Clinical Lymphoma Myeloma and Leukemia 2013;13:635-637
Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms
SUMMARY: MyeloProliferative Disorders (MPDs) are a group of clonal abnormalities associated with dysregulation of the multipotent hematopoietic stem cell (CD34). The most common MPDs include Chronic Myelogenous Leukemia (CML), Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Primary MyeloFibrosis (PMF). These diseases have one or more shared features including hypercellular bone marrow with or without marrow fibrosis, overproduction of one or more blood cell lines, thrombotic and/or hemorrhagic tendencies, extramedullary hematopoiesis involving the liver or spleen, transformation to acute leukemia and molecular abnormalities. The Philadelphia chromosome which was discovered in 1960 results from a reciprocal translocation between the long arms of chromosomes 9 and 22, demonstrable in all hematopoietic precursors. This translocation results in the transfer of the Abelson (ABL) gene from chromosome 9 to join the Breakpoint Cluster Region (BCR) gene on chromosome 22. This fused BCR/ABL gene now on chromosome 22 is called the Philadelphia chromosome. The fusion gene is diagnostic of CML and is responsible for abnormal tyrosine kinase activity resulting in disordered myelopoiesis. The discovery of Philadelphia chromosome, established for the very first time, a direct link between chromosomal abnormalities and malignancy, subsequently leading to the development of targeted therapies. With regards to the other MPDs, majority of the patients with PV have activating JAK2 mutations such as JAK2V617F (95%) and if negative have JAK2 exon 12 mutations (5%). About 50% of the patients with ET and PMF have JAK2 mutations and about 5% have activating mutations in the thrombopoietin receptor gene (MPL). So, in the remaining approximately 45% of patients without these mutations, no specific molecular marker has been discovered. To address this group, the authors analyzed 1107 samples from patients with MPDs and were able to identify mutations in the gene encoding CALRETICULIN (CALR mutations), in certain groups of patients. They noted that CALR mutations are frameshift mutations never seen in patients with PV. They are however only demonstrable in the stem cells of ET or PMF patients, without JAK2 or MPL gene mutations. Therefore, in ET and PMF, CALR mutations and JAK2 and MPL mutations are mutually exclusive. Patients with CALR mutations have a more indolent course compared to those with JAK2 activating mutations, with a lower risk of thrombosis and longer overall survival. The authors concluded that CALR mutations may play an important early role in the development of MPDs and identifying this molecular marker may be relevant in the management of patients with ET and PMF. Klampfl T, Gisslinger H, Harutyunyan AS, et al. N Engl J Med 2013; 369:2379-2390
Multiple Myeloma International Staging System – An Aging System
The authors in this provocative report recommend combining the Multiple Myeloma International Staging System (MM-ISS) with tumor cytogenetics, to more accurately predict prognosis in MM patients. The MM International Staging System (MM-ISS) takes into account a combination of Beta-2 Microglobulin (B2M) along with serum albumin (SA) levels to determine the prognosis in MM patients. Unfortunately both B2M and SA can be abnormal in elderly patients independent of Myeloma history and may predict disability and mortality in this patient group. The MM-ISS may therefore not accurately reflect the intrinsic malignancy of the myeloma cell clone. This information was published in Clinical Lymphoma Myeloma and Leukemia 2013. Read more at www.oncoprescribe.com
Safety and Efficacy of Everolimus With Exemestane vs Exemestane Alone in Elderly Patients With HER2-Negative, Hormone Receptor-Positive Breast Cancer in BOLERO-2
SUMMARY: Exemestane (AROMASIN®) is a steroidal, Aromatase Inhibitor (AI) which has been shown to improve Progression Free Survival (PFS) in postmenopausal patients with ER positive metastatic breast cancer. Patients tend to have limited clinical benefit with subsequent hormonal interventions if their disease recurs or progresses on AI’s. Further, cytotoxic chemotherapy may not be feasible in elderly patients. The PI3K/AKT/mTOR is a complex pathway, essential for cell proliferation, survival and apoptosis (programmed cell death). This pathway is of interest because of its increased activity in malignant cells as a result of amplification or mutation of the genes associated with PI3-kinase (phosphatidylinositol-3 kinase) and AKT, as well as loss of function of PTEN. PTEN normally prevents activation of AKT and its downstream pathways. Elevated ER signaling and breast cancer progression