Fast Facts: Molecular Profiling in Solid Tumors

P. Pisapia, B.S. Sheffield, E. Garralda, P. Cheema

Description

Identifying tumor-specific molecular aberrations via molecular profiling is vital for the use of targeted therapies. Understanding a patient’s unique tumor genetics provides predictive and prognostic information that enables a personalized care plan to be put in place, improving outcomes and minimizing ineffective treatments. 'Fast Facts: Molecular Profiling in Solid Tumors' provides a firm knowledge foundation of somatic molecular profiling methodologies, key information to help with the use of molecular profiling in daily practice and advice on communicating with patients about molecular testing and results. Table of Contents: • Molecular profiling: the basics • Rationale for testing • Sample collection • Test selection and process • Interpreting the report • Talking to patients • Challenges and opportunities

Sujets

• Medical
• Médecine
• Oncology

Informations

• Publié par: S. Karger AG
• Date de parution: 06 décembre 2022
• Nombre de lectures: 0
• EAN13: 9783318072129
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Fast Facts: Molecular Profiling in Solid Tumors
First published 2023
Text 2023 Parneet Cheema, Elena Garralda, Brandon S Sheffield, Pasquale Pisapia
2023 in this edition S. Karger Publishers Ltd
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ISBN 978-3-318-07075-0
Cheema P (Parneet)
Fast Facts: Molecular Profiling in Solid Tumors/
Parneet Cheema, Elena Garralda, Brandon S Sheffield, Pasquale Pisapia
Medical writing support by Anja Brunner PhD Meerbusch, Germany (member of Science Inbound).
Medical illustrations by Graeme Chambers, Belfast, UK
Typesetting by Amnet, Chennai, India
Printed in the UK with Xpedient Print
This publication was supported by a medical education grant from Thermo Fisher Scientific.
Abbreviations list
Introduction
Molecular profiling: the basics
Rationale for testing
Sample collection
Test selection and process
Interpreting the report
Talking to patients
Challenges and opportunities
Useful resources
Index
Abbreviations list
AMP: Association for Molecular Pathology
ASCO: American Society of Clinical Oncology
CAP: College of American Pathologists
cfDNA: cell-free DNA
CNS: central nervous system
CT: computed tomography
ctDNA: circulating tumor-derived DNA
dMMR: mismatch repair deficiency
DNA: deoxyribonucleic acid
EDTA: ethylenediaminetetraacetic acid
EORTC: European Organisation for Research and Treatment of Cancer
ESCAT: ESMO Scale for Clinical Actionability of molecular Targets
ESMO: European Society for Medical Oncology
FDA: US Food and Drug Administration
FFPE: formalin-fixed paraffin-embedded
FISH: fluorescence in situ hybridization
HGVS: Human Genome Variation Society
HRR: homologous recombination repair
IASLC: International Association for the Study of Lung Cancer
ICC: immunocytochemistry
IHC: immunohistochemistry
InDel: insertion-deletion variant
ISCN: International System of Human Cytogenetic Nomenclature
JCR: Joint Consensus Recommendation (AMP, ASCO and CAP)
mCRPC: metastatic castration-resistant prostate cancer
MDT: multidisciplinary team
MRD: minimal residual disease
MSI-H: microsatellite instability-high
MTB: molecular tumor board
NCCN: National Comprehensive Cancer Network
NGS: next-generation sequencing
NSCLC: non-small-cell lung cancer
OS: overall survival
PCR: polymerase chain reaction
PD-L1: programmed cell death ligand 1
RNA: ribonucleic acid
RT-PCR: reverse transcription-polymerase chain reaction
SNV: single nucleotide variant
SPECTA: Screening Patients for Efficient Clinical Trial Access
TKI: tyrosine kinase inhibitor
TMB: tumor mutation burden
WES: whole exome sequencing
WGS: whole genome sequencing
Introduction
The first targeted therapy for cancer - the estrogen receptor blocker tamoxifen - was approved in the 1970s. 1 , 2 However, 2001 marked a major turning point in the treatment of cancer when the first tyrosine kinase inhibitor, imatinib, was approved to treat chronic myeloid leukemia and gastrointestinal stromal tumors by targeting BCR-ABL1 and c-KIT. 3 That approval marked the beginning of a new era in anticancer drug development, with steadily growing approvals of targeted therapies for a broader array of cancers. 4
Identifying tumor-specific molecular aberrations via molecular profiling is vital for the use of targeted therapies. Understanding a patient s unique tumor genetics provides predictive and prognostic information that enables a personalized care plan to be put in place, improving outcomes and minimizing ineffective treatments.
All treating physicians need to know what test to perform and when it should be ordered, followed by correct interpretation of the results so that well-informed patient-personalized treatment decisions can be made. However, oncologists report varying confidence in their ability to use genomic findings appropriately. 5 , 6 With rapid advances in targeted therapy approvals and molecular profiling methodologies, it is difficult to stay abreast of the latest recommendations, let alone catch up with the vast amount of information already available. Fast Facts: Molecular Profiling in Solid Tumors provides a firm knowledge foundation of somatic molecular profiling methodologies, key information to help with the use of molecular profiling in daily practice and advice on communicating with patients about molecular testing and results.
It is important to recognize that healthcare structures and the implementation of molecular profiling vary significantly from country to country. The content herein represents the collective expertise of the authors. It serves as a starting point to understand and use molecular profiling in the treatment of solid tumors and should be complemented with information and recommendations specific to local settings.

