Decoding the PAM Pathway: What Your Biomarkers Mean
- Surviving Breast Cancer
- 4 days ago
- 9 min read
Updated: 2 hours ago
PIK3CA. AKT1. PTEN. mTOR. What the PI3K/AKT/mTOR pathway means for breast cancer treatment — and the questions worth bringing to your next appointment.
SurvivingBreastCancer.org. Editorial EDUCATION | BIOMARKERS
Breast cancer treatment is becoming increasingly personalized, but that progress comes with an entirely new vocabulary. PIK3CA. AKT1. PTEN. mTOR. These terms may appear on a biomarker report or come up when an oncologist is discussing why a treatment stopped working, or what treatment might come next. Together, they are part of the PI3K/AKT/mTOR pathway, often shortened to the PAM pathway. Understanding this pathway will not tell you exactly how your cancer will behave, but it may help explain what is driving it, why biomarker testing matters, and whether a targeted treatment could be an option.
For some people with breast cancer, changes within the PAM pathway can help cancer cells grow, survive, or become less responsive to treatment. Finding those changes through biomarker testing may help your care team identify a treatment designed to target what is driving the cancer.
Key Takeaways
The PI3K/AKT/mTOR, or PAM, pathway helps regulate how cells grow, use energy, and survive.
Changes involving genes such as PIK3CA, AKT1, or PTEN can allow cancer cells to continue receiving growth signals.
PAM pathway alterations are especially relevant in hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.
Biomarker testing may identify an alteration that helps guide treatment, but blood and tissue tests do not always provide the same information.
A negative liquid biopsy does not necessarily rule out a mutation. In some cases, testing tumor tissue may provide additional answers.
Having an alteration does not guarantee that a targeted treatment will work. Treatment decisions also depend on previous therapies, overall health, side-effect risks, and personal priorities.
Side-effect prevention and early management, particularly for high blood sugar, rash, diarrhea, and mouth sores, are an important part of treatment.
What is the PAM pathway?
The PAM pathway is one of the communication systems cells use to control growth, division, energy use, and survival. In a healthy cell, the pathway switches on when it is needed and quiets down when the job is complete. In some breast cancers, however, a mutation or another molecular change disrupts this process. The pathway may continue sending growth and survival signals even when it should stop.
Several genes and proteins play important roles:
PI3K helps begin and pass along signals that tell a cell to grow.
PIK3CA is the gene that provides instructions for making one part of the PI3K protein.
AKT carries growth and survival messages farther into the cell.
mTOR helps regulate cell growth, metabolism, and protein production.
PTEN helps slow the pathway down and acts as one of its natural brakes.
When PIK3CA or AKT becomes overly active, or when PTEN no longer functions properly, the cancer cell may gain another way to grow and survive.
WHY IT MATTERS
Why does this pathway matter in breast cancer?
Changes in the PAM pathway are found across different breast cancer subtypes, but they have become especially important in the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.
One of the most commonly discussed changes is a mutation in PIK3CA. A PIK3CA mutation can cause the PI3K protein to remain overly active, sending ongoing signals that encourage the cancer cell to grow.
Alterations involving AKT1 or a loss of normal PTEN function can have a similar effect by activating other parts of the pathway or removing the signals that would normally slow it down.
The PAM pathway may also play a role in treatment resistance. For example, a hormone receptor-positive breast cancer may initially rely heavily on estrogen to grow and respond well to endocrine therapy (also referred to as hormonal therapy). Over time, some cancer cells may begin using another signaling system such as the PAM pathway to continue growing despite treatment.
Cancer cells can change over time and develop new ways to survive. That is one reason biomarker testing may need to be revisited when cancer returns or progresses.
TESTING
What is biomarker testing, and why is it important?
Biomarker testing is different from testing for inherited cancer risk. A hereditary genetic test usually looks for changes you were born with such as certain mutations in BRCA1, BRCA2, or PALB2, among many others, that may be present throughout the body and passed through families.
