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Asia-Pacific Journal of Clinical Oncology 2014; 10: 378–380
doi: 10.1111/ajco.12265
CASE REPORT
Bespoke treatment: Drivers beware! Sharon PATTISON1,3,4 and John R ZALCBERG2 1 Cancer Genetics and Genomics Laboratory, 2Division of Cancer Medicine and Department of Oncology, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, and 3Sir Peter MacCallum Department of Oncology and 4Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
Abstract Significant progress has been made in the identification of molecular targets and targeted therapy is becoming a realistic option for patients with tumors for which potential driver mutations are identified. We present a case that highlights that the identification of a potential driver mutation does not confirm it as a key mutational event in every case and emphasizes the need for ongoing research to enable therapy to be more accurately directed for the benefit of patients.
CASE REPORT In June 2012, a 55-year-old woman underwent a computed tomography scan because of a rash suggestive of a paraneoplastic syndrome. This revealed bulky retroperitoneal lymphadenopathy and liver metastases, with no other abnormalities; of note, no pancreatic lesions were seen. The initial liver biopsy was reported as metastatic poorly differentiated adenocarcinoma with extensive necrosis, without specific features indicative of the site of origin. Mammography, colonoscopy, upper gastrointestinal (GI) endoscopy and pelvic ultrasound were all within normal limits. 18F-fluorodeoxyglucose positron emission tomography (PET) scan did not reveal a primary lesion. Repeat biopsy was performed in an area thought to contain viable tissue on the PET scan. The pathology from this showed an “immunoprofile consistent with a tumor showing intestinal differentiation and therefore possible primary sites include upper GI tract, pancreas and biliary tree.” Eighteen immunohistochemical markers were checked and the tumor was sent for the Healthscope (www.healthscopepathology.com.au) “carcinoma of unknown primary assay” but unfortunately, without further differentiation of the primary site.
Correspondence: Dr Sharon Pattison, MBChB, Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1 A’Beckett Street, Melbourne, Vic. 8006, Australia. Email: [email protected] Conflict of interest: none Accepted for publication 13 July 2014.
© 2014 Wiley Publishing Asia Pty Ltd
Initial treatment commenced in July 2012 with gemcitabine and oxaliplatin. Six cycles were completed prior to documentation of progressive disease. After progression, an excision biopsy of an abdominal lymph node was performed at laparoscopy. Unfortunately, the histology of this specimen could not identify the primary tumor and the tumor was sent for testing by Foundation Medicine (www.foundationmedicine.com). FOLFIRI (5-fluorouracil, leucovorin and irinotecan) was commenced in November 2012 as second line treatment and after six cycles, progression in both hepatic and nodal disease was noted. The Foundation One results, returned in December 2012, reported a tumor type of “pancreas ductal carcinoma” (Fig. 1). Six genomic alterations were identified, including an FGFR3-TACC3 fusion and amplification. Recurring oncogenic mutations in FGFR3 have been identified in urothelial cell carcinoma, glioblastoma and squamous cell carcinoma of the lung.1,2 Preclinical data suggest that the FGFR3-TACC3 fusion gene is an oncogenic driver that can be effectively targeted, with mice harboring FGFR3-TACC3-initiated gliomas experiencing prolonged survival following the administration of an oral FGFR inhibitor.2 Pazopanib is a multitargeted tyrosine kinase inhibitor. It is known to inhibit FGFR3 in its target spectrum. In addition, there is phase I evidence of partial response to pazopanib in combination with chemotherapy in a patient with pancreatic adenocarcinoma.3 With this information suggesting the identification of a targetable driver mutation, the patient commenced pazopanib at a dose of 400 mg once daily
Bespoke treatment
Figure 1
379
Reproduction of Foundation One result summary page.
in January 2013. The drug was provided on a compassionate basis by Glaxo Smith Kline (www.gsk.com.au). Restaging after 2 months of treatment revealed marked progression of the disease with innumerable pulmonary metastases and new hepatic metastases. The patient unfortunately died from her cancer in May of 2013.
