ER+ and PR+ Breast Cancer: Key Statistics and Molecular Insights

ER+/PR+ breast cancer is a subtype of ER positive breast cancer where the tumor cells express both estrogen receptors (ER) and progesterone receptors (PR) on the surface. As the most common type of hormone receptor positive breast cancer, it has both of these receptors which are necessary for tumor cell growth and proliferation. Tumors in this category are more responsive to hormonal therapies that target these receptors such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) and have better outcomes. ER+/PR+ is generally better prognosis than ER+/PR- or ER-/PR-.

ER+/PR+ breast cancer has come a long way in recent years. Research has given us more molecular insights on how estrogen and progesterone work together in tumorigenesis and how we can use this dual signaling for our benefit. ^[1] As a result ER+/PR+ breast cancer is still a hot area of breast cancer research with ongoing studies on the role of these receptors in tumor growth, mechanisms of resistance and new targeted therapies.

Table of Contents

• Prevalence and Features
• Endocrine Therapy for Hormone Receptor Positive Breast Cancer
• HER2 Status and ER+/PR+ Breast Cancer
• Emerging Trends and Technologies in ER+/PR+ Breast Cancer
• Closing Thoughts
• References

Prevalence and Features

Prevalence: ER+/PR+ breast cancers account for about 75.1% of all HER2 negative breast cancers making them the most common hormone receptor positive subtype. This high prevalence means we need to understand the biology and clinical behavior of ER+/PR+ tumors as they are the majority of hormone receptor positive breast cancers. The exact prevalence may vary slightly depending on the population studied and the diagnostic criteria used but ER+/PR+ is the most common breast cancer subtype globally.

Tumor Features

ER+/PR+ breast cancers generally have more favorable clinical features than other hormone receptor positive subtypes. Key features are:

• Lower high grade tumors:
• Only 16.0% of ER+/PR+ tumors are high grade (grade 3) compared to 34.2% of ER+/PR- tumors. This means ER+/PR+ tumors are less aggressive and grow slower.
• Less lymphovascular invasion:
• 17.9% of ER+/PR+ tumors show lymphovascular invasion which is a marker of metastatic spread. 19.6% of ER+/PR- tumors show this feature, further supporting that ER+/PR+ tumors are less likely to early disseminate.
• Lower node positive disease:
• 13.5% of ER+/PR+ tumors are node positive meaning the cancer has spread to the nearby lymph nodes. This is a good prognostic factor as node negative disease is generally associated with lower recurrence risk. ^[2] 19.7% of ER+/PR- tumors are node positive meaning higher risk of regional metastasis.

Analysis of breast tissue helps in determining the hormone receptor status which is important in understanding the tumor behavior and treatment decisions. These features make ER+/PR+ tumors less aggressive and patients with this subtype may have better overall outcomes. ER+/PR+ breast cancers are also diagnosed at an earlier stage than other subtypes which contributes to better outcomes.

Metastatic Breast Cancer Outcomes

Survival and Prognosis:

Patients with ER+/PR+ breast cancer have better survival outcomes than those with other breast cancer subtypes especially ER-/PR- tumors. Effective breast cancer treatment including endocrine therapy has been shown to improve survival for patients with ER+/PR+ breast cancer. ^[3] Overall ER+/PR+ breast cancer has better survival because of effective response to endocrine therapy which targets the estrogen and progesterone receptors on the tumor cells. These therapy have been shown to reduce recurrence and improve long term survival.

Response to Endocrine Therapy

Endocrine therapy is the mainstay of treatment for ER+/PR+ breast cancer, by blocking the hormones estrogen and progesterone that feed the tumor. Co-expression of both ER and PR makes the tumor more responsive to these therapy.

• Zhang et al. (2021) found ER+/PR+ tumors had a median progression free survival (PFS) of 25 months vs 7 months for ER+/PR- tumors (p< 0.001). The study also found 80.9% clinical benefit rate for ER+/PR+ tumors vs 55.6% for ER+/PR- tumors (p< 0.001). ^[4] This shows the importance of PR in predicting response to endocrine therapy. ^[2]
• Clinical benefit rate is the proportion of patients who have partial response or stable disease after treatment. The higher clinical benefit rate in ER+/PR+ patients means PR is not only a biomarker for better prognosis but also for better treatment outcome.

Given these findings PR should be considered in treatment decision. Maybe adding therapy that targets PR pathway or improving existing hormonal therapy can further improve patient outcome.

