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  • Michael Misialek, MD

Pathologists crucial to the success of precision medicine


The precision medicine revolution has fundamentally changed cancer care. With a deeper understanding of the mutations behind cancer, and ever increasingly easier and less costly tumor sequencing methods, cancer is becoming a manageable chronic disease rather than a death sentence of the past. The contributions of pathologists have been indispensible throughout this journey. They are a crucial member of the care team.

In contrast to conventional chemotherapy which involves toxic drugs that kill both cancerous and normal cells, causing many side effects, precision medicine selectively targets a patient’s unique tumor characteristics.

Pathologists are involved in each step of the process. First, a tumor may be biopsied in either the operating room or radiology under CAT scan guidance. Pathologists are called upon to assess the sample, ensuring it is adequate for both diagnosis and testing for precision medicine targets (“actionable mutations”).

In the lab, pathologists examine tissues under the microscope using various stains to make a diagnosis. When appropriate, a tumor is tested for the presence of “actionable mutations”. If discovered, the patient may be eligible for targeted therapy. The success of precision medicine depends on pathologists.

Earlier this year, President Obama announced the launch of a Precision Medicine Initiative. He pledged $215 million for the establishment of:

  • More and better treatments for cancer

  • Creation of a patient powered research cohort

  • Regulatory modernization

  • Public-private partnerships

Already there have been many successes with precision medicine. Patients with breast, lung, and colorectal cancers, as well as melanomas and leukemias, all have benefited. There is optimism for continued success.

Crucial to the precision medicine revolution is integrity of the tumor specimens removed from patients. The testing process of these specimens can be divided into 3 phases: Pre-analytic, analytic and post-analytic. Especially important is the pre-analytic phase which includes:

  • Specimen collection

  • Storage

  • Handling

  • Transport

  • Processing

Each step has specific and unique requirements. It is the pathologist that ensures each is met and specimens stay viable for testing.

New Trials

Many trials are underway investigating targeted therapy. The TAPUR and ALCHEMIST trials are just two of the many. The American Society of Clinical Oncology is launching its first ever clinical trial, “Targeted Agent and Profiling Utilization Registry” (TAPUR) Study. This will expand options of patients with advanced cancers access to targeted precision medicine therapies beyond those already with FDA approved indications. Instead of treating patients based on their cancer type (i.e. breast, lung, colon, etc.), therapy will be directed towards the unique genetic mutations of the particular cancer. Often called a “basket study” due to treating diverse cancer types, united by shared genetic mutations, this marks a new phase in the precision medicine revolution. This strategy would not be possible without a collaborative team approach to cancer care. Pathologists are crucial to its success.

The ALCHEMIST study will look at tumor specimens from patients who have non-squamous non-small cell lung cancer (adenocarcinoma) that have had their tumors completely removed. Patients will have completed standard chemotherapy and/or radiation. Pathologists will look for specific mutation in two genes known to play a role in lung cancer, ALK and EGFR. These actionable mutations have current targeted treatments available. Those patients found to have one of these mutations will be given either crizotinib (Xalkori) if ALK mutated or erlotinib (Tarceva) for EGFR mutated cancers. The hope is that by identifying patients with early-stage lung cancer with known genetic mutations in their tumor and treating them with a targeted therapy will help prevent recurrence and improves survival, and increase chances of a cure.

New Targets

One of the hottest are of research is immunotherapy, specifically that of “checkpoint inhibitors”. These release the brakes on the immune system, i.e. PD-1/PD-L1 and PARP inhibitors. Nivolumab (Opdivo) and pembrolizumab (Keytruda) target PD-1, a protein on T cells that is important in recognizing other cells. When PD-1 is blocked, the immune system “brakes” are released and the T cell response against cancer is boosted. These drugs have been shown to shrink some tumors or slow their growth. Both drugs have been approved for patients with non-small cell lung cancer as a second line treatment after tumor begins to grow after standard chemotherapy.

Interpreting Tests

In order to qualify for these drugs, pathologists must test a patient’s tumor, staining it for the presence or absence of the protein. The complex scoring system that will determine whether a patient is eligible or not for this transformative treatment depends on a pathologist’s accurate diagnosis and interpretation of these stains.

Companion Diagnostics

Such tests that determine eligibility are termed “companion diagnostics”. Pathologists are responsible for running these tests. Some might involve staining tumors (immunohistochemistry) while others are complex molecular tests (FISH) looking for molecular mutations. Discovery of these “actionable targets” makes precision medicine possible.

Precision medicine has transformed cancer care. Pathologists are invaluable members of the team and will continue to play a key role in future advances.

#pathology #precisionmedicine #companiondiagnostics #preanalytics

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