Cancer adapts and evolves over time and under the selective pressure of systemic treatment, becoming increasingly resistant over time. This brief slidedoc fo summarizes key points in how cancer adaptation leads to resistance and changes our treatment recommendations.

1. Key Clinical Implications Based on
How an Advanced Cancer Evolves
H. Jack West, MD

2. 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.

3. The Efficacy of Anti-Cancer Treatment
Diminishes 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 Response
Progression with
Resistance

4. Implications for Advanced
Cancer 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.

5. 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

6. 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.

7. For questions, comments, and
further information, check out
CancerGRACE.org