Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed outcomes for some malignancies. 1 Tumor complexity and heterogeneity suggest that the “precision medicine” paradigm of cancer therapy requires treatment to be personalized to the individual patient. 2 – 6 To date, precision oncology trials have been based upon molecular matching with predetermined monotherapies. 7 – 14 Several of these trials have been hindered by very low matching rates, often in the 5–10% range, 15 and low response rates. Low matching rates may be due to the use of limited gene panels, restrictive molecular matching algorithms, lack of drug availability or the deterioration and death of end-stage patients before therapy can be implemented. We hypothesized that personalized treatment with combination therapies would improve outcomes in patients with refractory malignancies. As a first test of this concept, we implemented a cross-institutional, prospective study (I-PREDICT, ) that used tumor DNA sequencing and timely recommendations for individualized treatment with combination therapies. We found that administration of customized multi-drug regimens was feasible, with 49% of consented patients receiving personalized treatment. Targeting of a larger fraction of identified molecular alterations, yielding a higher “matching score,” was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, as compared to when fewer somatic alterations were targeted. Our findings suggest that the current clinical trial paradigm for precision oncology, which pairs one driver mutation with one drug, may be optimized by treating molecularly complex and heterogeneous cancers with combinations of customized agents.
A B S T R A C T PurposeThe impact of a personalized cancer treatment strategy (ie, matching patients with drugs based on specific biomarkers) is still a matter of debate. MethodsWe reviewed phase II single-agent studies (570 studies; 32,149 patients) published between January 1, 2010, and December 31, 2012 (PubMed search). Response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared for arms that used a personalized strategy versus those that did not. ResultsMultivariable analysis (both weighted multiple linear regression and random effects metaregression) demonstrated that the personalized approach, compared with a nonpersonalized approach, consistently and independently correlated with higher median RR (31% v 10.5%, respectively; P Ͻ .001) and prolonged median PFS (5.9 v 2.7 months, respectively; P Ͻ .001) and OS (13.7 v 8.9 months, respectively; P Ͻ .001). Nonpersonalized targeted arms had poorer outcomes compared with either personalized targeted therapy or cytotoxics, with median RR of 4%, 30%, and 11.9%, respectively; median PFS of 2.6, 6.9, and 3.3 months, respectively (all P Ͻ .001); and median OS of 8.7, 15.9, and 9.4 months, respectively (all P Ͻ .05). Personalized arms using a genomic biomarker had higher median RR and prolonged median PFS and OS (all P Յ .05) compared with personalized arms using a protein biomarker. A personalized strategy was associated with a lower treatment-related death rate than a nonpersonalized strategy (median, 1.5% v 2.3%, respectively; P Ͻ .001). ConclusionComprehensive analysis of phase II, single-agent arms revealed that, across malignancies, a personalized strategy was an independent predictor of better outcomes and fewer toxic deaths. In addition, nonpersonalized targeted therapies were associated with significantly poorer outcomes than cytotoxic agents, which in turn were worse than personalized targeted therapy.
Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/− amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies.Electronic supplementary materialThe online version of this article (doi:10.1007/s10555-015-9552-6) contains supplementary material, which is available to authorized users.
In this meta-analysis, most phase 1 trials of targeted agents did not use a biomarker-based selection strategy. However, use of a biomarker-based approach was associated with significantly improved outcomes (RR and PFS). Response rates were significantly higher with genomic vs protein biomarkers. Studies that used targeted agents without a biomarker had negligible response rates.
Objective. DNA sequencing tests are enabling physicians to interrogate the molecular profiles of patients' tumors, but most oncologists have not been trained in advanced genomics. We initiated a molecular tumor board to provide expert multidisciplinary input for these patients. Materials and Methods. A team that included clinicians, basic scientists, geneticists, and bioinformatics/pathway scientists with expertise in various cancer types attended. Molecular tests were performed in a Clinical Laboratory Improvement Amendments environment. Results. Patients (n 5 34, since December 2012) had received a median of three prior therapies. The median time from physician order to receipt of molecular diagnostic test results was 27 days (range: 14-77 days). Patients had a median of 4 molecular abnormalities (range: 1-14 abnormalities) found by next-generation sequencing (182-or 236-gene panels).Seventy-four genes were involved, with 123 distinct abnormalities. Importantly, no two patients had the same aberrations, and 107 distinct abnormalities were seen only once. Among the 11 evaluable patients whose treatment had been informed by molecular diagnostics, 3 achieved partial responses (progression-free survival of 3.4 months, $6.5 months, and 7.6 months).The most common reasons for being unable to act on the molecular diagnostic results were that patients were ineligible for or could not travel to an appropriately targeted clinical trial and/or that insurance would not cover the cognate agents. Conclusion. Genomic sequencing is revealing complex molecular profiles that differ by patient. Multidisciplinary molecular tumor boards may help optimize management. Barriers to personalized therapy include access to appropriately targeted drugs. The Oncologist 2014;19:631-636Implications for Practice: Our study relates our experience with the initiation of molecular tumor board meetings, which are a new vehicle for managing patients with complex malignancies on whom molecular diagnostics have been performed. This experience could be of significant importance to oncologists who are increasingly faced with advanced molecular diagnostic data, yet have minimal training in genomics. Our article should help clinicians to handle practical issues related to setting up and efficiently utilizing molecular tumor board meetings. We also aim at helping oncologists and health care systems understand and address practical, logistical, and scientific issues, such as the challenges associated with interpretation of molecular testing for patients with advanced cancer. INTRODUCTIONTechnological developments in genomic sequencing are advancing at a breathtaking rate. These tests are rapidly being made available in the clinic, potentially facilitating a personalized treatment strategy [1][2][3][4]. The collaboration between biologists who interpret and confirm the functional relevance of molecular abnormalities and clinicians who assess relationships to cancer prognosis and response to therapy has led to the discovery of the activity of molecu...
