Posted on Jun 23, 2024

Endocrine therapy has for decades been one of the key treatment choices for hormone receptor-positive breast cancer. Yet predicting who will and won’t benefit from therapy remains a challenge. In this article, we explore whether gene expression profiling with MammaTyper® may make up for the shortfalls of IHC in this area.

Oestrogen receptor (ER) is one of the most important predictive biomarkers in breast cancer, identifying cancers which are likely responsive to endocrine therapies. By some estimates, as many as 80% of people with breast cancer have ER-positive tumours, making endocrine therapy one of the most used cancer therapies. Resistance to endocrine therapy is often based upon acquired mutations in the ESR1 gene which reactivate ER signalling, even in the presence of endocrine therapy. Alternatively, mutations may activate ER-independent pathways which promote cancer cell survival and growth (Hanker et al 2020, Cancer Cell).

Intrinsic resistance

Predicting intrinsic endocrine therapy resistance comes with its own challenges. The effectiveness of endocrine therapy is known to vary depending on ER expression. But the relationship between therapy response and ER expression as measured by immunohistochemistry (IHC) is not a linear correlation, according to a review by Emad Rakha and colleagues in 2022. “As such, the determination of the lowest cut-off that should be used to define ER positivity is difficult,” they write (Rakha et al 2022, Pathobiology).

The shortfalls of IHC – and potential of RT-qPCR

It’s long been known that many pre-analytical variables affect the reliability of IHC testing, for ER and other markers (Reisenbichler et al 2013, Am J Clin Path). As a result, we believe it is no longer acceptable to rely solely upon IHC for breast cancer subtyping, particularly for ER-positive breast cancer, the most common form of the disease. People affected by breast cancer deserve a better, more reliable technology.

There is a great opportunity presented for mRNA expression profiling of ER and other key biomarkers. It could be possible to test well-characterised breast cancer markers with RT-qPCR to predict resistance to endocrine therapies, allowing clinicians to adjust treatment for the benefit of breast cancer patients.

Therapy de-escalation

Another area where RT-qPCR testing could be beneficial is in the de-escalation of endocrine therapy. For instance, low-dose tamoxifen (babytam) has been shown to reduce recurrence of non-invasive breast cancers for at least 10 years (Lazzeroni et al 2023, JCO).

IHC has poor sensitivity at low levels of ER protein, which may affect the ability to identify patients that could benefit from de-escalation. On the other hand, RT-qPCR testing is proven to be very sensitive and reliable even at low levels of ESR1 mRNA expression.

Collaboration on studies to predict endocrine therapy resistance

Following extensive technical validation, we have shown that MammaTyper® is a linear, quantitative, reproducible, and standardised RT-qPCR test for ER and other key breast cancer markers: PR, HER2, and Ki67. Our mission for 2024 is to further demonstrate the clinical utility of the assay.

We are looking for collaborators to help us find simpler and more reliable ways to predict endocrine resistance, and ultimately improve survival for people affected by the most common type of breast cancer.

If you are interested in discussing a potential collaboration, please contact us at: