Author: RR

FDA Approves AXUMIN® to Identify Prostate Cancer Recurrence in Patients with Rising PSA

RR

SUMMARY: The FDA on May 27, 2016 approved AXUMIN® (Fluciclovine F18), a novel molecular radiopharmaceutical diagnostic agent, for Positron Emission Tomography (PET) imaging in men with suspected prostate cancer recurrence, based on elevated Prostate Specific Antigen (PSA) levels, following prior treatment. Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease.

The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse.

Rising PSA is therefore a sign of recurrent disease and identifying the site of recurrence can be of immense value for the clinician and can help determine the best course of therapy. The diagnostic accuracy of standard imaging tests, for the identification of sites of recurrence in patients with biochemical recurrence, is low. Almost 90% of the standard imaging tests such as CT/MRI and Bone Scan may be negative. More accurate non-invasive imaging techniques for the detection of recurrent tumor is an unmet need. Prostascint, a Single Photon Emission Computerized Tomography (SPECT) radiopharmaceutical agent, was approved in 1999 for the diagnostic imaging of post-prostatectomy patients with a rising PSA. PET scans have largely superseded this study. FluDeoxyGlucose F18 (FDG), a glucose analogue is the most widely used PET radiotracer, but is not generally used as an imaging agent in prostate cancer. This is because good and reliable quality images are not feasible due to indolent growth of prostate cancers and the high urinary excretion of FDG. The other PET radiotracer that is available, Choline C11, has been shown to improve cancer detection in men with biochemical recurrent prostate cancer, but this agent has a short half life of 20 minutes, requires greater patient preparation including 6 hours of fasting prior to administration of Choline C11, delivers higher radiation dose to patients and image quality is poor.

AXUMIN® (Fluciclovine), a diagnostic radiopharmaceutical, is a synthetic amino acid that is preferentially transported into prostate cancer cells by amino acid transporters such as LAT-1 and ASCT2, which are upregulated in prostate cancer cells. This agent is neither metabolized nor incorporated into newly synthesized proteins. The visualization of the increased amino acid transport is facilitated by labeling AXUMIN® with F18 for PET imaging. The FDA approval of AXUMIN® was based on two retrospective trials (Trial 1 and Trial 2) which evaluated the safety and efficacy of AXUMIN® for imaging prostate cancer, in patients with recurrent disease. Trial 1 compared 105 (N=105) AXUMIN® scans in men with suspected prostate cancer, to the histopathology (study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. PET/CT imaging generally included both abdomen and pelvic regions. Local radiologist read the scans initially and subsequently, three independent radiologists read the same scans in a blinded study. Trial 2 evaluated the concordance between 96 (N=96) AXUMIN® and Choline C11 scans, in patients with median PSA values of 1.44 ng/mL. Local radiologist read the Choline C11 scans, and the same three independent radiologists from Trial 1 read the scans, in this second blinded study.

The FDA reported that results of the independent scan readings were generally consistent and confirmed the local scan reading results, and both studies supported the safety and efficacy of AXUMIN® for imaging prostate cancer in men with elevated PSA levels, following prior treatment. It should be noted that a negative study does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended. The most commonly reported adverse events in patients were injection site pain, redness and a metallic taste in the mouth.

It was concluded that AXUMIN® can determine the location of the recurrent prostate cancer in patients with low PSA levels. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208054Orig1s000TOC.cfm

ASCO Guidelines on Use of Biomarkers in Early Stage Breast Cancer – Part II

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 therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. Developed by an expert panel based on systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies and prospective comparative observational studies published from 2006 through 2014, these recommendations are meant to provide guidance to the Health Care Provider, as appropriate treatment is considered for patients with newly diagnosed, early-stage invasive breast cancer.

Two important questions were addressed by these guidelines – The Part I edition last week (www.oncoprescribe.com) addressed the first clinical question. This week’s edition (Part II) addresses the second clinical question.

Clinical Question 2: For women with early-stage invasive breast cancer and with known estrogen receptor/progesterone receptor and HER2 status, which additional biomarkers have demonstrated clinical utility to guide the choice of specific drugs or regimens for adjuvant systemic therapy?

Tamoxifen

CYP2D6 polymorphisms should not be used to guide adjuvant endocrine therapy selection. The expression of p27 by IHC should not be used to guide adjuvant endocrine therapy selection.

Aromatase Inhibitors

Protein encoded by the MKI67 gene labeling index by IHC should not be used to guide adjuvant endocrine therapy.

Taxanes

Microtubule-associated protein Tau mRNA expression or mRNA expression by IHC should not be used to guide adjuvant chemotherapy selection. HER1/Epidermal Growth Factor Receptor expression by IHC should not be used to guide adjuvant chemotherapy selection.

