Q&A with Professor Dr Anand Sachithanandan on the future of personalized cancer treatment

Q: How has the concept of personalized cancer treatment evolved over the past decade?  

A: Lung cancer is a prime illustration of the tremendous evolution of personalized cancer treatments over the past 10 years. The advances in the diagnostic and treatment landscape of non-small cell lung cancer (NSCLC), the most common cancer and most common cancer-killer worldwide, is nothing short of a revolution. Genomic molecular profiling with next generation sequencing allows us to identify specific gene alterations in the tumor tissue that in some instances may be amenable to a type of bespoke oral chemotherapy called targeted therapy. This is especially pertinent to Asia and Malaysia as we have a higher proportion of sensitizing genomic mutations like EGFR or ALK in NSCLC that responds well to oral tyrosine kinase inhibitors or targeted therapies.

Recently, immunotherapy has emerged as a true gamechanger with vastly better outcomes for some lung cancer patients. The challenge remains in selecting the appropriate therapy for the correct patient at the right time, to achieve maximal benefit, and minimize cost and side effects in non-responders. A biomarker called PD-L1 is often used to identify which patients are most likely to get a good immuno-pathological response which in turn appears to correlate well with better clinical outcomes in terms of event-free survival and even overall survival. 

Q: What distinguishes personalized cancer treatments from traditional approaches?                                 

A: Personalized therapies are more precise or selective as these treatments are bespoke and tailored for specific patients whose tumor exhibit certain mutations. It is no longer the traditional ‘one-size-fits-all’ approach which has toxic side effects and limited efficacy in some patients.  With personalized therapies, detailed information on the genomic or molecular biology of the tumor will guide treatment options for each individual patient.

Q: What role does genomic profiling play in identifying the best treatment options for cancer patients?   

A: Using NSCLC as an example, approximately 40-60 percent of patients here will have an actionable or druggable sensitizing genomic mutation like EGFR or ALK. Such patients will benefit from adjuvant oral targeted therapy for 2-3 years following successful curative surgery to minimize the risk of cancer recurrence from occult micro-metastases. This has translated into better disease-free survival (DFS) and overall survival (OS). Genomic profiling can also help identify who is less likely to benefit from systemic immunotherapy as patients with actionable mutations (EGFR/ALK), generally fare better with the oral targeted therapy and hence should not be routinely treated with immune checkpoint inhibitors. The optimal care and outcomes for most lung cancer patients including those with early-stage disease often requires a multidisciplinary approach with multi-modal therapy. Genomic profiling of the tumor helps to refine and optimize patient selection for the combination and sequence in which these various cancer treatments are offered.

Q: Could you elaborate on the most significant advancements in precision medicine for cancer, such as targeted therapies or immunotherapies? 

Surgery with a curative intent remains the best treatment option for resectable early-stage NSCLC (stages 1A to-IIIB-N2 disease) but surgery alone is insufficient as evinced by unacceptably high recurrence rates.  The best outcomes are achieved with multi-modal therapy that combines surgery (for effective local control) with targeted therapy, or immunotherapy and/or conventional chemotherapy. The stage of disease, tumor histology and genomic biology of the tumor together with a patient’s fitness and financial affordability will dictate treatment decisions. Immunotherapy when given pre-surgery as neoadjuvant or peri-operative (ie. before and after surgery as a ‘sandwich’ regime) or following surgery as an adjuvant therapy, has vastly improved DFS and OS in patients who achieve a good immuno-pathological response. Being able to identify and target specific mutations or genetic alterations unique to an individual’s tumor, allows us to offer highly efficacious truly personalized precision treatments with less collateral damage to surrounding tissues and less toxic side effects which results in longer and better quality of life for patients.

Q: What challenges remain in making targeted therapies effective across diverse patient populations?   

A: Several challenges exist. First, cost and reimbursement is a major real-world issue. These highly efficacious drugs are often prohibitively expensive, and many eligible patients cannot afford them despite patient-assistance programmes (PAP) from the pharmaceutical manufacturers. Solutions to address this financial toxicity include an increased and ‘ring-fenced’ healthcare budget for cancer services and therapy, switching to high quality generics or biosimilars and government-to-government (G2G) negotiations for bulk purchasing and lower pricing. 