Endocrine Therapy for Hormone Receptor Positive Breast Cancer

Endocrine therapy is a type of hormone therapy used to treat hormone receptor positive breast cancer. Endocrine therapy works by blocking the body’s natural hormones that can feed the cancer cells. There are several types of endocrine therapy each with different mechanism of action. Tamoxifen is a selective estrogen receptor modulator (SERM) that blocks estrogen receptors on cancer cells so estrogen cannot bind and stimulate cancer growth. Aromatase inhibitors like anastrozole and letrozole blocks estrogen production in the body that can feed the cancer cells. Fulvestrant is a selective estrogen receptor degrader (SERD) that blocks estrogen receptors on cancer cells and promotes its degradation.

These endocrine therapy are effective in treating hormone receptor positive breast cancer by targeting the specific pathway that drives tumor growth. By blocking estrogen and progesterone on cancer cells these therapy can slow down or stop the disease progression. Choice of endocrine therapy depends on many factors including patient’s menopausal status, tumor characteristics and previous treatment received. Endocrine therapy is the mainstay of treatment for hormone receptor positive breast cancer with significant benefit in reducing recurrence and long term survival.

Molecular Mechanism in Hormone Receptor Positive Breast Cancer

Role of Progesterone Receptor (PR):

Progesterone receptor (PR) is a key player in the pathophysiology of ER+/PR+ breast cancer. PR is an estrogen receptor dependent gene product meaning estrogen signaling regulates PR expression. ^[5] Co-expression of both receptors can drive tumor growth through complex signaling network. Hormone receptor status including the presence of both ER and PR determines tumor growth and response to therapy.

• Tumorigenicity: Recent studies have shown that cancer associated fibroblasts (CAFs) in the tumor microenvironment can produce both estrogen and progesterone which can promote tumorigenic process such as:
• Anchorage independent growth: Tumor cells in ER+/PR+ cancers are more likely to grow outside of normal tissue structure, a characteristic of cancer.
• Tumorsphere formation: This is the ability of cancer cells to form sphere in vitro, a sign of stem like property that can contribute to tumor initiation and metastasis.
• Stem cell expansion: ER+/PR+ tumors have more stem like cancer cells which is associated with higher recurrence and resistance to treatment.

These findings suggest that PR may enhance the tumor promoting effect of estrogen to a more aggressive tumor phenotype. Targeting PR signaling either by inhibiting PR itself or by disrupting its interaction with other signaling pathway may be a new therapeutic opportunity.

HER2 Status and ER+/PR+ Breast Cancer

HER2 (human epidermal growth factor receptor 2) is a protein on the surface of some breast cancer cells. HER2 positive breast cancer is more aggressive and grow faster than HER2 negative breast cancer. ER+/PR+ breast cancer can be HER2 positive or HER2 negative and this is important for treatment planning. HER2 positive ER+/PR+ breast cancer are often treated with HER2 targeted therapy such as trastuzumab (Herceptin) in combination with hormone therapy. These targeted therapy work by attacking the HER2 protein on cancer cells and inhibiting its growth and survival.

HER2 negative ER+/PR+ breast cancer are treated with hormone therapy alone. These cancer do not over express HER2 protein so HER2 targeted therapy is not effective. Instead treatment focus on blocking the hormone receptors that drive the growth of these cancer cells. Knowing the HER2 status of ER+/PR+ breast cancer is important to choose the right treatment strategy so patients get the best care.

Proliferation Rate

Proliferation rate is the percentage of cancer cells that are actively dividing and is an important factor in determining the aggressiveness of the tumor. Generally the higher the proliferation rate the more aggressive the tumor is and more likely to metastasize. Ki-67 test is a way to measure proliferation rate. When cells are growing and dividing (proliferating) they produce proteins called proliferation antigens. Ki-67 is a proliferation antigen and the result of this test is reported as percentage of tumor cells with Ki-67 antigen. The higher the percentage the more aggressive the tumor is.

High proliferation rate in breast cancer cells means more aggressive tumor that may need more intense treatment. Low proliferation rate means less aggressive tumor that may respond to standard hormone therapy. By knowing the proliferation rate oncologists can get valuable information about the behavior of the cancer and plan the treatment accordingly. This will help in predicting the outcome of the disease and in making decision for the best treatment for each patient.

