- Email: [email protected]
Fantastic voyage: the future of cancer diagnostics
Comment
Fantastic voyage: the future of cancer diagnostics
GIPhotoStock/Corbis
The dominant paradigm in oncology for the past few years has been the application of precision medicine, whereby treatment is adapted to the individual genetic variations of a cancer. As such targeted therapies evolve and are joined by immunological treatments, initial therapeutic approaches are identified on the basis of molecular markers of the tumour. Potent cancer therapies might then lead to dramatic tumour shrinkage, but also to the acquisition of new genetic features resulting in drug resistance and cancer recurrence. The selection of further treatment options must reflect the change in tumour composition induced by the initial therapy. In fact, cancer diagnostics and therapeutics have become so closely intertwined that an advance in one defines an opportunity in the other. In non-small-cell lung cancer, the development of EGFR tyrosine kinase inhibitors (TKIs) preceded the identification of EGFR mutations that dictate sensitivity to this class of drugs. Once EGFR TKIs became standard therapy for EGFR-mutant lung cancer, the process of discovery reversed, and identification of the treatmentacquired EGFR mutation Thr790Met prompted the development of mutant-selective inhibitors capable of overcoming this resistance mechanism.1,2 The future of EGFR-mutant lung cancer is likely to involve close monitoring of the genetic and epigenetic status of the tumour, and occasionally profound alterations in tumour histopathology, followed by modification of treatment regimens to reflect these changes, and ongoing resampling of tumour markers during the
Panel: The future of cancer diagnostics • Diagnostic and therapeutic advances will undergo co-evolution in the era of personalised oncology • Tumour heterogeneity represents a substantial diagnostic and therapeutic challenge that will need to be overcome for the successful application of precision treatment • Non-invasive or minimally invasive diagnostic methods will prove particularly useful for detailed, longitudinal molecular characterisation of tumours, enabling effective sequential therapies • Advances in assay specificity and improvements in technical sensitivity will eventually permit highly individualised early cancer detection
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entire course of therapy. A similar approach is emerging in ALK-mutant lung cancer, leukaemia harbouring the BCR-ABL1 fusion, gastrointestinal stromal tumours with KIT mutations, BRAF-mutant melanoma, and oestrogen receptor α-mutant breast cancer. A high mutation burden might also predict clinical benefit from immune checkpoint inhibitors,3 laying a foundation for the development of more robust predictive markers in immuno-oncology that might mature into an analogous diagnostic perspective. Tumour monitoring, however, is no simple task. Multiregion sequencing efforts have revealed an extraordinary degree of heterogeneity among cancer cells within individual tumour masses and across different metastatic lesions within an individual patient.4 This heterogeneity only increases as cancers initially respond and then become resistant to sequential therapeutic regimens, which presents a diagnostic challenge in that biopsy of a single tumour lesion might not fully represent the entire cancer. Even within a single biopsy sample, averaging mutations that are present in aggregate among all the cells might not reveal underlying subclonal diversity. From a therapeutic standpoint, tumour heterogeneity can serve as a wellspring of acquired resistance whereby subclones that are no longer suppressed by a small-molecule inhibitor or that no longer express an immunological marker emerge. On the other hand, as we gain understanding of the various susceptibilities of different tumour subclones, their proliferative competition with each other might actually be exploited. For instance, withdrawing a targeted inhibitor might remove the selective advantage favouring proliferation of drug-resistant clones, ultimately leading to the reemergence of drug-sensitive cell populations that are susceptible to a second round of targeted therapy. To become a reality, such alternating treatment regimens aimed at managing cancer as a chronic disease will require real-time monitoring of clonal heterogeneity within tumour cell populations. Non-invasive or minimally invasive methods will prove essential for serially profiling the evolution of tumour heterogeneity over the course of treatment, while limiting the diagnostic burden on patients. Molecular imaging offers the potential to assess the entire tumour at once while visualising the activity of specific molecules, www.thelancet.com/oncology Vol 16 December 2015
Comment