DISCUSSION We are entering a period in oncology where the use of custom-made or “bespoke” treatment is becoming a reality. There are examples where this has worked with remarkable efficacy, including the activity seen with the use of imatinib in c-kit mutated gastrointestinal stromal tumors.4 Numerous case series from single institutions
Asia-Pac J Clin Oncol 2014; 10: 378–380
suggest that when a potential driver mutation is found, and an agent that targets this driver is available, targeted treatment results in improved outcomes.5 Case reports of dramatic responses to targeted therapies abound in the literature. However, there are also examples where targeted therapy does not produce the expected result. These serve to remind us that identification of a potential driver mutation is not the evidence that it is a driver in each patient or each tumor. Variable responses to therapies targeting specific pathways identified as important in oncogenesis are not new. In the 1970s, targeting the estrogen receptor (ER) in breast cancer was shown to have a survival benefit in a proportion of patients who were ER positive.6 A more recent example of intertumoral variation in response to targeting a driver mutation is seen with vemurafenib in
© 2014 Wiley Publishing Asia Pty Ltd
380
BRAF V600E-mutated melanoma. Although dramatic initial responses are seen in the majority of patients, a small proportion of patients show primary resistance to this approach.7 Vemurafenib, targeting the BRAF V600E mutation, also demonstrates the variation in response when targeting the same “driver” mutation in different tissues. In colorectal cancer (CRC), preclinical and early clinical evidence showed a much more heterogeneous and far less impressive response in tumors carrying the same mutation when treated with vemurafenib.8 The experience with vemurafenib in melanoma also highlights that cancers are dynamic and respond to environmental selection pressures, including treatment, with the development of resistance and progression on treatment almost inevitable.7 Variation in response and resistance to targeted therapies highlights the complexity of the cancer genome. Most do not contain isolated molecular abnormalities, but significant genomic instability with disruption of signaling pathways and networks that accumulate over successive cell divisions, producing spatial and temporal intratumoral heterogeneity.9 It is therefore not unexpected that targeting one abnormality, found on one biopsy specimen from one time point, does not result in dramatic or continued responses in all cases. The need for detailed functional studies of specific mutations to distinguish true “drivers” from “passengers” that do not contribute to the growth of the tumor remains, as targeting passenger mutations will not likely benefit the patient at all. Tissue is central to understanding the variability in response seen in the clinic. Prospective collection of multiple biospecimens at multiple time points within trials is essential to enable retrospective investigations of potential predictive and prognostic markers. In some cases, the genetic abnormalities present in early stages of tumor evolution may still be relevant in advanced disease as demonstrated by the evaluation of KRAS mutations and response to epidermal growth factor receptor monoclonal antibodies in CRC.10 However, this is often not the case, with time and intratumoral heterogeneity interfering with accurate interpretation of the data. The translation of results from the laboratory bench, and even clinical trials, to routine practice often takes longer than many patients have. For patients with rare tumors, or rare molecular aberrations, evidence from traditional studies may never be available. Longitudinal cohort studies where clinical, pathological, molecular, treatment and outcome data are collected may be one method of generating evidence for some of
© 2014 Wiley Publishing Asia Pty Ltd
S Pattison and JR Zalcberg
these situations, provided the relevant molecular and clinical data can be catalogued and accessed. Significant progress has been made in technologies that identify potential targets, meaning that many more patients will be in the situation of the patient described earlier, where a targetable “driver” mutation is found, and the inclination will be to use this to guide treatment. At present, however, we lack the ability to distinguish an actual driver mutation from a potential one in the individual patient setting and we need to remain cognizant of this. Ongoing international, translational and multidisciplinary collaborative efforts are required to gain a better understanding of tumor heterogeneity, to enable selection of actual targets, not just potential targets, and as a result of carefully and rigorously conducted clinical studies, ultimately, allow the use of appropriate agents for the appropriate patients.
REFERENCES 1 Greulich H, Pollock PM. Targeting mutant fibroblast growth factor receptors in cancer. Trends Mol Med 2011; 17 (5): 283–92. 2 Singh D, Chan JM, Zoppoli P et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012; 337 (6099): 1231–5. 3 Burris HA 3rd, Dowlati A, Moss RA et al. Phase I study of pazopanib in combination with paclitaxel and carboplatin given every 21 days in patients with advanced solid tumors. Mol Cancer Ther 2012; 11 (8): 1820–8. 4 Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001; 344 (14): 1052–6. 5 Tsimberidou AM, Iskander NG, Hong DS et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res 2012; 18 (22): 6373–83. 6 Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med 1988; 109 (3): 219–28. 7 Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364 (26): 2507–16. 8 Kopetz S, Desai J, Chan E et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumours. J Clin Oncol 2010; 28 (15s): abstract 3534. 9 Gerlinger M, Rowan AJ, Horswell S et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366 (10): 883–92. 10 Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359 (17): 1757–65.
