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Microdissected tumors from patients with lung adenocarcinoma (LADC) showed considerable heterogeneity, and in two patients both ALK fusions and EGFR mutations coexisted, researchers reported.
The study used laser-capture microdissection to isolate spatially separated tumor-cell subpopulations according to adenocarcinoma subtypes. In 20 ALK-positive patients analyzed, nine patients had tumors that harbored cells with both ALK fusions and ALK wild-type. In 20 EGFR mutated tumors analyzed, intratumoral heterogeneity was observed in five, both between different adenocarcinoma subtypes and within the same adenocarcinoma subtype (J Clin Oncol. 2015 Sep 28. doi:10.1200/jco.2014.58.8293).
“Importantly, our findings may provide a rationale for differently treating patients with LADC that harbors dual drivers. It seems reasonable to treat patients who do harbor dual drivers with two different targeted inhibitors if the oncogenic drivers of tumor cells within the same primary tumor are not all the same,” wrote Dr. Weijing Cai of Shanghai (China) Pulmonary Hospital, Tongji University, and colleagues.
The ALK fusions did not coexist with the EGFR mutations in all of the tumor cells. Researchers observed that different tumor regions had one, both, or neither mutation. In cells that had neither mutation, search for a possible third oncogene using a capture-based targeted DNA sequencing panel did not uncover another oncogenic mutation.
From 2004 to 2010, 629 patients with lung adenocarcinoma underwent surgical resection at Shanghai Pulmonary Hospital: 364 were positive for EGFR mutations and 30 for ALK fusions. In 20 ALK-positive tumors evaluated, 2 concurrently harbored ALK fusions and EGFR mutations, for a 0.3% incidence rate. Only 18.4% (116 of 629) of patients showed a single mutation pattern.
Although previous research found that intratumoral heterogeneity of EGFR mutations coincided with histologic subtypes in LADC, the current study showed that intratumoral heterogeneity exists in the same histologic subtype. Dr. Cai and associates speculated that clone evolution, not only histologic heterogeneity, may be responsible for molecular intratumoral heterogeneity.
Statistical analysis of 408 patients showed that ALK fusions were significantly more common in LADC with mucin production (P less than .001), they reported.
LADC shows high intratumoral and histologic heterogeneity, but the results of this study show that the correlation between the two has little significance for clinical diagnosis and treatment.
Dr. Cai reported having no disclosures. Several coauthors reported ties to industry sources.
In recent years it has become apparent that intratumoral heterogeneity is an inherent property of many types of cancer, including lung adenocarcinoma (LADC). Although previous studies have shown coexistence of ALK fusions with EGFR mutations in patients with LADC, Dr. Cai and associates have taken these observations further: In two patients with both ALK fusions and EGFR mutations, they examined four separate areas within one tumor. In different tumor regions, one, both, or neither mutation was present. In tumor regions with evidence of both mutations present, they found the relative abundance of ALK fusions and EGFR mutations differed, suggesting that at least some cancer cells did not harbor both mutations. It appears ALK fusions and EGFR mutations may not coexist in the same cancer cell population and may be later branched events in the evolution of the tumor. The specific EGFR mutations observed were inconsistent as well, either R832H or L858R.
If EGFR mutation–positive subclones within ALK-rearranged tumors cause relapse in a subset of patients, these patients may be candidates for subsequent treatment with anti-EGFR therapies. These findings support a role for repeated tumor analysis during the evolution of disease in patients who progress after ALK inhibitor therapy despite a prior EGFR-negative biopsy. Recognition of the limits of diagnostic assays and the influence that a minority of cells harboring oncogenic drivers may have on disease is important to advance precision medicine.
This study highlights the importance of evolutionary precision medicine in LADC and the need for genomic evaluations throughout the disease course. Advances in cell-free DNA detection may circumvent problems of tumor sampling and enable us to monitor evolving subclonal driver events in the tumor and in metastatic lesions so that therapy can be adapted accordingly.
Dr. Nicolai Juul Birkbak is a principal research associate at University College London. Dr. Crispin T. Hiley is a research fellow at University College London. Dr. Charles Swanton is a senior clinical research fellow and group leader of the translational cancer therapeutics laboratory at the London Research Institute and consultant medical oncologist at the Royal Marsden Hospital. These remarks were part of an editorial accompanying the report (J Clin Oncol. 2015 Sep 28. doi: 10.1200/jco.2014.58.8293). Dr. Birkbak disclosed stock or other ownership in Onxeo and royalties from Myriad Genetics. Dr. Hiley reported stock or other ownership in Bristol-Myers Squibb. Dr. Swanton reported stock or other ownership in Epic Sciences and Apogen Biotechnologies and honoraria or research funding from Roche, Boehringer Ingelheim, Novartis, and GlaxoSmithKline.
