EGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR-activating alterations relatively insensitive to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). ...However, recent early clinical data suggests these patients may benefit from newer-generation EGFR-TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co-occurring genomic alterations (GAs) present in NSCLC.
Hybrid capture-based CGP was performed prospectively on 14,483 clinically annotated consecutive NSCLC specimens to a mean coverage depth of greater than 650X for 236 or 315 cancer-related genes.
Of 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins, representing 12% (263 of 2251) of cases with EGFR mutations. Sixty-four unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%). EGFR amplification occurred in 22% (57 of 263). The most common co-occurring GAs effected tumor protein p53 (TP53) (56%), cyclin dependent kinase inhibitor 2A (CDKN2A) (22%), cyclin dependent kinase inhibitor 2B (CDKN2B) (16%), NK2 homeobox 1 (NKX2-1) (14%) and RB transcriptional corepressor 1 (RB1) (11%); co-occurring GAs in other known lung cancer drivers were rare (5%). Average tumor mutational burden was low (mean 4.3, range 0 to 40.3 mutations/Mb). Clinical outcomes to first- and second-generation EGFR TKIs were obtained for five patients and none responded.
In the largest series of EGFRex20ins NSCLC, diverse EGFRex20ins were detected in 12% of EGFR-mutant NSCLC, a higher frequency than previously reported in smaller single-institution studies. Clinical outcomes showed lack of response to EGFR TKIs. Tumor mutational burden was low, consistent with non–smoking associated NSCLC. Comprehensive sequencing revealed increased proportion and wide variety of EGFRex20ins, representing a population of patients significant enough for focused efforts on effective interventions.
Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered ...because of limited and inconsistent molecular characterization.
Hybrid capture–based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA.
The median age of the patients with PSC was 67 years (range 32–87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease.
Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.
Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site ...alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.
Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.
Purpose
Aromatase inhibitors are the most commonly prescribed adjuvant endocrine therapy for hormone-dependent early breast cancer in postmenopausal women. Among Canadian Cancer Trials Group MA.27 ...participants, anastrozole and exemestane had comparable 5-year event-free survival. This companion study examined differences in patient-reported treatment-related symptoms (TRS) and health-related quality of life (HRQL) among postmenopausal women randomized to anastrozole or exemestane.
Methods
MA.27 participants (
N
= 686, of 7576) randomized to 5 years of anastrozole (1 mg/day,
n
= 371, Arm A) or exemestane (25 mg/day,
n
= 315, Arm E) completed the 56-item Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire to assess TRS and HRQL. The FACT-ES was completed at baseline, 3, 6, 12, and 24 months.
Results
No significant differences in FACT-ES median scores measuring TRS and HRQL were observed between treatment arms at any time point. Change in TRS from baseline was statistically significant at 3, 6, 12, and 24 months. HRQL was stable over time in both arms. Greater TRS burden was associated with poorer HRQL (coefficient = 0.57,
p
< 0.001). Twenty percent of patients discontinued AI therapy by month 24 and 32% discontinued AIs at 4 years. In both arms, patients reporting more side effect bother prior to initiating study treatment had a higher risk of discontinuing treatment before completing protocol therapy (hazard ratio HR 1.29, 95% CI 1.08–1.55,
p
= 0.01).
Conclusions
TRS and HRQL were comparable between anastrozole and exemestane. TRS negatively affect HRQL. Women who report being bothered by treatment side effects prior to initiating an AI are at increased risk for early treatment discontinuation.
