A Better Option For Women With Common Type Of Advanced Breast Cancer: New Trial Data Provides Hope

The combination reduced the risk of disease progression or death by 56% in patients with HR+ breast cancer and an emerging ESR1 mutation and the phase III SERENA-6 study was the first to demonstrate the value of closely monitoring circulating tumor DNA (with a blood test) so cancer can be treated before progression shows up on scans.

“Hormone receptor positive cancer represents approximately 70% of all breast cancer patients in the metastatic setting,” Dr. Alison Dziarmaga, Vice President of drugmaker AstraZeneca’s U.S. Breast Cancer Franchise, tells SurvivorNet of the research’s significance. “… The [SERENA-6] trial is innovative really for two main reasons. The first is that it looks to catch cancer at its very earliest opportunity before it progresses onto a radiological scan.

“… The second is just the data, which is incredible. We’re really looking forward to showing a meaningful difference … where we show a reduction of 56% in disease progression and death and we hope that that offers additional options for consideration when you’re in the clinic. ”

SERENA-6 Trial: Hope In The Metastatic Setting

The promising findings came from the phase III SERENA-6 study, a clinical trial that enrolled people who had not yet experienced obvious progression on their first-line (first treatment) hormone therapy. Phase III trials are the most important piece of scientific evidence as they help researchers understand if a new treatment approach is better than what is already being used (the standard of care).

If you or someone you love is living with advanced breast cancer that feeds off a hormone (HR+), you probably know the routine: start with an aromatase inhibitor such as letrozole or anastrozole, add a CDK4/6 inhibitor like palbociclib, then watch and wait — hoping the cancer stays quiet.

Unfortunately, many tumors eventually outsmart aromatase inhibitors by picking up a change in the estrogen-receptor gene called ESR1. Once that mutation shows up, standard hormone pills lose their punch.

The SERENA-6 trial is the first to demonstrate that looking for this mutation with a blood test, before cancer growth is detected on scans, has value and early treatment can help patients live longer.

“SERENA-6 is a really important study in that it’s the first global, randomized phase III study that utilizes [circulating tumor] DNA guidance to direct therapy for patients,” Dr. Nancy Chan, director for breast cancer clinical research at NYU Langone Perlmutter Cancer Center, tells SurvivorNet.

“Currently the frontline metastatic regimen for patients with HR+, HER2-breast cancer entails endocrine therapy or anti-estrogen therapy with a CDK4/6 inhibitor. This trial actually implemented 8-week monitoring of a liquid biopsy, so it is monitoring the disease for a mutation called ESR1 every two months and should a patient develop an ESR1 mutation, then the therapy can change to an oral selective estrogen receptor degrader.”

Dr. Chan describes the approach as “staying ahead of changes at a mutational level in the blood and using that to guide early changes or interventions in therapy.”

Understanding the ESR1 Mutation

DNA is like an instruction manual. The ESR1 gene writes the recipe for the estrogen receptor.

When that gene mutates, the receptor changes shape. The new shape can stay “always on,” even if estrogen levels drop to near zero. About one in three people on prolonged aromatase-inhibitor therapy will develop an ESR1 mutation.

Implementing a liquid biopsy, which examines tiny fragments of tumor DNA that float in the bloodstream, lets doctors detect the change months before a routine scan shows growth.

Before the SERENA-6 trial, there was no proof that acting on the mutation early would help patients live longer without disease progression. The trial offers the first high-level evidence that it does.

SERDs: Selective Estrogen Receptor Degraders

Think of the estrogen receptor as a lock. Aromatase inhibitors lower estrogen, so fewer “keys” float around. SERDs go one step further by yanking the lock right out of the door. In early studies, camizestrant has shown it can break down mutant estrogen receptors that ignore low estrogen levels.

The SERENA-6 trial asked a straightforward question: If we spot the ESR1 mutation early in a blood test, can we get ahead of the cancer by swapping treatments before scans show tumors growing?

Camizestrant: A Next-Generation SERD

You might have heard of fulvestrant, the injectable SERD used for many years after first-line treatment fails. Fulvestrant works well, but must be given as a monthly intramuscular shot (injected into the muscle), and its large-molecule design limits how much reaches metastatic sites such as the liver or lungs.

Camizestrant is different in several ways, including:

• It is a small pill taken once daily, so no clinic visits for injections.
• In laboratory models it was 50 to 100 times more potent at degrading both normal and mutant estrogen receptors.
• Early-phase trials hinted that camizestrant plus a CDK4/6 inhibitor could postpone tumor growth in people whose cancers already carried an ESR1 mutation.

HR+, HER2- Advanced Breast Cancer

When a cancer is described as hormone-receptor positive (HR+), it means the cancer cells use estrogen and/or progesterone signals to grow.

HER2-negative (HER2-) means the disease does not overproduce the HER2 protein, so it usually does not respond to HER2-targeted drugs.

Advanced or metastatic indicates the cancer has spread beyond the breast and nearby lymph nodes. This stage is generally not curable, but it often responds to medicines that block estrogen signaling or cell-cycle machinery.

Today’s standard first-line care combines an aromatase inhibitor with one of three CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib). These drugs slow cancer growth by putting the cell-cycle “engine” into low gear. Most people enjoy a year and a half to two years of controlled disease on this doublet. The challenge arrives when the tumor finds a detour — often through an ESR1 mutation.

Questions To Ask Your Doctor

• Would liquid-biopsy ESR1 testing make sense for me, and how often?
• If a mutation appears, could I switch to camizestrant through a clinical trial or compassionate-use program?
• How do the possible side effects compare with my current medicine?
• Would the switch limit future options like antibody-drug conjugates or PI3K inhibitors?
• How will my quality of life be tracked and supported during treatment?
• Can I keep working, caring for my family, or traveling while on this therapy?

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