By profiling their patients' tumors, oncologists now have the option to use molecular results to match patients with drug(s) based on specific biomarkers. In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated. Outcomes for patients who received a "matched" versus "unmatched" therapy following their NGS results were compared. Eighty-seven patients (25%) were treated with a "matched" therapy, 93 (26.8%) with an "unmatched" therapy. More patients in the matched group achieved stable disease (SD) ! 6 months/partial response (PR)/complete response (CR), 34.5% vs. 16.1%, (P 0.020 multivariable or propensity score methods). Matched patients had a longer median progression-free survival (PFS; 4.0 vs. 3.0 months, P ¼ 0.039 in the Cox regression model). In analysis using PFS1 (PFS on the prior line of therapy) as a comparator to PFS after NGS, as expected, the unmatched group demonstrated a PFS2 significantly shorter than PFS1 (P ¼ 0.009); however, this shortening was not observed in the matched patients (P ¼ 0.595). Furthermore, 45.3% of the matched patients (24/53) had a PFS2/ PFS1 ratio !1.3 compared with 19.3% of patients (11/57) in the unmatched group (P ¼ 0.004 univariable and P ! 0.057 in multivariable/propensity score analysis). Patients with a "matching-score" (the number of matched drugs divided by the number of aberrations; unmatched patients had a score of zero) > 0.2 had a median overall survival (OS) of 15.7 months compared with 10.6 months when their matching-score was 0.2, (P ¼ 0.040 in the Cox regression model). Matched versus unmatched patients had higher rates of SD ! 6 months/PR/CR and longer PFS, and improvement in OS correlated with a higher matching score in multivariable analysis. Mol Cancer Ther; 15(4); 743-52. Ó2016 AACR.
Purpose: There is a growing interest in using circulating tumor DNA (ctDNA) testing in patients with cancer. Experimental Design: A total of 168 patients with diverse cancers were analyzed. Patients had digital next-generation sequencing (54 cancer-related gene panel including amplifications in ERBB2, EGFR, and MET) performed on their plasma. Type of genomic alterations, potential actionability, concordance with tissue testing, and patient outcome were examined. Results: Fifty-eight percent of patients (98/168) had ≥1 ctDNA alteration(s). Of the 98 patients with alterations, 71.4% had ≥ 1 alteration potentially actionable by an FDA-approved drug. The median time interval between the tissue biopsy and the blood draw was 2.7 months for patients with ≥ 1 alteration in common compared with 14.4 months (P = 0.006) for the patients in whom no common alterations were identified in the tissue and plasma. Overall concordance rates for tissue and ctDNA were 70.3% for TP53 and EGFR, 88.1% for PIK3CA, and 93.1% for ERBB2 alterations. There was a significant correlation between the cases with ≥ 1 alteration with ctDNA ≥ 5% and shorter survival (median = 4.03 months vs. not reached at median follow-up of 6.1 months; P < 0.001). Finally, 5 of the 12 evaluable patients (42%) matched to a treatment targeting an alteration(s) detected in their ctDNA test achieved stable disease ≥ 6 months/partial remission compared with 2 of 28 patients (7.1%) for the unmatched patients, P = 0.02. Conclusions: Our initial study demonstrates that ctDNA tests provide information complementary to that in tissue biopsies and may be useful in determining prognosis and treatment. Clin Cancer Res; 22(22); 5497–505. ©2016 AACR.
Background Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes. Methods and Findings Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications. Seventy-two patients (82%) had ≥ 1 ctDNA alteration(s); amongst these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in TP53 (44.3% of patients), EGFR (27.3%), MET (14.8%), KRAS (13.6%), and ALK (6.8%) genes. The concordance rate for EGFR alterations was 80.8% (100% versus 61.5% (≤ 1 versus > 1 month between tests; P = 0.04)) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥ 1 ctDNA alteration(s); 72.3% (N=16/22) of the evaluable matched patients achieved stable disease ≥ 6 months (SD) or partial response (PR). Five patients with ctDNA-detected EGFR T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥ 1 alteration with ≥ 5% variant allele fraction (versus < 5%) had a significantly shorter median survival (P = 0.012). Conclusions ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies.
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