Type B lactic acidosis is an uncommon medical emergency in which acid production overwhelms hepatic clearance. This specific etiology of lactic acidosis occurs without organ hypoperfusion and has ...been most commonly described in patients with hematologic malignancies but also in patients with solid tumors. The mechanism by which cancer cells switch their glucose metabolism toward increasingly anaerobic glycolytic phenotypes has been described as the “Warburg effect.” Without treating the underlying malignancy, the prognosis for patients diagnosed with malignancy-related type B lactic acidosis is extremely poor. Here, we present a case of a 66-year-old male who was diagnosed with type B lactic acidosis secondary to mantle cell lymphoma. Bicarbonate drip was started to correct the lactic acidosis. The patient was also immediately treated with rituximab chemotherapy combined with rasburicase to avoid the hyperuricemia associated with tumor lysis syndrome. He responded to the early treatment and was discharged with normal renal function. Type B lactic acidosis secondary to hematologic malignancy is important to recognize. In order to successfully treat this syndrome, early diagnosis and simultaneous treatment of the imbalance of lactic acid levels and the underlying malignancy are necessary.
Background.
Patients with advanced hepatocellular (HCC) and biliary tract carcinomas (BTC) have poor prognosis. While the EGFR pathway is overactive in HCC and BTC, single agent anti‐EGFR therapies ...confer modest activity. Preclinical data showed synergistic antiproliferative and proapoptotic effects between anti‐EGFR therapies and taxanes. We conducted a phase I study of erlotinib and docetaxel in solid tumors, and noted good tolerability and sustained complete (5 years +) and partial responses in patients with HCC and BTC. This trial evaluated the efficacy of erlotinib with docetaxel in refractory hepatobiliary cancers.
Methods.
Eligible patients were allowed to have two prior systemic therapies. Docetaxel 30 mg/m2 i.v. was administered on days 1, 8, 15, and erlotinib 150 mg was dosed orally on days 2–7, 9–14, 16–28 of each 28‐day cycle. The primary endpoint was 16 weeks progression‐free survival (PFS), and secondary endpoints included response, stable disease, and overall survival. Tumor samples were analyzed for KRAS gene mutations and E‐cadherin expression by immunohistochemistry (IHC). Patients with BTC and HCC were accrued and assessed in separate strata for the efficacy endpoints, but for the two‐stage initial design of the study, combined PFS was considered. A Simon optimal two‐stage design tested the hypothesis that the 16‐week PFS is ≤ 15% (clinically inactive) versus the alternative of ≥ 30% (warranting further study).
Results.
Twenty‐five patients, 14 with HCC and 11 with BTC, were enrolled. Common toxicities were rash (76%), diarrhea (56%), and fatigue (52%), mostly grade 1 or 2. No objective responses were seen. Seven BTC (64%) and 6 HCC patients (46%) had stable disease as best response, with a median duration of 16.1 weeks (95% CI 3.7–56.3) for BTC, and 17.6 weeks (95% CI 8.1–49.8) for HCC. The 16‐week PFS was 64% for BTC (95% CI 29.7–84.5), and 38% for HCC (95% CI 14.1–62.8). Median overall survival was 5.7 and 6.7 months for BTC and HCC patients, respectively. BTC patients with grade ≥ 2 rash had higher median PFS (6.2 vs 2.2 months) and OS (14.2 vs 4.2 months). HCC patients with negative/low E‐cadherin expression had higher median PFS (6.7 vs 2.1 months) and OS (14.5 vs 4 months).
Conclusion.
Erlotinib with docetaxel met the 16‐week PFS ≥ 30% endpoint,but overall survival was comparable to that seen with single‐agent erlotinib. With the limitation of small numbers of patients, grade ≥ 2 rash (in BTC), and negative/low E‐cadherin expression (HCC) were associated with higher PFS and OS.