Tumor biomarker testing looks primarily for changes that developed inside the cancer cells. These are called somatic alterations. Most PIK3CA mutations found in breast cancer are somatic. This means they developed in the tumor and were not necessarily inherited from a parent or passed on to a child.
Some people benefit from both hereditary genetic testing and tumor biomarker testing because the tests answer different questions.
How is the PAM pathway tested?
Testing may be performed using tissue from the tumor, from a blood sample, or both.
A laboratory may test tissue collected during a biopsy or surgery. In some cases, previously collected tissue can be used, although a newer sample may provide a more current picture of the cancer.
A liquid biopsy uses a blood sample to look for small pieces of tumor DNA circulating in the bloodstream. This is known as circulating tumor DNA, or ctDNA. Liquid biopsies are less invasive than tissue biopsies and may detect information released by cancer in different parts of the body. However, not every cancer releases enough DNA into the blood to be detected. A negative liquid biopsy does not always mean that an alteration is absent.
If your liquid biopsy comes back negative, an important question to raise with your oncology team would be:
“My blood test did not find a mutation. Could testing tumor tissue give us additional information?”
TREATMENT
What could a PAM pathway alteration mean for treatment?
Finding a PAM pathway alteration does not automatically determine your next treatment. It does, however, provide another piece of information your oncology team can use when comparing options.
Several medications target different parts of the pathway. Their FDA-approved uses currently focus primarily on specific groups of people with HR-positive, HER2-negative locally advanced or metastatic breast cancer.
These medications are not interchangeable. Eligibility depends on the exact alteration, previous treatments, timing of recurrence or profession, one’s overall health, and other individual factors.
Does having a mutation mean the treatment will work?
No biomarker can guarantee that a medication will work. A biomarker may tell your care team that a treatment is more likely to help a particular group of patients. But every cancer is complex. A tumor may have several alterations and use more than one pathway to grow. The presence of a mutation also does not tell us exactly how long a treatment will work for one individual.
Your care team will consider:
The exact alteration identified
Your breast cancer subtype
Previous treatments
How long earlier treatments controlled the cancer
Where the cancer is located
How quickly it is progressing
Your overall health
Diabetes, prediabetes, or other medical conditions
Possible medication interactions
Side effects and quality-of-life priorities
Available clinical trials
Biomarker testing can help personalize treatment, but it is one part of a much larger conversation.
SIDE EFFECTS
What side effects should patients know about?
The PAM pathway is involved in normal functions throughout the body, including blood sugar regulation, cell growth, and metabolism. Blocking the pathway can therefore affect healthy cells as well as cancer cells.
Side effects vary by medication, dose, treatment combination, and individual health.
High blood sugar
PI3K and AKT inhibitors can raise blood sugar, sometimes significantly.
Before beginning treatment, your care team may check:
Fasting blood glucose
Hemoglobin A1C
Current diabetes medications
Personal or family history of diabetes
Other factors that could increase your risk
Blood sugar may need to be monitored closely after treatment begins.
Contact your care team if you experience:
Increased thirst
Frequent urination
Unusual hunger
Blurred vision
Headaches
Weakness or extreme fatigue
Confusion
Having diabetes or prediabetes does not always mean that a pathway inhibitor cannot be used. It may mean that additional planning, monitoring, or support from an endocrinologist is needed.
Mouth sores
Mouth soreness or ulcers, sometimes called stomatitis, can occur with several pathway inhibitors.
Depending on the medication, your team may recommend a specific mouth rinse or other preventive strategy. Do not assume that all mouthwashes are appropriate, since products containing alcohol may worsen irritation.
Diarrhea
Diarrhea can lead to dehydration and electrolyte changes if it is not controlled.
Ask your team:
When should I start an antidiarrheal medication?
How many episodes should prompt a call?
What should I drink or eat?
When is diarrhea considered urgent?
Rash
Rash can occur with some PI3K and AKT inhibitors. Reporting it early gives your care team the opportunity to intervene before it becomes more severe.
Contact your team about new itching, redness, pain, blistering, peeling, or sores involving the skin, mouth, eyes, or genital area.