Anthracyclines

TOP2A gene amplification or TOP2A protein expression by IHC should not be used to guide adjuvant chemotherapy selection. HER2 and TOP2A gene coamplification, CEP17 duplication, TIMP-1, FOXP3, or p53 should not be used to guide adjuvant chemotherapy selection.

Trastuzumab

If a patient has HER2 positive breast cancer, PTEN should not be used to guide adjuvant therapy selection. If a patient has HER2 positive breast cancer, soluble HER2 levels should not be used to guide the selection of the type of adjuvant therapy.

Harris LN, Ismaila N, McShane LM, et al: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016;34:1134-1150.

KEYTRUDA® (Pembrolizumab)

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The FDA on December 18, 2015 expanded the label to include the approval of KEYTRUDA® injection for the treatment of patients with unresectable or metastatic Melanoma. This expansion now includes the initial treatment of patients with unresectable or metastatic Melanoma with KEYTRUDA®. KEYTRUDA® is a product of Merck Sharp & Dohme Corp.

ALECENSA® (Alectinib)

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The FDA granted accelerated approval to ALECENSA® capsules for the treatment of patients with Anaplastic Lymphoma Kinase (ALK)-positive metastatic Non-Small Cell Lung Cancer (NSCLC), who have progressed on or are intolerant to Crizotinib. ALECENSA® is a product of Hoffmann-La Roche Inc.

VISTOGARD® (Uridine Triacetate)

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The FDA on December 11, 2015 granted approval to VISTOGARD® granules for the emergency treatment of adult and pediatric patients following a Fluorouracil or Capecitabine overdose, regardless of the presence of symptoms, or who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia), within 96 hours following the end of Fluorouracil or Capecitabine administration. VISTOGARD® is a product of Wellstat Therapeutics Corporation.

EMPLICITI® (Elotuzumab)

RR

The FDA on November 30, 2015 approved EMPLICITI® in combination with Lenalidomide and Dexamethasone for the treatment of patients with Multiple Myeloma who have received one to three prior therapies. EMPLICITI® is a product of Bristol-Myers Squibb Company.

Interim PET Scan may Define Prognosis and Provide Treatment Guidance for Patients with Advanced Hodgkin Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in the United States for 2016, about 8500 new cases of Hodgkin lymphoma will be diagnosed and over 1100 patients will die of the disease. Hodgkin lymphoma is classified into two main groups – Classical Hodgkin lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

Advanced-stage (stage III to stage IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD regimen). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax. The second most often used regimen in the first-line setting, e-BEACOPP (escalated doses of Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone) has been associated with a higher Progression Free Survival as well as higher 5-year Overall Survival (approximately 90%). This regimen however is associated with short and long term toxicities such as prolonged fatigue, permanent fertility, Myelodysplasia and secondary malignancies.

A retrospective study by Gallamini and co-workers in 2007 had shown that a PET scan after two cycles of ABVD chemotherapy was an independent prognostic factor, with a 2-year Progression Free Survival rate of 95%, for those patients with negative interim PET scan, compared to only 12.8% for those with persistently positive PET scan. Based on these observations, the authors in this prospective trial evaluated the benefit of a “response-adapted” approach, by performing a PET scan following 2 cycles of ABVD treatment and modifying therapy based on the interim PET scan findings.

In this randomized controlled trial, 1203 eligible patients with newly diagnosed advanced Classical Hodgkin lymphoma were registered. The median age was 33 years. Following 2 cycles of chemotherapy with ABVD regimen, 1119 patients had an interim PET-CT scan and patients with negative PET findings (83.7%) were randomly assigned in a 1:1 ratio to continue ABVD regimen (ABVD group) or receive ABVD omitting Bleomycin (AVD group), for cycles 3 through 6. Radiotherapy was not recommended for patients with negative findings on interim PET scans. Patients with positive interim PET scan findings following two cycles of ABVD (16%), received 4-6 cycles of BEACOPP regimen. The primary outcome was the difference in the 3-year Progression Free Survival rate between randomized groups.

With a median follow up of 41 months, the 3-year Progression Free Survival was 85.7% with ABVD and 84.4% with AVD and 3 year Overall Survival was 97.2% and 97.6% in these two respective groups. Pulmonary toxicities were more severe in the ABVD group than in the AVD group and deleting Bleomycin following 2 cycles of ABVD, in patients with negative interim PET scan, did not compromise outcomes. Patients who received BEACOPP regimen based on a positive interim PET scan after the first 2 cycles of ABVD (N=172), had a 3-year Progression Free Survival of 67.5% and Overall Survival rate of 87.8%.