Asia-Pac J Clin Oncol 2014; 10: 378–380
Copyright of Asia Pacific Journal of Clinical Oncology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Asia-Pacific Journal of Clinical Oncology 2014; 10: 378–380
doi: 10.1111/ajco.12265
CASE REPORT
Bespoke treatment: Drivers beware! Sharon PATTISON1,3,4 and John R ZALCBERG2 1 Cancer Genetics and Genomics Laboratory, 2Division of Cancer Medicine and Department of Oncology, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, and 3Sir Peter MacCallum Department of Oncology and 4Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
Abstract Significant progress has been made in the identification of molecular targets and targeted therapy is becoming a realistic option for patients with tumors for which potential driver mutations are identified. We present a case that highlights that the identification of a potential driver mutation does not confirm it as a key mutational event in every case and emphasizes the need for ongoing research to enable therapy to be more accurately directed for the benefit of patients.
CASE REPORT In June 2012, a 55-year-old woman underwent a computed tomography scan because of a rash suggestive of a paraneoplastic syndrome. This revealed bulky retroperitoneal lymphadenopathy and liver metastases, with no other abnormalities; of note, no pancreatic lesions were seen. The initial liver biopsy was reported as metastatic poorly differentiated adenocarcinoma with extensive necrosis, without specific features indicative of the site of origin. Mammography, colonoscopy, upper gastrointestinal (GI) endoscopy and pelvic ultrasound were all within normal limits. 18F-fluorodeoxyglucose positron emission tomography (PET) scan did not reveal a primary lesion. Repeat biopsy was performed in an area thought to contain viable tissue on the PET scan. The pathology from this showed an “immunoprofile consistent with a tumor showing intestinal differentiation and therefore possible primary sites include upper GI tract, pancreas and biliary tree.” Eighteen immunohistochemical markers were checked and the tumor was sent for the Healthscope (www.healthscopepathology.com.au) “carcinoma of unknown primary assay” but unfortunately, without further differentiation of the primary site.
Correspondence: Dr Sharon Pattison, MBChB, Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1 A’Beckett Street, Melbourne, Vic. 8006, Australia. Email: [email protected] Conflict of interest: none Accepted for publication 13 July 2014.
© 2014 Wiley Publishing Asia Pty Ltd
Initial treatment commenced in July 2012 with gemcitabine and oxaliplatin. Six cycles were completed prior to documentation of progressive disease. After progression, an excision biopsy of an abdominal lymph node was performed at laparoscopy. Unfortunately, the histology of this specimen could not identify the primary tumor and the tumor was sent for testing by Foundation Medicine (www.foundationmedicine.com). FOLFIRI (5-fluorouracil, leucovorin and irinotecan) was commenced in November 2012 as second line treatment and after six cycles, progression in both hepatic and nodal disease was noted. The Foundation One results, returned in December 2012, reported a tumor type of “pancreas ductal carcinoma” (Fig. 1). Six genomic alterations were identified, including an FGFR3-TACC3 fusion and amplification. Recurring oncogenic mutations in FGFR3 have been identified in urothelial cell carcinoma, glioblastoma and squamous cell carcinoma of the lung.1,2 Preclinical data suggest that the FGFR3-TACC3 fusion gene is an oncogenic driver that can be effectively targeted, with mice harboring FGFR3-TACC3-initiated gliomas experiencing prolonged survival following the administration of an oral FGFR inhibitor.2 Pazopanib is a multitargeted tyrosine kinase inhibitor. It is known to inhibit FGFR3 in its target spectrum. In addition, there is phase I evidence of partial response to pazopanib in combination with chemotherapy in a patient with pancreatic adenocarcinoma.3 With this information suggesting the identification of a targetable driver mutation, the patient commenced pazopanib at a dose of 400 mg once daily
Bespoke treatment
Figure 1
379
Reproduction of Foundation One result summary page.
in January 2013. The drug was provided on a compassionate basis by Glaxo Smith Kline (www.gsk.com.au). Restaging after 2 months of treatment revealed marked progression of the disease with innumerable pulmonary metastases and new hepatic metastases. The patient unfortunately died from her cancer in May of 2013.
