Evolution of Personalized Cancer Care With Molecular Profiling

DNA research concept: © catalin - stock.adobe.com

Molecular oncology is reshaping how oncologists understand, diagnose, and treat cancer. In contrast to traditional methods, which primarily rely on histopathological examination, molecular oncology delves deeper, identifying the genetic and molecular changes that fuel tumor growth.

By sequencing a patient’s tumor and mapping its unique genetic alterations, clinicians can tailor treatments to the individual, leading to more precise and effective outcomes.

“For many years, cancer was completely defined by what it looked like under the microscope. We still do that, but now we have additional information that we can get by sequencing these tumors and learning what causes them to be the genetic drivers. It can tell us things about how they are going to respond to therapies and it can make them be able to use certain therapies that are targeted to these specific mutations,” explained Alec Kimmelman, MD, PhD, in an interview with Targeted Oncology^TM.

Alec Kimmelman, MD, PhD

Current Successes in Molecular Oncology

Targeted Therapies

Molecular profiling has already led to several successes across cancer types, resulting in targeted therapies that are changing the standard of care. In cancers like lung, breast, and colorectal, molecular testing has allowed for more precise identification of mutations and alterations that can be targeted by specific treatments.

In non–small cell lung cancer (NSCLC), genetic testing has identified mutations in the EGFR gene. In patients with these mutations, targeted therapies like erlotinib (Tarceva) and gefitinib (Iressa) have improved survival rates by focusing on the specific genetic cause of the cancer.

“In lung cancer therapy, it is basically part of everyone's cancer treatment pathway to have this baseline testing done when they have advanced disease,” Sarah Kerr, MD, a pathologist at Allina Health, told Targeted Oncology, in an interview.

Both erlotinib and gefitinib are FDA-approved as targeted therapies for patients with EGFR-mutant NSCLC, based on findings from the IPASS (NCT00322452), EURTAC (NCT00446225), and OPTIMAL (NCT00874419) trials.^1-3 As a result, EGFR mutation testing has become a standard part of the diagnostic pathway for patients with advanced NSCLC.

In breast cancer, molecular profiling has also yielded success with the identification of the HER2 gene. Agents like trastuzumab (Herceptin) now specifically target HER2-positive tumors, offering a precision approach that has transformed breast cancer treatment, particularly for advanced or metastatic cases.

Sarah Kerr, MD

Clinical trials, including HERA (NCT00045032), CLEOPATRA (NCT00567190), and NCCTG N9831 (NCT00004067; NCT00005970),^4-6 have demonstrated significant improvements in overall and progression-free survival for patients with HER2-positive breast cancer. Additionally, newer therapies like pertuzumab (Perjeta) and trastuzumab deruxtecan (Enhertu) have improved outcomes, providing more options for patients.

Other prime examples are imatinib (Gleevec), which offered a new treatment for patients with chronic myeloid leukemia by targeting the BCR-ABL fusion protein⁷, and vemurafenib (Zelboraf) for patients with melanoma harboring BRAF V600E mutations.⁸

“The key part of developing a molecular program, whether you have that molecular lab in-house or are sending it out to a commercial lab, is having that good process, pre analytically, to have the best specimens so that you can get the most information out of them. That is usually my message to the oncologists out there,” added Kerr in the interview.

Immunotherapy

Immunotherapy represents another significant achievement in molecular oncology. Checkpoint inhibitors, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), and ipilimumab (Yervoy), block proteins like PD-1 and CTLA-4 that cancer cells use to evade the immune system. These drugs have shown efficacy in melanoma, NSCLC, and renal cell carcinoma.⁹

Another advancement is chimeric antigen receptor (CAR) T-cell therapy, where a patient’s T cells are genetically engineered to recognize and destroy cancer cells.¹⁰ CAR T-cell therapies have achieved success in certain blood cancers, including B-cell acute lymphoblastic leukemia and large B-cell lymphoma.

Combining immunotherapies with traditional treatments like chemotherapy and radiation or targeted therapies can also enhance overall treatment effectiveness for patients with cancer. Clinical trials have shown that combining immune checkpoint inhibitors with chemotherapy or radiation can lead to synergistic effects, like with the combination of nivolumab with ipilimumab in treating melanoma.¹¹

Advances in Molecular Diagnostics

Pashtoon Kasi, MD, MS

Next-generation sequencing (NGS) marks another advancement in molecular oncology as it enables comprehensive tumor profiling, allowing clinicians to identify genetic mutations and alterations that are driving cancer growth. Liquid biopsies, which detect circulating tumor DNA (ctDNA) from a simple blood draw, represent a non-invasive alternative to traditional biopsies, allowing for real-time monitoring of tumor progression and treatment efficacy.

"Liquid biopsy or ctDNA started with advanced next-generation sequencing-based platforms but has now moved into detecting minimal residual disease. This allows us to spare patients the toxicity of unnecessary treatments and focus on those who need it," explained Pashtoon Kasi, MD, MS, medical director at City of Hope, highlighting the impact of ctDNA on patient care.