The authors concluded that following 2 cycles of ABVD regimen, omitting Bleomycin from the ABVD regimen, based on a negative interim PET scan (response-adapted therapy), resulted in lower incidence of pulmonary toxicities, compared with continued treatment with ABVD, without compromising efficacy. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. Johnson P, Federico M, Kirkwood A, et al. N Engl J Med 2016; 374:2419-2429

ASCO Guidelines on Use of Biomarkers in Early Stage Breast Cancer Part 1

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 therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. A multitude of biomarker assays are presently available for the practicing Health Care Provider. Choosing the appropriate biomarker assay for a given patient can be a daunting task and the ASCO guidelines set forth herein, were developed by an expert panel based on systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies, published from 2006 through 2014. These guidelines are only applicable for patients with newly diagnosed, non-metastatic, primary breast cancer, to prognosticate and predict outcomes but they do not however comment on the choice of specific treatment or regimens based on recurrence score. Treatment decisions should take into consideration disease stage, comorbidities and patient preferences. Even though several tests are now recommended in the guidelines, only one test should be used to guide therapy for an individual patient.

Two important questions were addressed by these guidelines – This edition (Part 1) addresses the first Clinical Question

Clinical Question 1: For women with early-stage invasive breast cancer and with known Estrogen receptor/Progesterone receptor and HER2 status, which other biomarkers have demonstrated clinical utility to guide decisions on the need for adjuvant systemic therapy?

Oncotype DX

If a patient has ER/PR positive, HER2 negative, node negative breast cancer, the Oncotype DX 21-gene recurrence score may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node positive disease. It should not be used in patients with HER2 positive or triple negative disease.

PAM50 Risk of Recurrence Score

If a patient has ER/PR positive, HER2 negative, node-negative breast cancer, the PAM50 Risk of Recurrence score may be used in conjunction with other clinicopathologic variables to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node-positive disease. It should not be used in patients with HER2 positive breast cancer and those with triple-negative breast cancer to guide decisions on adjuvant systemic therapy.

EndoPredict

If a patient has ER/PR positive, HER2 negative, node-negative breast cancer, EndoPredict 12-gene risk score may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node-positive disease. It should not be used in patients with HER2 positive or triple-negative disease.

Breast Cancer Index

If a patient has ER/PR positive, HER2 negative, node-negative breast cancer, the Breast Cancer Index may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node-positive disease. It should not be used in patients with HER2 positive or triple negative breast cancer to guide decisions on adjuvant systemic therapy.

Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor Type 1

If a patient has ER/PR positive, HER2 negative, node negative breast cancer, Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with HER2 positive or triple negative breast cancer.

MammaPrint

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, the MammaPrint 70-gene assay should not be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with HER2 positive disease. It should not be used in patients with triple negative breast cancer.

Mammostrat

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, the Mammostrat 5-protein assay should not be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with HER2 positive or triple negative breast cancer.

Immunohistochemistry 4

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, Immunohistochemistry 4 (IHC4) should not be used to guide decisions on adjuvant systemic chemotherapy. It should not be used in patients with HER2 positive or triple negative breast cancer.

Circulating Tumor Cells

The clinician should not use circulating tumor cells to guide decisions on adjuvant systemic therapy.

Tumor-Infiltrating Lymphocytes

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, Tumor-Infiltrating Lymphocytes should not be used for decision making. It should not be used in patients with HER2 positive or triple negative breast cancer.

Protein Encoded by MKI67 Gene

Protein encoded by the MKI67 gene labeling index by IHC should not be used to guide choice on adjuvant chemotherapy.

Extended Endocrine Therapy

If a patient has ER/PR positive, HER2 negative (node-negative) breast cancer and has had 5 years of endocrine therapy without evidence of recurrence, multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, or IHC4) should not be used to guide decisions on extended endocrine therapy.

The Clinical Question 2 will be addressed in the eNL edition (Part 2) next week.

Harris LN, Ismaila N, McShane LM, et al: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016;34:1134-1150.

Late Breaking Abstract – ASCO 2016 Liquid Biopsy Can Rapidly Detect Certain Gene Mutations with High Specificity

RR

Late Breaking Abstract – ASCO 2016: Liquid Biopsy Can Rapidly Detect Certain Gene Mutations with High Specificity

SUMMARY: The FDA approved the first “Liquid Biopsy” test on June 1, 2016 for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the Epidermal Growth Factor Receptor (EGFR) gene. On the heels of this approval, Zill and colleagues reported the results of the largest liquid biopsy study ever conducted thus far. 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, also called liquid biopsy, 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 authors in this study utilized Next Generation Sequencing (NGS) of circulating tumor DNA (ctDNA), isolated from plasma specimens (liquid biopsy specimens) of 15,191 patients of whom 37% had advanced lung cancer, 14% had breast cancer, 10% had colorectal cancer and 39% had other malignancies. Seventy genes were targeted and accuracy of ctDNA sequencing was assessed by comparing with matched tissue tests for 386 patients and frequencies of somatic ctDNA alterations per gene were compared to those previously described in tissue sequencing projects such as data from The Cancer Genome Atlas (TCGA).

