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Personalized Medicine: Hopes and Hypes
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Abstracts / The Breast 36 S1 (2017) S19–S76
and this increases the likelihood completing the therapy. In addition, the recurrence risk is undoubtedly lowered, and the risk of late radiation-induced morbidity is also decreased. To further lower the risk of late effects, the patient is also informed to quit smoking to lower her risk of developing late skin morbidity and second cancer.
potential roles in early cancer for residual disease detection and cancer screening. Whilst there is great promise, there is limited evidence of clinical validity and clinical utility for ctDNA analysis. Substantial further research is required to assess how ctDNA analysis is best integrated into clinical practice to improve patient care.
IN20 MULTIGENE TESTING: AID OR CLINICAL NIGHTMARE Fabrice André Gustave Roussy Institute, Department of Medical Oncology, Villejuif, France Molecular characterisation of breast cancer led to the concept that this disease includes large number of different genomic segment, each one defined by a specific driver. Each of the driver is not associated with the same level of evidence for targetability. ERBB2 amplification is level 1 evidence and its presence is an indication for anti-Her2 therapy. BRCA1/2, PIK3CA, AKT1, ERBB2, ESR1 mutations are level 2 evidence and their presence should lead to the inclusion of patient in a clinical trial. Beyond these seven alterations, there are around 20 genomic alterations for which preclinical studies suggest that a targeted therapy could have antitumor effects. Considering the large number of genomic alterations, several groups have investigated the clinical utility of testing multiple genes. Initial studies have shown that assessing whole genome copy numbers and targeted sequencing was feasible in the context of clinical trial. In the SAFIR01 trial, a very good correlation was observed between CGH array and FISH to determine ERBB2 amplification status. Similar observation was done for next generation sequencing. Altogether, these data suggested that multigene technologies have a good analytical validity. Several studies then evaluated the clinical utility of using these technologies. The SHIVA randomized trial could not detect a PFS improvement in patients treated according to sequencing approach. In the MOSCATO phase II trial, using patient as his own control, it was estimated that next generation sequencing could benefit in around 30% of the patients. Overall, these studies did not report convincing evidence that using large panel of genes could improve outcome. There are several explanations for this apparent lack of efficacy. First, most of the study do not have access to a large portfolio of drugs. Second, there is currently no tool to identify the driver alteration in individual and it’s very likely that some of the alterations selected in these trials were actually passengers. Following these results, clinical research is moving in three ways. First, there are ongoing trials to evaluate the clinical utility of multigene sequencing using a large portfolio of drugs. Second, there are some attempts to develop software and bioinformatics tools to better define a driver. Finally, some are trying to understand which genomic alteration is associated with primary resistance. Finally, besides the utility of multigene sequencing, efforts in the field of targeted therapies are focusing on understanding 2ry resistance and to assess synergism with immunotherapeutics.
IN21 CIRCUALTING TUMOUR DNA ANALYSIS IN BREAST CANCER Nicholas C. Turner Breast Cancer Now Research Center at the Institute of Cancer Research, London, UK Circulating tumour DNA analysis allows a highly accurate and current analysis of tumor genetics, allowing tumor genotyping for patients with advanced cancer, monitoring of therapy, and
IN22 PRECISION/PERSONALIZED MEDICINE: HOPES AND HYPES George W. Sledge Stanford University School of Medicine, Stanford, USA The past twenty years have been dominated by the emergence of therapies targeting the specific biology of breast cancer subtypes, associated with an improving understanding of breast cancer genomics as well as the development of technologies (e.g., whole exome sequencing and ctDNA) allowing for rapid evaluation of individual patients’ cancers. These converging approaches offer patients and physicians the possibility of true personalized medicine, matching the right drugs with the right tumors for therapeutic benefit, minimizing the toxicity of ineffective therapeutics through their elimination and reducing healthcare costs through appropriate allocation of increasingly expensive drugs. At the same time, ‘precision’ or ‘personalized’ medicine, like many previous therapeutic waves, is easily over-sold as a solution for the cancer problem, promising but inevitably failing to deliver longterm benefits. The underlying biology of many cancers, in particular due to the complexity of far too many cancers, results in therapeutic futility. The ‘N of 1’ approach to cancer therapeutics resulting from genoic analyses inevitably emphasizes rare successes over all-to-common and usually unreported, therapeutic failures and violates many hard-won lessons that led to current successes. Finding the balance between hope and hype remains an important goal for the next generation of breast cancer researchers.
IN23 PREVENTION AND MANAGEMENT OF CANCER TREATMENT INDUCED NEUROTOXICITY Matti S. Aapro Cancer Center, Clinique de Genolier, Genolier, Switzerland Surgery, radiation therapy and medical therapy may have detrimental effects on either the central or peripheral nervous system. Pain after breast surgery is not uncommon even one-year after the procedure. Radiation therapy techniques have been improved and tend to spare cerebral tissues, resulting in lesser long-term damage, like loss of cognitive function which tended to be universal several years after whole brain treatment. Central nervous system neurotoxicity after medical therapy manifests as a wide range of clinical syndromes, with a complex cognitive function complaint manly discussed in early (adjuvant) therapy settings. In the peripheral nervous system, chemotherapy-induced peripheral neuropathy (CIPN) is the most frequently observed damage. An impressive amount of agents or procedures has been evaluated to prevent or treat CIPN. In most cases, rigours double-blind trial methodology has shown that these approaches cannot be recommended with sufficient levels of certainty. Duloxetine is accepted by most experts with a moderate level of recommendation. Tricyclic antidepressants (e.g. nortriptyline or desipramine), gabapentin and pregabalin are also considered. Topical gels might be tried. In conclusion, various forms of cancer treatment
Abstracts / The Breast 36 S1 (2017) S19–S76
and this increases the likelihood completing the therapy. In addition, the recurrence risk is undoubtedly lowered, and the risk of late radiation-induced morbidity is also decreased. To further lower the risk of late effects, the patient is also informed to quit smoking to lower her risk of developing late skin morbidity and second cancer.
potential roles in early cancer for residual disease detection and cancer screening. Whilst there is great promise, there is limited evidence of clinical validity and clinical utility for ctDNA analysis. Substantial further research is required to assess how ctDNA analysis is best integrated into clinical practice to improve patient care.