Other side effects
Depending on the treatment, additional effects may include:
Nausea
Decreased appetite
Changes in blood counts
Increased risk of infection
Changes in liver or kidney laboratory results
Inflammation involving the lungs
Changes affecting the eyes
This does not mean that every patient will experience every side effect. It means that having a clear monitoring and management plan matters.
Managing side effects is part of treatment
Side-effect management is not an afterthought. It is part of receiving cancer treatment safely. Addressing symptoms early may help prevent complications, reduce interruptions, and make it easier to remain on treatment when the medication is helping.
Before starting a PAM pathway inhibitor, consider asking:
What side effects are most common with this exact medication?
Which symptoms require an immediate call?
How often will my blood sugar and laboratory results be checked?
Will I need to monitor my blood sugar at home?
Should I meet with an endocrinologist before treatment?
Will you recommend medications to help prevent rash or mouth sores?
Are there foods, supplements, or medications I should avoid?
Who should I contact during evenings or weekends?
Does the PAM pathway matter in early-stage breast cancer?
The pathway can be present and biologically important in early-stage breast cancer, but most established PAM-targeted treatment uses in breast cancer currently apply to locally advanced or metastatic disease.
Finding a PIK3CA, AKT1, or PTEN alteration in an early-stage tumor does not automatically mean that a PAM pathway inhibitor should be added to treatment.
Researchers continue to study whether these medicines could help prevent recurrence or improve outcomes in earlier-stage disease. Clinical trials are necessary to determine whether a treatment is both safe and beneficial in a new setting.
What about triple-negative or HER2-positive breast cancer?
PAM pathway alterations can also occur in triple-negative and HER2-positive breast cancers.
However, finding an alteration does not necessarily mean that one of the currently approved PAM-targeted treatments is appropriate.
Researchers are studying pathway inhibitors in different breast cancer subtypes and in combination with:
Chemotherapy
HER2-targeted therapies
Endocrine therapy
Immunotherapy
Other targeted treatments
A clinical trial may be an option for some patients whose tumor has a pathway alteration but who do not meet the criteria for an existing FDA-approved treatment.
How might targeting the pathway improve outcomes?
Biomarker testing may reveal a specific alteration that can be targeted with an available medication. Blocking the PAM pathway may help interrupt one of the routes cancer cells use to continue growing despite endocrine therapy. For some patients, combining endocrine therapy with a targeted treatment may help control cancer longer than endocrine therapy alone.
Questions to ask your care team
Consider bringing these questions to your next appointment:
Has my cancer been tested for PIK3CA, AKT1, PTEN, and other actionable biomarkers?
Was the testing performed on blood, tumor tissue, or both?
Which genes were included in the test?
If my liquid biopsy was negative, should tumor tissue also be tested?
Could my cancer’s biomarkers have changed since my original diagnosis?
Does my result make me eligible for an FDA-approved treatment?
How does this option compare with the other treatments available to me?
What benefit was seen in clinical trials for patients whose situation was similar to mine?
What side effects should I expect, and what can we do to prevent or manage them?
Will I need blood sugar monitoring or support from an endocrinologist?
Is there a clinical trial targeting this pathway that may be appropriate for me?
Can I have a copy of my biomarker-testing report?
What This Means for Patients
The science behind the PAM pathway is complex, but its relevance to patients is much more practical: it may help explain why a cancer is growing, why a previous treatment is no longer working, and whether another treatment could target a specific feature of the tumor.
Most importantly, you deserve more than a list of unfamiliar letters on a laboratory report. Ask your oncology team to walk you through what was found, what was not found, and whether the results change your options..
Understanding the science does not mean carrying the responsibility for making these decisions alone. It means having the information you need to participate meaningfully in your care.
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This article is intended for educational purposes and is not a substitute for personalized medical advice. Treatment approvals, guidelines, and research continue to evolve. Always discuss biomarker testing, medications, side effects, and treatment decisions with your oncology team.
Funding from Celcuity helps SurvivingBreastCancer.org provide free, evidence-informed education to people affected by breast cancer. Sponsorship does not constitute an endorsement of any product, treatment, or company.