The Physician You Never Knew You Had and How They Guide the Hands of Precision Oncologists

By Anthony M Magliocco, MD & Chair of Anatomic Pathology, Moffitt Cancer Center

Anthony M Magliocco, MD & Chair of Anatomic Pathology, Moffitt Cancer Center

Medical practice is changing, and its changing rapidly, particularly in the world of oncology.

We are now living in a time of “precision medicine” and “personalized Oncology” practice. The changes we are currently experiencing in the diagnosis and selection of treatment for cancer patients are truly revolutionary and are making a significant impact in ability to treat and cure cancer patients.

The initiation, development and growth of a cancer likely have a long natural history in a patient but generally the initial point of diagnosis is made at the end of a microscope by a tissue pathologist.

Pathology is often a misunderstood specialty that holds a vital role in supporting the accurate delivery of quality cancer treatment. The word “pathology” is derived from “pathos” meaning suffering, and “Logos” meaning study of—the study of suffering, or more precisely the study of disease.

Pathology is the translational science that underpins and supports the practice of clinical medicine.

Pathologists are fully qualified medical doctors who have spent 4 to 5 years specializing in the specialties of pathology after they have completed medical school. The specialties include anatomic pathology and clinical pathology. Often the pathologist will do further subspecialty training in a subspecialty such as breast pathology or hematology and some will even do additional research training in molecular diagnostics or translational research.

"Immunohistochemical stains can help determine what driver mutations are present within a cancer helping an oncologist select a specific treatment"

When a patient has a biopsy or tissue removed, it is processed in a tissue pathology laboratory and thin slices are placed on a glass slide and stained with special dyes to highlight various components within the tissue. An expert pathologist will examine the slides and determine what the medical diagnosis is. The examination will determine if a lesion is benign or malignant, will determine the grade of a malignancy-grade is a measure of biological aggressiveness. Generally grading is assigned from 1 to 3 with 3 representing the most poorly differentiated tumors and ones with the greatest risk of spread.

In addition, the pathologist will examine the margins of the surgical excision to determine if a cancer has been completely excised and will also examine adjacent tissues such as regional lymph nodes to determine if cancer has spread. Determining how far cancer has spread defines the stage of the lesion and gives information as to whether a cancer can be cured by surgical means alone.

Cancers that are localized are generally curable using a combination of surgery and possibly radiation therapy. Other tumors that have spread beyond the primary organ to adjacent organs or lymph nodes require systemic therapy which now could be endocrine therapy, chemotherapy, targeted therapy, or immunotherapy or a combination of all of these.

The pathologist has an array of advanced diagnostic tools at their disposal. They will generally use immunohistochemistry—a method that can “paint” tumors with a dye to determine if a specific protein is present.

This can be used to help determine the primary origin of a metastatic cancer when the primary is unknown. Stains such as S100 or keratin can help determine if a tumor is a melanoma or a carcinoma. A stain such as TTF1 can determine whether the tumor might be of lung origin.

Other immunohistochemical stains can help determine what driver mutations are present within a cancer helping an oncologist select a specific treatment. A good example is breast cancer. In invasive breast cancer all new cases undergo staining with antibodies against estrogen receptor, progesterone receptor, HER2, ki67 and sometimes Androgen receptor. This combination of stains can help determine if a breast cancer might be likely to respond to an anti-hormonal treatment such as tamoxifen or if an anti HER2 receptor treatment such as trastuzumab could be used.

Some cancers such as lung cancer require an extensive molecular evaluation. This examination requires performing a combination of Immunohistochemistry, fluorescent hybridization (FISH) and gene sequence analysis. This complex testing algorithm is necessary to screen for presence of targetable DNA mutations such as EGFR activating mutations, ALK, RET, ROS, NTRK translocations, or overexpression of the checkpoint control molecular PDL1.

Lung cancer with its complexity is considered one of cancers with the most advanced treatment algorithms and a plethora of treatment options. Targeted therapies have resulted in significant improvements of disease free survival. Immunotherapies have added to this with even more dramatic responses in some patients with extraordinary durable responses in some patients.

There is now an extraordinary explosion of new treatment options and therapy modalities. This is creating a crisis in clinical trials in which there are so many trials now open making it hard to fill them or to best select patients for a particular therapy.

This challenge will likely be met through the work of molecular pathologists who will create better companion diagnostics to better select patients for a specific treatment. Another tool, the liquid biopsy, which can measure mutant DNA in blood or circulating malignant cells in blood can now offer the opportunity to measure a cancer in “real time” and adjust medication on the fly—optimizing dosing to minimize toxic side effects and manage tumor control in an optimal way to avoid induction of growth escape.

While the world of precision medicine and personalized oncology continues to explode, the pathologist and molecular pathologist maintain a central role in managing the tissue and testing of samples from patients to ensure that the safest and most effective treatment options are available for use by a treating oncologist.

The role of the physician you never knew you had continues to grow!