has been associated with activation of this mTOR (mammalian Target Of Rapamycin) pathway. Everolimus (AFINITOR®) is a mTOR inhibitor that has been shown to inhibit ER signaling and restore sensitivity to anti-estrogen therapies. In the phase III BOLERO-2 study, patients with ER positive, advanced breast cancer, who had recurred or progressed on prior therapy with nonsteroidal AI’s such as Anastrozole (ARIMIDEX®) or Letrazole (FEMARA®), had doubling of PFS with a combination of AROMASIN® and AFINITOR® compared to AROMASIN® alone. The authors now report the Safety and Efficacy of AROMASIN® and AFINITOR® combination in 316 patients, 65 years of age or older, out of the 724 patients in the BOLERO-2 study. The median follow up was 18 months. Baseline treatment characteristics were similar in all treatment subsets. The treatment combination resulted in 55% reduction in the risk of disease progression regardless of the age compared to AROMASIN® alone (PFS – 7.8 months vs 3.2 months, HR=0.45, P<0.0001). Further the combination treatment resulted in greater clinical benefit compared to single agent AROMASIN®. Approximately two third of the patients regardless of their age required dose modifications and the most common adverse events in all age groups with similar incidences were stomatitis, rash, fatigue , hyperglycemia and pneumonitis. It is recommended that elderly patients be carefully monitored and toxicities promptly addressed during treatment. The authors concluded that a combination of AROMASIN® and AFINITOR® can provide significant clinical benefit with acceptable toxicities, even in patients 65 years of age or older, thereby delaying the need for chemotherapy. Pritchard KI, Burris HA, Ito Y, et al. Clinical Breast Cancer 2013;13:421-432.
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib and Rituximab for Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL)
SUMMARY: PI3K 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. Idelalisib is a highly selective oral inhibitor of the enzyme phosphoinositide 3-kinase (PI3K) and specifically blocks the delta isoform of PI3K enzyme and its signaling pathway. Following promising data from Phase I trials, a Phase III study was conducted in which 220 previously treated patients with recurrent CLL, measurable lymphadenopathy and ineligible to receive chemotherapy due to comorbidities, were enrolled. Patients received first dose of RITUXAN® (Rituximab) at 375 mg/m2 and then 500 mg/m2 q2 weeks x 4, followed by RITUXAN® q4 wks x 3 for a total of 8 doses along with Idelalisib 150 mg PO BID continuously until disease progression (N=110) or along with placebo. The median age was 71 years and patients had received a median of three prior therapies. Poor prognosis patients included 44% with 17p deletion/p53 mutation and 84% who had unmutated immunoglobulin variable region heavy chain (IgVH) gene. Primary endpoint was progression-free survival (PFS). Following a recommendation by an Independent Data Monitoring Committee after an interim analysis that showed superiority of RITUXAN®/Idelalisib combination, this trial was stopped early. The PFS at 24 weeks was 93% for the RITUXAN® plus Idelalisib group compared to 46% for those treated with RITUXAN® and placebo. The median PFS for the RITUXAN®/Idelalisib combination group has not yet been reached, whereas the the median PFS for the RITUXAN®/placebo arm was 5.5 months (Hazard Ratio [HR] = 0.15; P < .0001). Further, the PFS was favorable in the poor prognosis patients with either a 17p deletion or p53 mutation, when Idelalisib was combined with RITUXAN® (HR = 0.12). An improvement in the Overall Survival (OS) was also noted in the Idelalisib group compared with patients in the RITUXAN® alone group (HR = 0.28; P = 0.018). The combination of Idelalisib and RITUXAN® had an overall response rate of 81% compared with 13% in the RITUXAN®alone group (P <0 .0001). Patients treated with a combination of Idelalisib and RITUXAN® also had a higher decrease in lymphadenopathy (93%) compared with 4% in the RITUXAN® alone group (P < 0.0001). The most common adverse events which included pyrexia, fatigue, nausea and chills were similar in both treatment groups. The authors concluded that Idelalisib plus RITUXAN® may be a new treatment option for patients with previously treated CLL, who are not eligible for chemotherapy, as well as those with unfavorable cytogenetics. Furman RR, Sharman JP, Coutre SE, et al. Blood 2013;122:LBA-6
American Society of Clinical Oncology 2013 Top Five List in Oncology
SUMMARY: The 2013 Top five list in Oncology was published to optimize the use of diagnostic and therapeutic modalities and enhance patient care, by following evidence-based guidelines, thereby providing cost-effective medical care.