which can enable particularly rapid, individualised assessment of treatment response. A PET-imaging method to measure intratumoral changes in androgen receptor (AR) signalling with a radiolabelled antibody to prostate-specific membrane antigen (PSMA) might quantitatively measure the response of individual lesions to AR inhibition in castrate-resistant prostate cancer.5 Molecular imaging could also transform our ability to assess the tumour microenvironment. New techniques to specifically label myeloid cells6 might allow clinicians to appraise the accumulation of an inflammatory response, possibly serving as a biomarker for immunomodulatory drugs. Further clinical development of these imaging strategies is eagerly anticipated. Blood-based analyses, including circulating tumour cells, circulating tumour DNA (ctDNA), and tumourderived extracellular vesicles, have shown particular promise and seem poised for integration into clinical practice in the near future. Studies of tumour cell-based markers present within a standard blood specimen offer both ease of application and the likely advantage of sampling all sites of disease, instead of being restricted to a single tumour lesion accessible for biopsy. Rapid progress in technologies for isolation of circulating tumour cells and in molecular analyses of ctDNA is likely to make such approaches the dominant methods for real-time tumour monitoring. As these techniques continue to improve in sensitivity, they might find increasing use in early stages of cancer. Already, in earlystage breast cancer, ctDNA detection might predict recurrence many months before clinical evidence of relapse,7 raising the prospect of the earlier application of appropriately targeted therapy before heavy tumour burdens, associated with high degrees of cellular heterogeneity, preclude long lasting response. How far can we go in diagnosing early invasive cancer with these novel diagnostic methods? We and others have identified the presence of circulating tumour cells in the blood of a subset of patients with localised prostate cancer, which became undetectable after resection of the primary tumour.8 None of these patients went on to develop recurrent metastatic prostate cancer, consistent with the notion that early invasive cancers can shed cells into the bloodstream long before any of these cells become competent to initiate a metastatic lesion. Sequencing of peripheral blood cells has shown an increasing frequency of telltale genetic lesions www.thelancet.com/oncology Vol 16 December 2015
associated with increasing age, potentially representing a harbinger of incipient malignant leukaemic clones.9 More recently, emerging data suggest that detection of the proteoglycan molecule, GPC1, bound to extracellular vesicles could detect precancerous pancreas lesions.10 Tumour-derived genetic material contained in extracellular vesicles can also be sequenced and might enable molecular profiling of clinically occult tumours. Although extraordinarily promising, the idea that bloodbased signatures of cancer might enable detection of early malignancy faces substantial hurdles. To be clinically useful, blood-based assays must be highly sensitive in detecting true signals derived from malignant cells in the blood, along with some indication of their likely tissue of origin. On the other hand, these blood-based signatures must not be overly sensitive in identifying rare genetic abnormalities from errant cells destined to die or from precancerous cells unlikely to produce an invasive tumour within a patient’s lifetime. Nonetheless, we believe these challenges are ultimately solvable through improved understanding of cancer biology and genetics and rapidly advancing molecular diagnostic capabilities. By offering the possibility of removing a localised invasive cancer and administering potentially individualised therapy before a large and heterogeneous tumour burden limits their curative potential, such early screening stands to be a transformative strategy that would alter the landscape of cancer treatment. We have described only part of the new world of cancer diagnostics that is emerging as a result of deeper molecular insights into cancer biology, powerful bioengineering and nucleotide sequencing platforms, and the realisation that new and increasingly effective therapies induce dramatic changes in tumour composition that warrant close and repeated monitoring to keep cancer in check. Additional discoveries, ranging from advances in computational medicine to monitoring of the microbiome, are also poised to alter the diagnostic landscape. It is our hope that in the future, invasive cancers will be identified early, with personalised diagnostics that improve the chance of curative treatment. In cases in which cancers are discovered at a later stage, detailed longitudinal molecular characterisation will allow sequential treatment strategies that improve our chance of turning cancer into a chronic disease. We believe this is a reality that is within reach and that will greatly reduce the worldwide burden of cancer. 1597
Comment
Tilak K Sundaresan, *Daniel A Haber Massachusetts General Hospital Cancer Center, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02129, USA [email protected] DAH reports grants from Janssen Diagnostics, outside the submitted work, and holds patents issued for EGFR genotyping and for CTC isolation technologies. TKS declares no competing interests. 1 2 3 4
1598
Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015; 372: 1700–09. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015; 372: 1689–99. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. The N Engl J Med 2015; 372: 2509–20. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883–92.