In recent years it has become apparent that intratumoral heterogeneity is an inherent property of many types of cancer, including lung adenocarcinoma (LADC). Although previous studies have shown coexistence of ALK fusions with EGFR mutations in patients with LADC, Dr. Cai and associates have taken these observations further: In two patients with both ALK fusions and EGFR mutations, they examined four separate areas within one tumor. In different tumor regions, one, both, or neither mutation was present. In tumor regions with evidence of both mutations present, they found the relative abundance of ALK fusions and EGFR mutations differed, suggesting that at least some cancer cells did not harbor both mutations. It appears ALK fusions and EGFR mutations may not coexist in the same cancer cell population and may be later branched events in the evolution of the tumor. The specific EGFR mutations observed were inconsistent as well, either R832H or L858R.
If EGFR mutation–positive subclones within ALK-rearranged tumors cause relapse in a subset of patients, these patients may be candidates for subsequent treatment with anti-EGFR therapies. These findings support a role for repeated tumor analysis during the evolution of disease in patients who progress after ALK inhibitor therapy despite a prior EGFR-negative biopsy. Recognition of the limits of diagnostic assays and the influence that a minority of cells harboring oncogenic drivers may have on disease is important to advance precision medicine.
This study highlights the importance of evolutionary precision medicine in LADC and the need for genomic evaluations throughout the disease course. Advances in cell-free DNA detection may circumvent problems of tumor sampling and enable us to monitor evolving subclonal driver events in the tumor and in metastatic lesions so that therapy can be adapted accordingly.
Dr. Nicolai Juul Birkbak is a principal research associate at University College London. Dr. Crispin T. Hiley is a research fellow at University College London. Dr. Charles Swanton is a senior clinical research fellow and group leader of the translational cancer therapeutics laboratory at the London Research Institute and consultant medical oncologist at the Royal Marsden Hospital. These remarks were part of an editorial accompanying the report (J Clin Oncol. 2015 Sep 28. doi: 10.1200/jco.2014.58.8293). Dr. Birkbak disclosed stock or other ownership in Onxeo and royalties from Myriad Genetics. Dr. Hiley reported stock or other ownership in Bristol-Myers Squibb. Dr. Swanton reported stock or other ownership in Epic Sciences and Apogen Biotechnologies and honoraria or research funding from Roche, Boehringer Ingelheim, Novartis, and GlaxoSmithKline.
In recent years it has become apparent that intratumoral heterogeneity is an inherent property of many types of cancer, including lung adenocarcinoma (LADC). Although previous studies have shown coexistence of ALK fusions with EGFR mutations in patients with LADC, Dr. Cai and associates have taken these observations further: In two patients with both ALK fusions and EGFR mutations, they examined four separate areas within one tumor. In different tumor regions, one, both, or neither mutation was present. In tumor regions with evidence of both mutations present, they found the relative abundance of ALK fusions and EGFR mutations differed, suggesting that at least some cancer cells did not harbor both mutations. It appears ALK fusions and EGFR mutations may not coexist in the same cancer cell population and may be later branched events in the evolution of the tumor. The specific EGFR mutations observed were inconsistent as well, either R832H or L858R.
If EGFR mutation–positive subclones within ALK-rearranged tumors cause relapse in a subset of patients, these patients may be candidates for subsequent treatment with anti-EGFR therapies. These findings support a role for repeated tumor analysis during the evolution of disease in patients who progress after ALK inhibitor therapy despite a prior EGFR-negative biopsy. Recognition of the limits of diagnostic assays and the influence that a minority of cells harboring oncogenic drivers may have on disease is important to advance precision medicine.
This study highlights the importance of evolutionary precision medicine in LADC and the need for genomic evaluations throughout the disease course. Advances in cell-free DNA detection may circumvent problems of tumor sampling and enable us to monitor evolving subclonal driver events in the tumor and in metastatic lesions so that therapy can be adapted accordingly.
Dr. Nicolai Juul Birkbak is a principal research associate at University College London. Dr. Crispin T. Hiley is a research fellow at University College London. Dr. Charles Swanton is a senior clinical research fellow and group leader of the translational cancer therapeutics laboratory at the London Research Institute and consultant medical oncologist at the Royal Marsden Hospital. These remarks were part of an editorial accompanying the report (J Clin Oncol. 2015 Sep 28. doi: 10.1200/jco.2014.58.8293). Dr. Birkbak disclosed stock or other ownership in Onxeo and royalties from Myriad Genetics. Dr. Hiley reported stock or other ownership in Bristol-Myers Squibb. Dr. Swanton reported stock or other ownership in Epic Sciences and Apogen Biotechnologies and honoraria or research funding from Roche, Boehringer Ingelheim, Novartis, and GlaxoSmithKline.
Microdissected tumors from patients with lung adenocarcinoma (LADC) showed considerable heterogeneity, and in two patients both ALK fusions and EGFR mutations coexisted, researchers reported.