Challenges and Future Directions in Hormone Therapy

Although ER+/PR+ breast cancer has good outcome, there are still challenges in fully understanding and treating this subtype:

• Understanding Molecular Pathways: More research is needed to know the exact molecular mechanism of how PR modulate tumor growth and resistance to treatment. Identifying PR associated signaling pathway that contribute to the development and progression of ER+/PR+ tumor may lead to more targeted treatment.
• Targeted Therapy: There is still need to develop therapy that target the unique characteristic of ER+/PR+ tumor. For example combining PR targeted therapy with endocrine therapy or using selective modulator of PR signaling may further improve the outcome.
• Overcoming Resistance: While ER+/PR+ tumor generally respond well to endocrine therapy, resistance to these treatment can develop especially in advanced or metastatic disease. Understanding the mechanism of resistance especially in hormone receptor negative cases such as alteration in the PR receptor itself or changes in the tumor microenvironment will be important in developing strategy to overcome this challenge.

Emerging Trends and Technologies in ER+/PR+ Breast Cancer

There are several emerging trends and technologies in ER+/PR+ breast cancer, including new hormone therapy, biomarker to predict treatment response and combination therapy. One of the promising area of research is the development of CDK4/6 inhibitors which block the activity of cyclin dependent kinases 4 and 6, proteins involved in cell cycle progression. These inhibitors have shown promising results in ER+/PR+ breast cancer by slowing down the proliferation of cancer cells.

Another area of research is the use of PIK3CA inhibitors which block the activity of phosphatidylinositol 3-kinase alpha (PI3Kα) a key player in cell signaling pathway that promote cancer cell growth and survival. Researchers are also exploring combination therapy such as combination of hormone therapy with targeted therapy to improve treatment outcome for ER+/PR+ breast cancer patients. By combining different approach of therapy may overcome treatment resistance and control the disease better.

Biomarker to predict treatment response is also another area of research. Biomarkers are biological molecules that can indicate the presence or progression of the disease and can help identify which patient will benefit most from a particular treatment. By identifying and validating new biomarker researchers hope to develop more personalized treatment that is tailored to each patient’s cancer. These emerging trends and technologies will help in managing and improving the outcome of ER+/PR+ breast cancer and give hope to patients and their families.

Closing Thoughts

ER+/PR+ breast cancer is the most common subtype of hormone receptor positive breast cancer and majority of HER2 negative cases. This subtype has favorable tumor characteristic such as lower tumor grade and less lymphovascular invasion which lead to better survival and response to endocrine therapy. Co-expression of estrogen and progesterone receptor play a key role in the growth and progression of this tumor and PR is a important biomarker for prognosis and treatment decision.

More research on the molecular mechanism of ER+/PR+ breast cancer and development of targeted therapy that address both hormone receptor will help improve patient outcome and overcome treatment resistance. Ongoing research will further reduce breast cancer risk by developing more effective targeted therapy for ER+/PR+ breast cancer.

References

^{[1] Dembinski, R., Prasath, V., Bohnak, C., Siotos, C., Sebai, M. E., Psoter, K., Gani, F., Canner, J., Camp, M. S., Azizi, A., Jacobs, L., & Habibi, M. (2020). Estrogen Receptor Positive and Progesterone Receptor Negative Breast Cancer: the Role of Hormone Therapy. Hormones & cancer, 11(3-4), 148–154. https://doi.org/10.1007/s12672-020-00387-1}

^{[2] Zhang, M., Yan, M., Lv, H., Niu, L., & Zeng, H. (2021). Clinical study of first-line endocrine therapy for type ER+/PR+ and ER+/PR- advanced breast cancer. Annals of palliative medicine, 10(1), 238–243. https://doi.org/10.21037/apm-20-2180}

^{[3] Wei S. (2023). Hormone receptors in breast cancer: An update on the uncommon subtypes. Pathology, research and practice, 250, 154791. https://doi.org/10.1016/j.prp.2023.154791}

^{[4] Hu, T., Chen, Y., Liu, Y., Zhang, D., Pan, J., & Long, M. (2021). Classification of PR-positive and PR-negative subtypes in ER-positive and HER2-negative breast cancers based on pathway scores. BMC medical research methodology, 21(1), 108. https://doi.org/10.1186/s12874-021-01297-8}

^{[5] Jain, A. J., Schultz, K., Brainerd, M. J., Murimwa, G. Z., Fleming, A. M., Fackche, N., Bilir, E., Chiba, A., Martin, A. N., Singh, P., Childers, C. P., Friedman, L. R., Zafar, S. N., Abdelsattar, Z., Cortina, C., Stewart, C., Cowher, M. D., Ganai, S., Merck, B., Nandakumar, G., … Ahmad, S. A. (2024). The Top Ten Annals of Surgical Oncology Original Articles on Twitter/X: 2020-2023. Annals of surgical oncology, 31(13), 9100–9111. https://doi.org/10.1245/s10434-024-15936-z}