Second, is the need to increase awareness (amongst patients and clinicians alike) on the importance of testing for biomarkers like PD-L1 and common genomic mutations (eg. EGFR/ALK) to guide adoption of biomarker driven treatment strategies. Reimbursement for testing must be covered by insurance or provided at cost/free in the public sector. Reflex testing (upon diagnosis of eg. NSCLC) is another way to increase testing rates and shorten laboratory turnaround times (TAT). Delays should be minimized so that definitive treatment can commence as quickly as possible. Time-to-treatment initiation is a predictor of outcomes and patient prognosis especially with earlier stage curable disease.

Q: How are artificial intelligence and big data analytics helping to personalize cancer treatments?

A: AI can help with detection of lung cancer and other cancers with deep learning algorithms of various imaging scans thereby enhancing diagnostic accuracy and reducing the workload of human radiologists. AI can also aid with personalizing surveillance scan intervals for treated cancer patients. Similarly, AI can facilitate computational pathology, redefining diagnosis and treatments with digital pathological imaging to identify features beyond the perception of the human eye.             

Q: How does personalized treatment improve patient outcomes compared to conventional treatments? 

A: Data from global clinical trials and real-world experience has demonstrated that use of oral targeted therapies for oncogene-driven NSCLC and systemic immunotherapy for tumors with a high PD-L1 expression has yielded impressive outcomes in terms of vastly improved DFS and OS for NSCLC patients compared to conventional platinum chemotherapy alone. These treatments also appear to be better tolerated.

Q:  What are the psychological and financial implications of personalized treatments for patients? 

A: As previously mentioned, financial toxicity is a serious real-world concern. All the relevant stakeholders (MOH/ ‘Big Pharma’/ insurance/ hospitals and healthcare providers/regulators) need to collaborate with sincerity and clarity to make such highly efficacious treatments more affordable and thus accessible. Psychologically, patients and caregivers may experience emotional distress upon realizing they cannot avail of the best available therapies due to their lack of means. This will negatively impact their recovery or coping mechanisms and is detrimental to their overall well-being.

Q: What is the potential of liquid biopsies in monitoring and adapting cancer treatments in real-time? 

A: Liquid biopsies or plasma circulating tumor DNA (ct-DNA) holds tremendous promise in the screening, diagnosis and surveillance of many cancers including lung cancer.  In NSCLC, some surgical patients who have a good response with neoadjuvant chemo-immunotherapy may achieve a complete pathological response (pCR) which means there is no viable cancer cells in the resected tumor or lymph nodes. In these patients with a pCR, the absence of any detectable circulating tumor DNA in the post-surgery liquid biopsy (ie. plasma ct-DNA negative) suggests no minimal residual disease (MRD) and they could be potentially ‘cured’. In such cases, the liquid biopsy can help with de-escalation of adjuvant chemo-immunotherapy sparing patients unnecessary cost and toxicity. However, presently, concerns still exist regarding the sensitivity and negative predictive value of such MRD assays to adopt this adaptive approach. However, in time as assay technology improves it is likely such a strategy will significantly shape mainstream clinical practice.

Q: What are the current barriers to widespread adoption of personalized treatments, particularly in low-resource settings?          

A: The two main issues are awareness and cost. We need to educate all stakeholders on the importance of early reflex genomic testing in NSCLC for example, to guide personalized biomarker-driven treatment strategies and expedite timely initiation of treatment. Addressing cost is more complex and challenging but requires political will, cross industry multi stakeholder collaboration and innovative sustainable healthcare financing including some reasonable co-payment from patients. 

Q: What do you foresee as the most exciting developments in personalized cancer care in the next 5 to 10 years?

A: Liquid biopsy (plasma ct-DNA) holds immense potential to screen, triage and detect early-stage cancers that are more amenable to curative treatments. It will also guide adaptive treatment strategies for escalation or de-escalation of treatments and help personalize surveillance scan intervals in tandem with state-of-the-art artificial intelligence-enabled imaging. Personalized cancer vaccines are being developed and trialed and may well be available ‘off the shelf’ in the next decade! Scientists are working on how to modulate the immune system to better recognize and eliminate foreign tumor antigen/cells. 

Anand Sachithanandan is a cardiothoracic surgeon with a clinical and academic interest in lung cancer. He is the founding president of LCNM.