The study used laser-capture microdissection to isolate spatially separated tumor-cell subpopulations according to adenocarcinoma subtypes. In 20 ALK-positive patients analyzed, nine patients had tumors that harbored cells with both ALK fusions and ALK wild-type. In 20 EGFR mutated tumors analyzed, intratumoral heterogeneity was observed in five, both between different adenocarcinoma subtypes and within the same adenocarcinoma subtype (J Clin Oncol. 2015 Sep 28. doi:10.1200/jco.2014.58.8293).
“Importantly, our findings may provide a rationale for differently treating patients with LADC that harbors dual drivers. It seems reasonable to treat patients who do harbor dual drivers with two different targeted inhibitors if the oncogenic drivers of tumor cells within the same primary tumor are not all the same,” wrote Dr. Weijing Cai of Shanghai (China) Pulmonary Hospital, Tongji University, and colleagues.
The ALK fusions did not coexist with the EGFR mutations in all of the tumor cells. Researchers observed that different tumor regions had one, both, or neither mutation. In cells that had neither mutation, search for a possible third oncogene using a capture-based targeted DNA sequencing panel did not uncover another oncogenic mutation.
From 2004 to 2010, 629 patients with lung adenocarcinoma underwent surgical resection at Shanghai Pulmonary Hospital: 364 were positive for EGFR mutations and 30 for ALK fusions. In 20 ALK-positive tumors evaluated, 2 concurrently harbored ALK fusions and EGFR mutations, for a 0.3% incidence rate. Only 18.4% (116 of 629) of patients showed a single mutation pattern.
Although previous research found that intratumoral heterogeneity of EGFR mutations coincided with histologic subtypes in LADC, the current study showed that intratumoral heterogeneity exists in the same histologic subtype. Dr. Cai and associates speculated that clone evolution, not only histologic heterogeneity, may be responsible for molecular intratumoral heterogeneity.
Statistical analysis of 408 patients showed that ALK fusions were significantly more common in LADC with mucin production (P less than .001), they reported.
LADC shows high intratumoral and histologic heterogeneity, but the results of this study show that the correlation between the two has little significance for clinical diagnosis and treatment.
Dr. Cai reported having no disclosures. Several coauthors reported ties to industry sources.
Microdissected tumors from patients with lung adenocarcinoma (LADC) showed considerable heterogeneity, and in two patients both ALK fusions and EGFR mutations coexisted, researchers reported.
The study used laser-capture microdissection to isolate spatially separated tumor-cell subpopulations according to adenocarcinoma subtypes. In 20 ALK-positive patients analyzed, nine patients had tumors that harbored cells with both ALK fusions and ALK wild-type. In 20 EGFR mutated tumors analyzed, intratumoral heterogeneity was observed in five, both between different adenocarcinoma subtypes and within the same adenocarcinoma subtype (J Clin Oncol. 2015 Sep 28. doi:10.1200/jco.2014.58.8293).
“Importantly, our findings may provide a rationale for differently treating patients with LADC that harbors dual drivers. It seems reasonable to treat patients who do harbor dual drivers with two different targeted inhibitors if the oncogenic drivers of tumor cells within the same primary tumor are not all the same,” wrote Dr. Weijing Cai of Shanghai (China) Pulmonary Hospital, Tongji University, and colleagues.
The ALK fusions did not coexist with the EGFR mutations in all of the tumor cells. Researchers observed that different tumor regions had one, both, or neither mutation. In cells that had neither mutation, search for a possible third oncogene using a capture-based targeted DNA sequencing panel did not uncover another oncogenic mutation.
From 2004 to 2010, 629 patients with lung adenocarcinoma underwent surgical resection at Shanghai Pulmonary Hospital: 364 were positive for EGFR mutations and 30 for ALK fusions. In 20 ALK-positive tumors evaluated, 2 concurrently harbored ALK fusions and EGFR mutations, for a 0.3% incidence rate. Only 18.4% (116 of 629) of patients showed a single mutation pattern.
Although previous research found that intratumoral heterogeneity of EGFR mutations coincided with histologic subtypes in LADC, the current study showed that intratumoral heterogeneity exists in the same histologic subtype. Dr. Cai and associates speculated that clone evolution, not only histologic heterogeneity, may be responsible for molecular intratumoral heterogeneity.
Statistical analysis of 408 patients showed that ALK fusions were significantly more common in LADC with mucin production (P less than .001), they reported.
LADC shows high intratumoral and histologic heterogeneity, but the results of this study show that the correlation between the two has little significance for clinical diagnosis and treatment.
Dr. Cai reported having no disclosures. Several coauthors reported ties to industry sources.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Tumor cells within the same primary tumor were found to harbor both ALK fusions and EGFR driver mutations.
Major finding: In 20 patients with ALK-positive tumors, 2 concurrently harbored ALK fusions and EGFR mutations, for a 0.3% incidence rate.
Data source: From 2004 to 2010, 629 patients with lung adenocarcinoma underwent surgical resection in Shanghai, China: 364 were positive for EGFR mutations and 30 for ALK fusions.
Disclosures: Dr. Cai reported having no disclosures. Several coauthors reported ties to industry sources.
