Era of precision medicine in oncology

Mangai suseela M

Consultant medical and hematooncologist, Kauvery Hospital – Trichy

Introduction

India is facing a dual burden of infectious diseases and non-communicable diseases.

Cancer cycle

What Is precision medicine in oncology?

Use information from a variety of sources to provide best possible care tailored to each patient – Personalised medicine. Information in precision medicine comes from DNA, RNA, proteins, or related molecules. As tests that detect these molecules, Molecular Diagnostics are a fundamental component of precision medicine.

Molecular biomarkers in cancer

Certain alterations in chromosomes, DNA, RNA, proteins, and related molecules have the potential to cause cancer or other diseases.
When such alterations are linked with a particular state of disease or health, they are known as molecular biomarkers.

Human genome

Sample requirements for molecular testing

Blood, bone marrow aspirate and biopsy samples
Body fluids (ascitic, pleural, CSF etc.)
Cytology and cell blocks
FFPE tissue (Formalin Fixed Paraffin Embedded Tissues)

Molecular methods in cancer

Immunohistochemistry – Ag-Ab binding
Fluorescent in situ hybridization (FISH) – Probe
Polymerase chain reaction (PCR) – Amplification of DNA

Reverse Transcription (RT) PCR
Allele-specific PCR
Digital droplet PCR
Multiplex ligation-dependent probe amplification (MLPA) PCR

DNA Sequencing methods

Sanger sequencing – low throughput
Next-generation sequencing – high throughput

Circulating tumor DNA (ctDNA)

Detection of cell free circulating DNA derived from tumor
Surrogate for entire tumor genome
Useful when invasive biopsy is not feasible
Correlates with tumor burden
For assessment of response to treatment
Can detect tumor specific mutations from ctDNA
Detect clonal evolution of tumors after treatment (Genemic drift)
Detect MRD post-Surgery/ Curative treatment
Disadvantage: Is <1% of cell free DNA

Molecular methods – over view

Testing Method	Testing method	Testing method	Testing method	Testing method	Testing method
IHC	3-5 days	Rs 1600 per IHC	FFPE, Cell block	Diagnosis/ Prognosis	False negative
					Non-specific
FISH	7-15 days	Rs 12000 -15000	FFPE	Translocations; Karyotyping	Needs probes/ cumbersome
PCR	7-10 days	Rs 10000- 15000	FFPE, Body fluids		Unknown mutations not detected; False -ve
NGS Comprehensive	21 days	Rs 28000-35000	FFPE, Blood	Point mutations	Costly
					Longer TAT
NGS Hotspot panel	7-10 days	Rs 15000-20000	FFPE, Blood	Point mutations	Miss uncommon mutations
MLPA PCR	14 days	Rs 10000-15000	Blood	Large deletion and duplication	Not for SNV

Precision medicine – Cancer therapeutics

Why we need precision medicine in oncology

Drawbacks of chemotherapy

Nonspecific
Response variable
Side effects
Drug resistance
Disease recurrence
Affects quality of life
Social stigma

Case Presentation

Case 1

A 47-year-old female, nil addictions admitted with chronic cough/weight loss/Back pain. Treated outside with antibiotics.

CT done shows symptoms of right upper lobe mass and Multiple lung nodules/mediastinal nodes.
PET reveal multiple lytic lesions in vertebrae.
Biopsy shows adenocarcinoma.

Case 2

A 68-year-old male, 40 years of smoking came with a complaint of chronic cough/breathlessness/weight loss.

Imaging shows Left sided pleural effusion/lung mass/bilateral lung nodules
Biopsy shows adenocarcinoma

Case 3

A 55-year-old male, occasional smoking admitted with seizures.

MRI Brain shows multiple brain mets
PET CT shows lung mass/mediastinal nodes
Biopsy shows adenocarcinoma.

Discussion

All the three patients are Stage IV Adenocarcinoma lung, but the clinical profile is different
Case 1 Middle aged female/No smoking history. Case 2 is an elderly male/40 years smoking. Case 3 is a middle aged male/light smokers.
Case 1 – EGFR Positive started on T. Gefitinib responded very well. Disease control for 1.5 years then disease progression—started on 3^rd generation TKI osimertinib. Still in PR post 3 years of diagnosis
Case 2 – No driver mutation so started on IV chemotherapy. Remained progression free for duration 10 months, then succumbed
Case 3 – ALK fusion +, started on lorlatinib. Still progression free after 3 years of therapy.

In CA Lung

Driver mutation	Tumour heterogeneity
Younger age	Older age /smokers/non-small cell lung ca
No smokers /light smokers	Driver mutations are seen
Adenocarcinoma

Gefitinib Vs Chemo – NEJ 002

ALK + CA lung Crown trial

Chronic smokers
High PD L 1 expression
PD L 1 > 50 % – can offer Pembrolizumab monotherapy

In CA lung – Molecular panel

EGFR mutation
ALK fusion
ROS fusion
RET
MET
BRAF
KRAS
HER 2
PD L1

In Breast cancer

Her 2 overexpression by IHC or FISH
Trastuzumab and Pertuzumab – monoclonal antibodies targeting the HER2 protein – Neoadjuvant/adjuvant/metastatic setting
ADC – Antibody drug conjugates -Trastuzumab emtansine, Trastuzumab deruxtecan

In Colon and Endometrial Cancer

IHC MMR
MSI by PCR

Tumor agnostic therapy

MSI H/dMMR

Indication	Line of therapy	medications
Any tumour type	>2nd line metastatic	pembrolizumab
Colorectal cancer	first line	Pembrolizumab
Colorectal cancer	2nd line	Nivolumab
Endometrial cancer	progression after platinum	Dostarlimab

TMB high (>10 mut/mb)

Indication	Line of herapy	medications
Any tumour type	>2nd line metastatic	pembrolizumab

NTRK fusion

Indication	Line of herapy	medications
Any tumour type	Any line	Larotrectinib/entrectininb

BRAF V600E

Indication	Line of herapy	medications
Melanoma	Any metastatic line	Vemurafenib + Cobimetinib
	Any metastatic line	Dabrafenib + Trametinib
	1st line	Atezolizumab, Vemurafenib and Cobimetinib
NSCLC	2nd line	Dabrafenib + Trametinib
Anaplastic thyroid	Any line	Dabrafenib + trametinib
Colorectal	2nd line	Encorafenib + cetuximab

Take home message

Whenever possible complete molecular profiling of tumour is important
Targeted therapies are less toxic than conventional chemotherapies
Irrespective of the site & histology
Appropriate targeted therapy will have better response rates.

Kauverian Bookshelf

Applied Medical Statistics

Era of precision medicine in oncology