It was noted that the ctDNA mutation patterns were highly concordant with tissue analysis as reported by the TCGA. The overall accuracy of ctDNA sequencing in comparison with matched tissue tests was 87% and the accuracy increased to 98% when blood and tumor were collected less than six months apart. Pearson Correlation between sets of data is a measure of how well these sets are related. Between 0.5 and 1.0 is considered high correlation. Pearson correlation for TP53 gene was 0.94, for KRAS was 0.99 and for PIK3CA was 0.99.

The researchers commented on the clinical outcome benefits using liquid biopsy, in four distinct groups:

1) Testing for actionable mutations (ALK fusion, EGFR or BRAF activating mutations in lung; ERBB2 amplification in gastric cancer) in cases with insufficient tissue quantity.

2) Testing for actionable resistance mutations (MET amplification or EGFR T790M in lung cancer), at the time of progression.

3) Genomic evolution upon progression such as ERBB2-amplified metastatic breast cancer in patients with triple negative primary tumor.

4) Tumors with genotypes that need more extensive driver mutation testing such as BRAF V600E in lung.

The authors concluded that there is a high correlation between ctDNA plasma samples and tissue testing with the exception of resistance mutations such as EGFR T790M mutation which evolve while on anti-EGFR inhibitor therapy and consequently may not correlate with the TCGA, probably because patients in the tissue-based population had not yet received the anti-EGFR inhibitor therapy that promotes the mutation. Patients who received treatment based on ctDNA findings also experienced better clinical outcomes. Zill OA, Mortimer S, Banks KC, et al Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA. J Clin Oncol. 2016;34(suppl; abstr LBA11501).

YONDELIS® – A Marine-Derived Drug for Soft Tissue Sarcomas

RR

SUMMARY: The FDA approved the first “Liquid Biopsy” test on June 1, 2016 for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the Epidermal Growth Factor Receptor (EGFR) gene. On the heels of this approval, Zill and colleagues reported the results of the largest liquid biopsy study ever conducted thus far. 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, also called liquid biopsy, 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 authors in this study utilized Next Generation Sequencing (NGS) of circulating tumor DNA (ctDNA), isolated from plasma specimens (liquid biopsy specimens) of 15,191 patients of whom 37% had advanced lung cancer, 14% had breast cancer, 10% had colorectal cancer and 39% had other malignancies. Seventy genes were targeted and accuracy of ctDNA sequencing was assessed by comparing with matched tissue tests for 386 patients and frequencies of somatic ctDNA alterations per gene were compared to those previously described in tissue sequencing projects such as data from The Cancer Genome Atlas (TCGA).

It was noted that the ctDNA mutation patterns were highly concordant with tissue analysis as reported by the TCGA. The overall accuracy of ctDNA sequencing in comparison with matched tissue tests was 87% and the accuracy increased to 98% when blood and tumor were collected less than six months apart. Pearson Correlation between sets of data is a measure of how well these sets are related. Between 0.5 and 1.0 is considered high correlation. Pearson correlation for TP53 gene was 0.94, for KRAS was 0.99 and for PIK3CA was 0.99.

The researchers commented on the clinical outcome benefits using liquid biopsy, in four distinct groups:

1) Testing for actionable mutations (ALK fusion, EGFR or BRAF activating mutations in lung; ERBB2 amplification in gastric cancer) in cases with insufficient tissue quantity.

2) Testing for actionable resistance mutations (MET amplification or EGFR T790M in lung cancer), at the time of progression.

3) Genomic evolution upon progression such as ERBB2-amplified metastatic breast cancer in patients with triple negative primary tumor.

4) Tumors with genotypes that need more extensive driver mutation testing such as BRAF V600E in lung.

The authors concluded that there is a high correlation between ctDNA plasma samples and tissue testing with the exception of resistance mutations such as EGFR T790M mutation which evolve while on anti-EGFR inhibitor therapy and consequently may not correlate with the TCGA, probably because patients in the tissue-based population had not yet received the anti-EGFR inhibitor therapy that promotes the mutation. Patients who received treatment based on ctDNA findings also experienced better clinical outcomes. Zill OA, Mortimer S, Banks KC, et al Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA. J Clin Oncol. 2016;34(suppl; abstr LBA11501).