This method also enables clinicians to monitor patients over time without the need for frequent, invasive procedures, offering a real-time understanding of how a tumor is evolving and responding to treatment.

"Some institutions pride themselves on not using ctDNA, while others are early adopters. It is important to recognize the value of ctDNA as another tool in our toolbox," Kasi added.

Emerging Trends in Molecular Oncology

As molecular oncology continues to evolve, several exciting developments are on the horizon. Artificial Intelligence (AI) is beginning to play a key role in analyzing genomic data, enabling faster and more accurate identification of new therapeutic targets. AI is also streamlining the discovery process for new agents, accelerating the development of new therapies tailored to specific genetic mutations.¹²

“AI is a hot topic across everything, from medicine to finance to city planning and everything in between,” Geoffrey D. Moorer, MD, medical oncologist at Virginia Cancer Specialists, told Targeted Oncology^TM. “What I would predict is that as all these massive amounts of data are coming in, patients are getting next-generation sequencing, we are going to find more targets, more mutations, other biomarkers that tell us what treatments may work for what patient but then you also have the added complexity of the sequencing of those treatments, as well as what comorbidities that patients may have.”

Geoffrey D. Moorer, MD

New AI tools are emerging to help interpret both germline and somatic mutations in cancer, improving the accuracy of variant annotation. For example, deep learning models like those used in prostate cancer and melanoma detection have shown superior performance over traditional methods.¹²

"Dig" is a deep learning framework that identifies somatic mutations under positive selection, while AlphaMissense predicts pathogenic variants in the proteome, though its oncogenic potential is still under study. AI platforms such as CancerVar also predict the oncogenicity of somatic variants, offering an alternative to curated databases. AI is also advancing cell-of-origin prediction for cancers of unknown primary, which can guide treatment strategies. These predictions use genomics-based algorithms, transcriptomic algorithms, and multi-input molecular approaches.

AI is also being applied in molecular oncology for novel therapies, such as personalized cancer vaccines, where AI is used to identify cancer-specific neoantigens and T-cell receptors. Moreover, deep learning strategies are increasingly influencing clinical trials and immunotherapy approaches in cancer treatment.

“I see that as a space where artificial intelligence is sort of compiling all of those different factors, patient factors, disease factors, etc. and predicting what treatments will be most efficacious for what patient at what time. I think there will be more to come very rapidly over the next several months to years,” said Moorer.

“We believe it’s possible to streamline processes and ensure that we have the right pathways in place to get the right results quickly,” added Kimmelman, chair of radiation oncology and director of the Perlmutter Cancer Center at NYU Langone Health. “AI will help us identify new therapeutic targets, streamline the process of drug discovery, and even predict how a patient will respond to treatment.”

The field is also expanding to include more types of cancer. While some cancers have benefited from molecular profiling, there is a growing focus on rare or difficult-to-treat cancers, where the identification of novel genetic alterations could lead to breakthrough treatments.¹³

“I think we’ve made tremendous advances to where we are now,” Kimmelman said, “but I do agree that we’re going to see some amazing developments in the next 5 to 10 years. Some of these advances will be in speed—the ability to do things right away and get test results immediately. Others will come from the comprehensiveness of the tests we’re developing here, which are far more sensitive to detecting ctDNA.”

Challenges and Opportunities

While the potential for molecular oncology is immense, there are still significant challenges to address, particularly around accessibility and cost. As the technology advances, the need for broader adoption and insurance coverage remains a key barrier. Additionally, the complexity of cancer’s molecular landscape means that much remains to be discovered, and more work is needed to identify and target additional mutations.

Cancer cell illustration in high detail, generative AI: © LAYHONG - stock.adobe.com

Additionally, the molecular landscape of cancer is complex, meaning there is still much to learn about how different mutations interact and how they can be targeted with therapies. Kimmelman acknowledges that while progress is being made, especially in identifying targetable mutations, there is still much work to be done.

"You cannot expect someone who treats every kind of cancer to be an expert in every molecular alteration and in every cancer, or to know which clinical trials the patient would be eligible for,” said Kimmelman.

“Work with your pathologist, work with the radiologists and pulmonologists, and ask us to make sure you are getting the best specimens,” added Kerr.

Despite these challenges, the opportunities are vast as the future of cancer care lies in the continued evolution of molecular oncology. Here, personalized treatments and cutting-edge diagnostics will work together to improve patient outcomes and reduce AEs.

The Personalized Approach to Cancer Care

The future of molecular oncology is bright. As more cancer types are profiled and more therapies are tailored to individual genetic profiles, oncologists will have an ever-growing arsenal of tools to combat cancer. The continued development of precision medicine will allow patients to benefit from highly personalized, evidence-based treatment plans, ultimately improving outcomes and enhancing the quality of care.

"In many cases, the best therapy is a clinical trial. We can alert their physicians about the trials the patients are eligible for, so they can have a discussion with the oncologist and make sure that, at the very least, the patient is aware of the pros and cons of a particular clinical trial," concluded Kimmelman.

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