DISCUSSION We are entering a period in oncology where the use of custom-made or “bespoke” treatment is becoming a reality. There are examples where this has worked with remarkable efficacy, including the activity seen with the use of imatinib in c-kit mutated gastrointestinal stromal tumors.4 Numerous case series from single institutions
Asia-Pac J Clin Oncol 2014; 10: 378–380
suggest that when a potential driver mutation is found, and an agent that targets this driver is available, targeted treatment results in improved outcomes.5 Case reports of dramatic responses to targeted therapies abound in the literature. However, there are also examples where targeted therapy does not produce the expected result. These serve to remind us that identification of a potential driver mutation is not the evidence that it is a driver in each patient or each tumor. Variable responses to therapies targeting specific pathways identified as important in oncogenesis are not new. In the 1970s, targeting the estrogen receptor (ER) in breast cancer was shown to have a survival benefit in a proportion of patients who were ER positive.6 A more recent example of intertumoral variation in response to targeting a driver mutation is seen with vemurafenib in
© 2014 Wiley Publishing Asia Pty Ltd
380
BRAF V600E-mutated melanoma. Although dramatic initial responses are seen in the majority of patients, a small proportion of patients show primary resistance to this approach.7 Vemurafenib, targeting the BRAF V600E mutation, also demonstrates the variation in response when targeting the same “driver” mutation in different tissues. In colorectal cancer (CRC), preclinical and early clinical evidence showed a much more heterogeneous and far less impressive response in tumors carrying the same mutation when treated with vemurafenib.8 The experience with vemurafenib in melanoma also highlights that cancers are dynamic and respond to environmental selection pressures, including treatment, with the development of resistance and progression on treatment almost inevitable.7 Variation in response and resistance to targeted therapies highlights the complexity of the cancer genome. Most do not contain isolated molecular abnormalities, but significant genomic instability with disruption of signaling pathways and networks that accumulate over successive cell divisions, producing spatial and temporal intratumoral heterogeneity.9 It is therefore not unexpected that targeting one abnormality, found on one biopsy specimen from one time point, does not result in dramatic or continued responses in all cases. The need for detailed functional studies of specific mutations to distinguish true “drivers” from “passengers” that do not contribute to the growth of the tumor remains, as targeting passenger mutations will not likely benefit the patient at all. Tissue is central to understanding the variability in response seen in the clinic. Prospective collection of multiple biospecimens at multiple time points within trials is essential to enable retrospective investigations of potential predictive and prognostic markers. In some cases, the genetic abnormalities present in early stages of tumor evolution may still be relevant in advanced disease as demonstrated by the evaluation of KRAS mutations and response to epidermal growth factor receptor monoclonal antibodies in CRC.10 However, this is often not the case, with time and intratumoral heterogeneity interfering with accurate interpretation of the data. The translation of results from the laboratory bench, and even clinical trials, to routine practice often takes longer than many patients have. For patients with rare tumors, or rare molecular aberrations, evidence from traditional studies may never be available. Longitudinal cohort studies where clinical, pathological, molecular, treatment and outcome data are collected may be one method of generating evidence for some of
© 2014 Wiley Publishing Asia Pty Ltd
S Pattison and JR Zalcberg
these situations, provided the relevant molecular and clinical data can be catalogued and accessed. Significant progress has been made in technologies that identify potential targets, meaning that many more patients will be in the situation of the patient described earlier, where a targetable “driver” mutation is found, and the inclination will be to use this to guide treatment. At present, however, we lack the ability to distinguish an actual driver mutation from a potential one in the individual patient setting and we need to remain cognizant of this. Ongoing international, translational and multidisciplinary collaborative efforts are required to gain a better understanding of tumor heterogeneity, to enable selection of actual targets, not just potential targets, and as a result of carefully and rigorously conducted clinical studies, ultimately, allow the use of appropriate agents for the appropriate patients.
REFERENCES 1 Greulich H, Pollock PM. Targeting mutant fibroblast growth factor receptors in cancer. Trends Mol Med 2011; 17 (5): 283–92. 2 Singh D, Chan JM, Zoppoli P et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012; 337 (6099): 1231–5. 3 Burris HA 3rd, Dowlati A, Moss RA et al. Phase I study of pazopanib in combination with paclitaxel and carboplatin given every 21 days in patients with advanced solid tumors. Mol Cancer Ther 2012; 11 (8): 1820–8. 4 Joensuu H, Roberts PJ, Sarlomo-Rikala M et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001; 344 (14): 1052–6. 5 Tsimberidou AM, Iskander NG, Hong DS et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res 2012; 18 (22): 6373–83. 6 Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med 1988; 109 (3): 219–28. 7 Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364 (26): 2507–16. 8 Kopetz S, Desai J, Chan E et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumours. J Clin Oncol 2010; 28 (15s): abstract 3534. 9 Gerlinger M, Rowan AJ, Horswell S et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366 (10): 883–92. 10 Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359 (17): 1757–65.
Asia-Pac J Clin Oncol 2014; 10: 378–380
Copyright of Asia Pacific Journal of Clinical Oncology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
