Here, we decode the PAM pathway in breast cancer, what it means and explain why it might come up during a conversation about metastatic breast cancer (MBC) treatment. If you have heard terms like PIK3CA, PI3 kinase, AKT1, PTEN or mTOR, the letters can get confusing. However, these terms are part of an important signaling system inside cells that helps control how cells grow and survive.
We’ll walk through what the PAM pathway is (also referred to as the PI3K, PI3 kinase or PI3K/AKT/mTOR pathway), what testing can tell you and how drugs that target this pathway fit alongside your treatment – with insight from Beth Guendjoian, a member of Susan G. Komen’s MBC Steering Committee who was diagnosed with metastatic breast cancer.
Why the PAM pathway matters in breast cancer
PAM stands for three proteins: PI3K, AKT and mTOR. Think of them like a row of on/off switches that pass messages to all the cells in your body. When the pathway is turned on, usually by growth signals from outside of the cell, it tells cells to grow, divide and survive. A protein called PTEN acts like a brake to turn off the pathway, and in healthy cells, the whole process is tightly controlled.
In cancer cells, mutations at several points can leave these switches stuck “on.”
- A PIK3CA gene mutation can make the PI3K protein overactive.
- An AKT1 mutation can leave AKT switched on.
- Changes in PTEN can prevent the brake from being applied, leaving the pathway permanently active.
This can be visualized clearly in our PAM Pathway Visual Resource. Dysregulation of the PAM pathway can occur with or without activating mutations, promoting tumor cell growth and survival. This pathway also talks to other systems that cancer cells use to grow, including estrogen receptor signaling. If hormone therapy blocks estrogen receptor signaling, cancer cells may rely more heavily on another pathway. It’s similar to a game of whack-a-mole, where blocking one growth signal may result in another popping up.
What testing can tell you
Mutations in PIK3CA, AKT1 and PTEN together affect about half of hormone receptor-positive (HR+) breast cancers, with PIK3CA mutations being the most common. Guidelines recommend that people with HR-positive, HER2-negative metastatic breast cancers are tested for changes in these three genes. Testing can use tissue from a biopsy or circulating tumor DNA in the blood, sometimes called a liquid biopsy.
Beth is a strong proponent of genomic testing. Decades after her diagnosis, a stored sample from her tumor still had something to say. “My tumor actually was tested 26 years after I had cancer, and they still got a marker from it,” she explained. “It gives the doctor so much more of an edge.” Ask your doctor which test was used and what your results mean for your treatment.
A result showing a change in PIK3CA, AKT1 or PTEN can help to identify a targeted drug option, but Beth has found that patients are rarely told how testing fits into their plan of care.
PAM pathway drugs are not all the same
There are FDA-approved drugs that target different parts of the PAM pathway. Some are used only when certain biomarkers (measurable molecules detected in your body) are present. Alpelisib and inavolisib are used for cancers with a PIK3CA mutation, while capivasertib may be used for cancers with changes in PIK3CA, AKT1 or PTEN. Everolimus targets mTOR and can be used regardless of what mutations are (or are not) detected in the PAM pathway.
Beth often hears confusion about how these drugs fit into a treatment plan. People may not be told “what each one is” or that it is “an additive therapy to what they’re already doing.”
To be clear: these drugs are given with hormone therapy, not instead of it (often after prior treatments stop working) – and sometimes alongside a CDK4/6 inhibitor.
Understanding possible side effects from treatment
Targeting the PAM pathway has been historically challenging. Because it exists in every cell in the body, blocking it can affect healthy cells along with cancer cells. As a result, side effects for each drug vary but commonly include high blood sugar, rash and stomatitis (inflammation or sores in the mouth). Preventative mouthwash can be prescribed to help reduce symptoms of stomatitis.
High blood sugar, or hyperglycemia, is a particularly challenging issue with these types of drugs and sometimes needs to be managed similar to diabetes. Beth described the importance of knowing this possibility ahead of time, not after. “An endocrinologist may have to be involved, because this happens a lot with this type of therapy,” she said. “This way, they’re not blindsided by it.” For some people already managing diabetes, this can complicate the use of certain PAM pathway drugs.
A long list of possible side effects is not a prediction, though. “You’re reading like 90 of them and you’re thinking, why would I want to sign up for that,” said Beth, noting that you don’t typically experience all of them. Before treatment, ask how often your blood sugar will be checked and which side effects are most likely for you.
Evolving treatment options
Given the importance of the PAM pathway, researchers continue to study new drugs that may overcome the challenges of targeting it with the hope of reducing side effects as well as increasing their availability to more patients. The FDA recently approved gedatolisib (PAM pathway inhibitor) with fulvestrant (hormone therapy), with or without palbociclib (CDK4/6 inhibitor), for HR+/ HER2- advanced or MBC without a detected PIK3CA gene mutation that has progressed after initial treatment with hormone therapy (typically in combination with CDK4/6 inhibitors). Unlike other PAM pathway drugs, gedatolisib blocks the PAM pathway at more than one point (PI3K and mTOR) rather than flipping a single switch. Blocking at these points also indirectly inhibits downstream AKT.
In combination with fulvestrant with or without palbociclib, gedatolisib delays cancer progression, and trials have shown relatively lower hyperglycemia than observed in clinical trials testing other PAM pathway drugs. While gedatolisib has been approved for cancers that do not have a detected PIK3CA mutation, positive clinical trial results have also been reported for those with mutations as well.
Researchers are also investigating drugs like zovegalisib and tersolisib, which are designed to block the mutated form of PI3K while largely sparing the normal version found in healthy cells. In clinical trials so far, this approach has been associated with less hyperglycemia, rash and stomatitis.
Clinical trials pave the way for new treatment options
One cancer center may offer different trials than another. Beth has attributed a clinical trial to saving her life. “Every facility doesn’t have every trial or access to every trial. This is where Komen and other organizations come in to help,” she said.“The conversation needs to be what clinical trials are available to me, not only here, but elsewhere. We, as cancer patients, need to be educated to know…where we’re going to get better.”
Clinical trial information can be overwhelming. “And that’s where a good team comes in place. Somebody has to guide us through that,” Beth said.
Your care team can help you understand how a trial fits with your tumor biomarkers, previous treatments, quality-of-life goals and travel limitations. You do not have to sort through every acronym, test result and treatment option alone. The PAM pathway can seem complex, but testing and understanding it can help guide conversations with your care team and open the door to newer, more targeted options.
Content covered in the Know More Educational Series may be an emerging area in research or technology. Talk with your doctor about what is right for you.
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Explore more resources:
Four Things to Know About Clinical Trials When You’re Diagnosed with Breast Cancer
Breast Cancer Breakthroughs Episode 16: On the Horizon of PI3K Pathway Inhibition
Understanding Metastasis and Four Ways to Take Charge of a Metastatic Breast Cancer Diagnosis