IN20 MULTIGENE TESTING: AID OR CLINICAL NIGHTMARE Fabrice André Gustave Roussy Institute, Department of Medical Oncology, Villejuif, France Molecular characterisation of breast cancer led to the concept that this disease includes large number of different genomic segment, each one defined by a specific driver. Each of the driver is not associated with the same level of evidence for targetability. ERBB2 amplification is level 1 evidence and its presence is an indication for anti-Her2 therapy. BRCA1/2, PIK3CA, AKT1, ERBB2, ESR1 mutations are level 2 evidence and their presence should lead to the inclusion of patient in a clinical trial. Beyond these seven alterations, there are around 20 genomic alterations for which preclinical studies suggest that a targeted therapy could have antitumor effects. Considering the large number of genomic alterations, several groups have investigated the clinical utility of testing multiple genes. Initial studies have shown that assessing whole genome copy numbers and targeted sequencing was feasible in the context of clinical trial. In the SAFIR01 trial, a very good correlation was observed between CGH array and FISH to determine ERBB2 amplification status. Similar observation was done for next generation sequencing. Altogether, these data suggested that multigene technologies have a good analytical validity. Several studies then evaluated the clinical utility of using these technologies. The SHIVA randomized trial could not detect a PFS improvement in patients treated according to sequencing approach. In the MOSCATO phase II trial, using patient as his own control, it was estimated that next generation sequencing could benefit in around 30% of the patients. Overall, these studies did not report convincing evidence that using large panel of genes could improve outcome. There are several explanations for this apparent lack of efficacy. First, most of the study do not have access to a large portfolio of drugs. Second, there is currently no tool to identify the driver alteration in individual and it’s very likely that some of the alterations selected in these trials were actually passengers. Following these results, clinical research is moving in three ways. First, there are ongoing trials to evaluate the clinical utility of multigene sequencing using a large portfolio of drugs. Second, there are some attempts to develop software and bioinformatics tools to better define a driver. Finally, some are trying to understand which genomic alteration is associated with primary resistance. Finally, besides the utility of multigene sequencing, efforts in the field of targeted therapies are focusing on understanding 2ry resistance and to assess synergism with immunotherapeutics.
IN21 CIRCUALTING TUMOUR DNA ANALYSIS IN BREAST CANCER Nicholas C. Turner Breast Cancer Now Research Center at the Institute of Cancer Research, London, UK Circulating tumour DNA analysis allows a highly accurate and current analysis of tumor genetics, allowing tumor genotyping for patients with advanced cancer, monitoring of therapy, and
IN22 PRECISION/PERSONALIZED MEDICINE: HOPES AND HYPES George W. Sledge Stanford University School of Medicine, Stanford, USA The past twenty years have been dominated by the emergence of therapies targeting the specific biology of breast cancer subtypes, associated with an improving understanding of breast cancer genomics as well as the development of technologies (e.g., whole exome sequencing and ctDNA) allowing for rapid evaluation of individual patients’ cancers. These converging approaches offer patients and physicians the possibility of true personalized medicine, matching the right drugs with the right tumors for therapeutic benefit, minimizing the toxicity of ineffective therapeutics through their elimination and reducing healthcare costs through appropriate allocation of increasingly expensive drugs. At the same time, ‘precision’ or ‘personalized’ medicine, like many previous therapeutic waves, is easily over-sold as a solution for the cancer problem, promising but inevitably failing to deliver longterm benefits. The underlying biology of many cancers, in particular due to the complexity of far too many cancers, results in therapeutic futility. The ‘N of 1’ approach to cancer therapeutics resulting from genoic analyses inevitably emphasizes rare successes over all-to-common and usually unreported, therapeutic failures and violates many hard-won lessons that led to current successes. Finding the balance between hope and hype remains an important goal for the next generation of breast cancer researchers.
IN23 PREVENTION AND MANAGEMENT OF CANCER TREATMENT INDUCED NEUROTOXICITY Matti S. Aapro Cancer Center, Clinique de Genolier, Genolier, Switzerland Surgery, radiation therapy and medical therapy may have detrimental effects on either the central or peripheral nervous system. Pain after breast surgery is not uncommon even one-year after the procedure. Radiation therapy techniques have been improved and tend to spare cerebral tissues, resulting in lesser long-term damage, like loss of cognitive function which tended to be universal several years after whole brain treatment. Central nervous system neurotoxicity after medical therapy manifests as a wide range of clinical syndromes, with a complex cognitive function complaint manly discussed in early (adjuvant) therapy settings. In the peripheral nervous system, chemotherapy-induced peripheral neuropathy (CIPN) is the most frequently observed damage. An impressive amount of agents or procedures has been evaluated to prevent or treat CIPN. In most cases, rigours double-blind trial methodology has shown that these approaches cannot be recommended with sufficient levels of certainty. Duloxetine is accepted by most experts with a moderate level of recommendation. Tricyclic antidepressants (e.g. nortriptyline or desipramine), gabapentin and pregabalin are also considered. Topical gels might be tried. In conclusion, various forms of cancer treatment