5
6 7
8
9 10
Evans MJ, Smith-Jones PM, Wongvipat J, et al. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci USA 2011; 108: 9578–82. Rashidian M, Keliher EJ, Bilate AM, et al. Noninvasive imaging of immune responses. Proc Natl Acad Sci USA 2015; 112: 6146–51. Garcia-Murillas I, Schiavon G, Weigelt B, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 2015; 7: 302ra133. Stott SL, Lee RJ, Nagrath S, et al. Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med 2010; 2: 25ra3. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371: 2488–98. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523: 177–82.
www.thelancet.com/oncology Vol 16 December 2015
Fantastic voyage: the future of cancer diagnostics
GIPhotoStock/Corbis
The dominant paradigm in oncology for the past few years has been the application of precision medicine, whereby treatment is adapted to the individual genetic variations of a cancer. As such targeted therapies evolve and are joined by immunological treatments, initial therapeutic approaches are identified on the basis of molecular markers of the tumour. Potent cancer therapies might then lead to dramatic tumour shrinkage, but also to the acquisition of new genetic features resulting in drug resistance and cancer recurrence. The selection of further treatment options must reflect the change in tumour composition induced by the initial therapy. In fact, cancer diagnostics and therapeutics have become so closely intertwined that an advance in one defines an opportunity in the other. In non-small-cell lung cancer, the development of EGFR tyrosine kinase inhibitors (TKIs) preceded the identification of EGFR mutations that dictate sensitivity to this class of drugs. Once EGFR TKIs became standard therapy for EGFR-mutant lung cancer, the process of discovery reversed, and identification of the treatmentacquired EGFR mutation Thr790Met prompted the development of mutant-selective inhibitors capable of overcoming this resistance mechanism.1,2 The future of EGFR-mutant lung cancer is likely to involve close monitoring of the genetic and epigenetic status of the tumour, and occasionally profound alterations in tumour histopathology, followed by modification of treatment regimens to reflect these changes, and ongoing resampling of tumour markers during the
Panel: The future of cancer diagnostics • Diagnostic and therapeutic advances will undergo co-evolution in the era of personalised oncology • Tumour heterogeneity represents a substantial diagnostic and therapeutic challenge that will need to be overcome for the successful application of precision treatment • Non-invasive or minimally invasive diagnostic methods will prove particularly useful for detailed, longitudinal molecular characterisation of tumours, enabling effective sequential therapies • Advances in assay specificity and improvements in technical sensitivity will eventually permit highly individualised early cancer detection
1596
entire course of therapy. A similar approach is emerging in ALK-mutant lung cancer, leukaemia harbouring the BCR-ABL1 fusion, gastrointestinal stromal tumours with KIT mutations, BRAF-mutant melanoma, and oestrogen receptor α-mutant breast cancer. A high mutation burden might also predict clinical benefit from immune checkpoint inhibitors,3 laying a foundation for the development of more robust predictive markers in immuno-oncology that might mature into an analogous diagnostic perspective. Tumour monitoring, however, is no simple task. Multiregion sequencing efforts have revealed an extraordinary degree of heterogeneity among cancer cells within individual tumour masses and across different metastatic lesions within an individual patient.4 This heterogeneity only increases as cancers initially respond and then become resistant to sequential therapeutic regimens, which presents a diagnostic challenge in that biopsy of a single tumour lesion might not fully represent the entire cancer. Even within a single biopsy sample, averaging mutations that are present in aggregate among all the cells might not reveal underlying subclonal diversity. From a therapeutic standpoint, tumour heterogeneity can serve as a wellspring of acquired resistance whereby subclones that are no longer suppressed by a small-molecule inhibitor or that no longer express an immunological marker emerge. On the other hand, as we gain understanding of the various susceptibilities of different tumour subclones, their proliferative competition with each other might actually be exploited. For instance, withdrawing a targeted inhibitor might remove the selective advantage favouring proliferation of drug-resistant clones, ultimately leading to the reemergence of drug-sensitive cell populations that are susceptible to a second round of targeted therapy. To become a reality, such alternating treatment regimens aimed at managing cancer as a chronic disease will require real-time monitoring of clonal heterogeneity within tumour cell populations. Non-invasive or minimally invasive methods will prove essential for serially profiling the evolution of tumour heterogeneity over the course of treatment, while limiting the diagnostic burden on patients. Molecular imaging offers the potential to assess the entire tumour at once while visualising the activity of specific molecules, www.thelancet.com/oncology Vol 16 December 2015
Comment