摘要
目的 晚期肝细胞癌（HCC）和胆管癌（BTC）患者的预后不佳。虽然HCC和BTC中EGFR通路过度活化，但单药抗EGFR疗法的活性仅为中度。临床前数据显示，抗EGFR疗法与紫杉烷类药物存在协同抗增殖和促凋亡效应。作者开展过厄罗替尼和多西他赛治疗实体瘤的I期研究，发现HCC和BTC患者耐受良好、能维持完全（5年+）和部分缓解。本试验评估厄罗替尼联合多西他赛治疗难治性肝胆癌症的疗效。
方法 符合条件的患者之前可接受两种全身疗法。第1、8、15天给予多西他赛30 mg/m2 i.v.，第2~7、9~14、16~28天口服厄罗替尼150 mg，每28天为一个周期。主要终点为16周无进展生存（PFS），次要终点包括缓解、疾病稳定和总生存。采用免疫组化法（IHC）分析肿瘤样本的KRAS基因突变和E‐钙粘蛋白表达。BTC和HCC患者分层募集、评估有效性终点，但本研究最初为两阶段设计，因此PFS合并考虑。采用Simon最优两阶段设计检验16周PFS≤15%（无临床活性）的假设vs. 备择假设≥30%（值得进一步研究）。
结果 25例患者入选，14例为HCC，11例为BTC。常见毒性有皮疹（76%）、腹泻（56%）和疲乏（52%），大多为1级或2级。未见客观缓解。7例BTC（64%）和6例HCC患者（46%）的最佳反应为疾病稳定，BTC患者的中位持续时间为16.1周（95% CI，3.7~56.3周），HCC患者为17.6周（8.1~49.8周）。BTC和HCC患者的16周PFS分别为64%（95% CI，29.7~84.5）和38%（95% CI，14.1~62.8）。BTC和HCC患者的中位总生存期分别为5.7和6.7个月。伴有≥2级皮疹的BTC患者的中位PFS（6.2 vs. 2.2个月）和OS（14.2 vs. 4.2个月）较长。E‐钙粘蛋白阴性/低表达的HCC患者的中位PFS（6.7 vs. 2.1个月）和OS（14.5 vs. 4个月）较长。
结论 厄罗替尼联合多西他赛达到16周PFS≥30%的终点，但总生存期与单药厄罗替尼相当。本研究的局限性在于病例数少，≥2级皮疹（BTC）和E‐钙粘蛋白阴性/低表达（HCC）者PFS和OS较长。
讨论 难治性胆管癌和肝细胞癌难以治疗，化疗或生物靶向疗法均无法改善生存。基于临床前协同效应和先前I期研究的数据，作者开展了本项EGFR靶向药物厄罗替尼联合多西他赛序贯治疗的多中心研究。
is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that
(KL) or
(KP) comutations define distinct subgroups of
-mutant LUAC. Here, we examine the efficacy of ...PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (
< 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with
-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%;
= 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (
< 0.001) and overall (
= 0.0015) survival compared with
;
LUAC. Among 924 LUACs,
alterations were the only marker significantly associated with PD-L1 negativity in TMB
LUAC. The impact of
alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1-positive non-small cell lung cancer. In
-mutant murine LUAC models,
loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify
alterations as a major driver of primary resistance to PD-1 blockade in
-mutant LUAC.
This work identifies
alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in
-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets.
.
To examine studies of normal colon and colorectal cancer for evidence that the location of the primary tumor proximal or distal to the splenic flexure of the colon may determine distinct genetic ...categories of this disease.
Studies were identified through a manual search of journals, through MEDLINE, and through review of bibliographies in identified articles.
Approximately 300 articles were examined. About 150 articles were excluded because tumor location was not reported or was reported in a way that did not permit correlation with results or conclusions.
Articles were selected either because the presentation of data permitted correlation of results with anatomic regions of the colon or because they were relevant to inherited colorectal cancer. RESULTS OF THE ANALYSIS: Differences were noted in biologic properties of proximal and distal segments of normal fetal and adult colonic epithelium and in the epidemiologic, pathologic, cytogenetic, and molecular features of proximal and distal colorectal cancer. Some differences correlated with the features of inherited colorectal cancer (proximal, nonpolyposis or distal, and polyposis forms).
Developmental and biologic differences in proximal and distal colon may reflect differing susceptibilities to neoplastic transformation. Differences in proximal and distal colorectal cancer suggest that each may arise through different pathogenetic mechanisms. Proximal tumors appear to represent a genetically more stable form of the disease and may arise through the same mechanisms that underlie inherited nonpolyposis colon cancer. Distal tumors show evidence of greater genetic instability and may develop through the same mechanisms that underlie polyposis-associated colorectal cancer syndromes.
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