Key Clinical Implications Based on How an Advanced Cancer Evolves

H. Jack West, MD

Cancer Evolves and Adapts

• A cancer is especially prone to developing new, potentially adaptive mutations as it grows and divides faster and less well controlled than normal cells.

• Cancer typically follows a pattern of being most responsive to treatment early, then becomes more resistant over time, as mutated, resistant cancer cells grow under “selective pressure” of the anticancer therapy.

• Cancer is caused by a collection of mutations in a cell that lead to loss of control of the cell growth process, typically a combination of faster growth & cell division along with loss of inhibitory controls.

The Efficacy of Anti-Cancer TreatmentDiminishes Over Time

• Over the course of treatment, the efficacy of treatment is greatest early on, as the treatment kills a greater proportion of the cancer cells. For many cancers, even a very effective systemic therapy kills a proportion but not all of a cancer.

• As treatment continues, a greater proportion of the cancer cells that remain are resistant to that therapy. As the sensitive cells die, the remaining ones grow, leaving more of the cancer newly resistant to the same treatment that was effective previously.

Sensitive cancer cell

Resistant cancer cell Time/Ongoing treatment

Untreated Cancer Partial ResponseProgression with

Resistance

Implications for AdvancedCancer Treatment

• When a cancer cannot be entirely removed or radiated, treatment is typically with the most effective systemic (whole body) therapy, producing the greatest tumor shrinkage early on.

• In advanced lung cancer, for example, initial chemotherapy treatment is typically 4-6 cycles, when it reaches a point of diminishing returns.

• Beyond that point, we often offer a break from treatment or transition to a less intensive maintenance therapy that is not likely to further shrink the cancer but can control it and slow the time before it progresses.

• Over time, the cancer develops acquired resistance to ongoing treatment and requires a change to a different approach to which the cancer cells may be more sensitive.

Cancer Can Become More Aggressive Over Time

• We use the observed pace of the cancer to predict the future behavior of that cancer.

• Some cancers are very aggressive and grow quickly. Some are much more indolent and grow slowly.

• A cancer can gradually or suddenly develop a new mutation and change its behavior. Under the microscope, a biopsy may show a change from well to poorly differentiated as it changes from clinically indolent to more aggressive.

Well differentiated adenocarcinoma

Poorly differentiated adenocarcinoma

The Challenge of Treating an Incurable Cancer as it Becomes More Resistant

Tumor burden

Time

First line treatment

Maintenance

Second line

Third line

• As treatment continues and a patient experiences cumulative side effects and more weakness from growing cancer, risks of further treatment grow.

• As treatment continues and the cancer becomes more resistant, treatment works less effectively and for a shorter period with ongoing lines of treatment.

Side effects

• At a point that varies from patient to patient, further treatment is more likely to cause harm than benefit. It is appropriate to favor a transition to symptomatic care exclusively at that time.

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