which can enable particularly rapid, individualised assessment of treatment response. A PET-imaging method to measure intratumoral changes in androgen receptor (AR) signalling with a radiolabelled antibody to prostate-specific membrane antigen (PSMA) might quantitatively measure the response of individual lesions to AR inhibition in castrate-resistant prostate cancer.5 Molecular imaging could also transform our ability to assess the tumour microenvironment. New techniques to specifically label myeloid cells6 might allow clinicians to appraise the accumulation of an inflammatory response, possibly serving as a biomarker for immunomodulatory drugs. Further clinical development of these imaging strategies is eagerly anticipated. Blood-based analyses, including circulating tumour cells, circulating tumour DNA (ctDNA), and tumourderived extracellular vesicles, have shown particular promise and seem poised for integration into clinical practice in the near future. Studies of tumour cell-based markers present within a standard blood specimen offer both ease of application and the likely advantage of sampling all sites of disease, instead of being restricted to a single tumour lesion accessible for biopsy. Rapid progress in technologies for isolation of circulating tumour cells and in molecular analyses of ctDNA is likely to make such approaches the dominant methods for real-time tumour monitoring. As these techniques continue to improve in sensitivity, they might find increasing use in early stages of cancer. Already, in earlystage breast cancer, ctDNA detection might predict recurrence many months before clinical evidence of relapse,7 raising the prospect of the earlier application of appropriately targeted therapy before heavy tumour burdens, associated with high degrees of cellular heterogeneity, preclude long lasting response. How far can we go in diagnosing early invasive cancer with these novel diagnostic methods? We and others have identified the presence of circulating tumour cells in the blood of a subset of patients with localised prostate cancer, which became undetectable after resection of the primary tumour.8 None of these patients went on to develop recurrent metastatic prostate cancer, consistent with the notion that early invasive cancers can shed cells into the bloodstream long before any of these cells become competent to initiate a metastatic lesion. Sequencing of peripheral blood cells has shown an increasing frequency of telltale genetic lesions www.thelancet.com/oncology Vol 16 December 2015
associated with increasing age, potentially representing a harbinger of incipient malignant leukaemic clones.9 More recently, emerging data suggest that detection of the proteoglycan molecule, GPC1, bound to extracellular vesicles could detect precancerous pancreas lesions.10 Tumour-derived genetic material contained in extracellular vesicles can also be sequenced and might enable molecular profiling of clinically occult tumours. Although extraordinarily promising, the idea that bloodbased signatures of cancer might enable detection of early malignancy faces substantial hurdles. To be clinically useful, blood-based assays must be highly sensitive in detecting true signals derived from malignant cells in the blood, along with some indication of their likely tissue of origin. On the other hand, these blood-based signatures must not be overly sensitive in identifying rare genetic abnormalities from errant cells destined to die or from precancerous cells unlikely to produce an invasive tumour within a patient’s lifetime. Nonetheless, we believe these challenges are ultimately solvable through improved understanding of cancer biology and genetics and rapidly advancing molecular diagnostic capabilities. By offering the possibility of removing a localised invasive cancer and administering potentially individualised therapy before a large and heterogeneous tumour burden limits their curative potential, such early screening stands to be a transformative strategy that would alter the landscape of cancer treatment. We have described only part of the new world of cancer diagnostics that is emerging as a result of deeper molecular insights into cancer biology, powerful bioengineering and nucleotide sequencing platforms, and the realisation that new and increasingly effective therapies induce dramatic changes in tumour composition that warrant close and repeated monitoring to keep cancer in check. Additional discoveries, ranging from advances in computational medicine to monitoring of the microbiome, are also poised to alter the diagnostic landscape. It is our hope that in the future, invasive cancers will be identified early, with personalised diagnostics that improve the chance of curative treatment. In cases in which cancers are discovered at a later stage, detailed longitudinal molecular characterisation will allow sequential treatment strategies that improve our chance of turning cancer into a chronic disease. We believe this is a reality that is within reach and that will greatly reduce the worldwide burden of cancer. 1597
Comment
Tilak K Sundaresan, *Daniel A Haber Massachusetts General Hospital Cancer Center, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02129, USA [email protected] DAH reports grants from Janssen Diagnostics, outside the submitted work, and holds patents issued for EGFR genotyping and for CTC isolation technologies. TKS declares no competing interests. 1 2 3 4
1598
Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med 2015; 372: 1700–09. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015; 372: 1689–99. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. The N Engl J Med 2015; 372: 2509–20. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883–92.
5
6 7
8
9 10
Evans MJ, Smith-Jones PM, Wongvipat J, et al. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci USA 2011; 108: 9578–82. Rashidian M, Keliher EJ, Bilate AM, et al. Noninvasive imaging of immune responses. Proc Natl Acad Sci USA 2015; 112: 6146–51. Garcia-Murillas I, Schiavon G, Weigelt B, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 2015; 7: 302ra133. Stott SL, Lee RJ, Nagrath S, et al. Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med 2010; 2: 25ra3. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371: 2488–98. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523: 177–82.
www.thelancet.com/oncology Vol 16 December 2015