1) Do not give patients starting a chemotherapy regimen that has a low or moderate risk of causing nausea or vomiting antiemetic drugs intended for use with a regimen that has a high risk of causing nausea or vomiting.
Highly emetogenic chemotherapy: The recommendations are a three drug combination of an NK1 receptor antagonist given on days 1-3 for oral Aprepitant (EMEND®) or IV EMEND® given on Day 1 only, a 5-HT3 receptor antagonist given on day 1 only and Dexamethasone (DECADRON®) given on days 1-3 or 4.
Moderately emetogenic chemotherapy: A two drug combination of Palonosetron (ALOXI®) given on day 1 only and DECADRON® given on days 1-3 is recommended. Even though ALOXI® is the preferred agent, a first-generation 5-HT3 serotonin receptor antagonist such as Granisetron (KYTRIL®) or Ondansetron (ZOFRAN®) may be substituted if it is not feasible to give ALOXI®.
Low emetogenic chemotherapy: A 5-HT3 serotonin receptor antagonist is recommended. Patients experiencing nausea and vomiting while on Radiation therapy may need prophylaxis with these agents throughout the course of their therapy.
2) Do not use combination chemotherapy (multiple drugs) instead of chemotherapy with one drug when treating an individual for metastatic breast cancer unless the patient needs a rapid response to relieve tumor-related symptoms.
Combination chemotherapy for metastatic Breast Cancer is only recommended when a patient has significant symptoms related to tumor burden and a rapid tumor response is needed for symptom palliation. Because combination chemotherapy can be associated with significant toxicity without improvement in overall survival (OS), it is recommended that single agent therapy given sequentially reduces the risk of toxicity besides allowing optimal drug delivery and could improve quality of life, without compromising OS. It should be noted however that in tumors overexpressing a specific biomarker such as HER 2, anti–HER 2 therapy in combination with cytotoxic chemotherapy can improve survival compared with chemotherapy alone. Patients with hormone receptor–positive tumors should receive sequential endocrine therapies before cytotoxic chemotherapy, in the absence of life threatening organ dysfunction. Combining cytotoxic chemotherapy with an anti-hormonal agent is not beneficial. Rapid symptom palliation using Radiation treatment, insertion of a stent, surgical intervention, etc., if more efficacious, has to be considered under appropriate circumstances, before initiating chemotherapy.
3) Avoid using positron emission tomography or positron emission tomography–computed tomography scanning as part of routine follow-up care to monitor for cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that such imaging will change the outcome.
Once staging and restaging is complete, routine surveillance using PET or PET-CT scanning for solid tumors and lymphomas remains unproven and is not recommended. This has been validated in multiple studies and has been endorsed by cancer organizations both in the U.S. and abroad.
4) Do not perform prostate-specific antigen testing for prostate cancer screening in men with no symptoms of the disease when they are expected to live fewer than 10 years.
Elevated levels of PSA can be associated with conditions other than Prostate Cancer such as Benign Prostate Hyperplasia. Even though men who undergo PSA testing are less likely to die specifically as a result of prostate cancer, when all cause mortality is taken into consideration, men undergoing PSA screening do not live any longer than those who do not undergo screening. If the life expectancy of an individual is less than 10 years based on medical conditions, PSA screening is unlikely to benefit this individual, as there is a greater probability of dying as a result of the underlying medical problems rather than asymptomatic prostate cancer. The US Preventive Services Task Force, American College of Physicians, American Urological Association, have all changed their recommendations in accordance to these findings.
5) Do not use a targeted therapy intended for use against a specific genetic aberration unless a patient’s tumor cells have a specific biomarker that predicts an effective response to the targeted therapy.
Targeted therapy is expensive and can be associated with toxicities, but can benefit patients significantly if their tumor cells demonstrate the specific gene alteration that makes the tumor cells susceptible to the targeted therapy. Usually, a specific biomarker is present in the tumor cells that may in turn predict effectiveness of the targeted therapy. Exceptions include high level evidence supporting the use of a targeted agent despite absence of the biomarker. It is recommended that targeted agents be used only as intended.
Schnipper LE, Lyman GH, Blayney DW, et al. J Clin Oncol 2013;31:4362-4370