References
1 . Jordan CV. Tamoxifen: a most unlikely pioneering medicine. Nature Rev Drug Disc 2003;2:205-13.
2 . Yan L, Rosen N, Arteaga C. Targeted cancer therapies. Chin J Cancer 2011;30:1-4.
3 . Savage DG, Antman KH. Imatinib mesylate - a new oral targeted therapy. N Engl J Med 2002;346:683-93.
4 . Zhong L, Li Y, Xiong L et al. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct Target Ther 2021;6:201-49.
5 . Schwartzberg L, Kim ES, Liu D et al. Precision oncology: what, when, and when not? Am Soc Clin Oncol Educ Book 2018;37:160-9.
6 . Singh BP, Britton SL, Prins P et al. Molecular profiling (MP) for malignancies: knowledge gaps and variable practice patterns among United States oncologists. J Clin Oncol 2019;37(15_suppl):10510.
1 Molecular profiling: the basics
Molecular profiling in oncology commonly refers to the testing of tissue samples or biofluids (serum, plasma, urine, etc.) with the aim of identifying tumor-specific molecular alterations (that is, biomarker status) that provide a distinctive genetic signature . 1
Aims of molecular profiling
Established applications. As of 2022, a fast-growing number of biomarkers (discussed in the following sections) can be identified via molecular profiling primarily to support diagnosis, drive appropriate targeted therapy, qualify the patient for a clinical trial, inform disease progression and prognosis or gauge treatment response.
Patient stratification for targeted therapies. Matching molecular alterations to a targeted therapy improves clinical outcome and has become the standard of care in several solid tumors, including breast, lung, melanoma and colorectal cancers.
Case study 1.1 - patient stratification for targeted therapies against metastatic colon cancer 2
Case description
A 49-year-old woman with a history of treated colon cancer complained of wheezing when lying down. A chest radiograph revealed a large lesion in her right lung, confirmed by a CT scan that showed a pulmonary mass invading the lower lobe bronchus and possibly pulmonary arteries. Immunohistochemical analysis of a biopsy showed the tumor to be positive for CK20 and CDX2 and negative for TTF-1 and CK7, leading to a diagnosis of metastatic colon cancer.
Molecular profiling
As there was insufficient tissue biopsy material for further analysis, ctDNA from a liquid biopsy was analyzed by NGS. The results were positive for mutations in APC , NOTCH1 and TP53 but not in KRAS .
Action taken
The patient was deemed to be a candidate for anti-EGFR therapy and was treated with cetuximab. Note that the two-gene mutation signature of APC and TP53 mutations predicts sensitivity to anti-EGFR therapy, whereas patients with KRAS mutations are unlikely to benefit from anti-EGFR therapy. 3
CDX2, caudal-type homeobox 2 transcription factor; CK7/20, cytokeratin 7/20; ctDNA, circulating tumor-derived DNA; EGFR, epidermal growth factor receptor; NGS, next-generation sequencing; TTF-1, thyroid transcription factor 1.
Prognosis of disease course. Precise classification of tumor subtypes correlated with known disease progression and prognosis can inform treatment planning and palliative care.
Case study 1.2 - unfavorable prognosis for colorectal cancer 4
Case description
A 68-year-old woman, who initially presented with rectal tenesmus and blood in her stool, was found to have a fungating and bleeding stenotic mass on colonoscopy. She underwent surgery (colectomy and splenectomy) and adjuvant chemotherapy. A total body CT scan 2 years after treatment revealed a suspicious liver lesion. Histology of biopsied material confirmed a diagnosis of metastatic colorectal cancer.
Molecular profiling
Pyrosequencing results were positive for KRAS and BRAF mutations in the hepatic metastases and BRAF p.V600E mutations in the primary tumor.
Action taken
The KRAS mutatio