Progesterone Receptor Positive (PR+) Breast Cancer: Characteristics, Treatment and Prognosis

Progesterone Receptor Positive (PR+) breast cancer is a distinct biological subtype of hormone receptor positive breast cancer. This type of cancer grows in response to progesterone, a hormone that is key in the menstrual cycle and pregnancy. Breast cancer cells with hormone receptors, such as estrogen and progesterone sensitive ones, drive cancer growth and are key to treatment decisions.

Like Estrogen Receptor Positive (ER+) breast cancer, PR+ tumors are treated with hormone therapy so they are a key part of the bigger picture of breast cancer. ^[1] Knowing the molecular underpinnings, treatment and prognosis of PR+ breast cancer is crucial to get the best outcome for patients.

Table of Contents

• Epidemiology and Clinical Relevance
• Diagnosis: Screening Modalities, Biomarkers and Staging Systems
• Treatment: Hormone Therapy and Emerging Therapies
• Case Studies: Clinical Scenarios to Illustrate Decision-Making
• Patient Care: Psychosocial Considerations and Survivorship
• Closing Thoughts
• References

Epidemiology and Clinical Relevance

Breast cancer is the most common cancer in women worldwide with many subtypes and characteristics including hormone receptor positive subtypes (ER+/PR+) which account for about 70% of cases. PR is found in a large proportion of ER+ tumors and is associated with better outcomes as endocrine therapies are more effective. ^[3] But challenges remain including resistance mechanisms and the impact of menopausal hormone therapy on cancer risk.

Pathophysiology: Molecular Mechanisms and Risk Factors

Hormonal Regulation and Hormone Receptor Status: The progesterone receptor (PR) is an estrogen receptor (ER) dependent gene product meaning its expression is driven by ER activation. ^[5] Hormones estrogen and progesterone are key in breast cancer as cancer cells use hormone receptors to fuel their growth. This close relationship between the receptors is biological interdependence in breast cancer.

Modulation of Estrogen Receptor-α (ERα): PR acts as a modulator of ERα, how estrogen receptor pathways drive tumor growth. This is key to understanding the different responses to hormone therapies. ^[2]

Risk Factors

• Endogenous Hormones: High lifetime exposure to estrogen and progesterone increases the risk of hormone receptor positive breast cancer.
• Exogenous Hormones: A study by Salagame et al. found an adjusted odds ratio (aOR) of 2.29 (95% CI: 1.41-3.72) for ER+/PR+ breast cancer in women on menopausal hormone therapy. Hormone receptor negative tumors do not have the receptors for hormone therapies to be effective so have different treatment limitations and different recurrence risk compared to hormone receptor positive tumors. ^[4]
• Genetic Factors: BRCA1/2 mutations and single nucleotide polymorphisms (SNPs) in hormone receptor genes may be involved.

Diagnosis: Screening Modalities, Biomarkers and Staging Systems

Screening and Detection

• Mammography: Still the gold standard for detection.
• Ultrasound and MRI: Used adjunctively in dense breast tissue.
• Hormone Receptor Testing: On breast tumors, estrogen and progesterone receptors, is key as it drives cancer cell growth and helps clinicians tailor treatment based on the characteristics of the tumors.
• Biomarkers: Immunohistochemistry (IHC): Determines ER and PR status, the foundation of breast cancer classification.
• Ki-67 Proliferation Index: Gives insight into tumor aggressiveness.
• Oncotype DX and MammaPrint: Genomic tests that predict recurrence risk and guide treatment decisions.

The presence of hormone receptors on cancer cells determines treatment and tumor growth, so both diagnostic and therapeutic implications of different types of breast cancer.

Staging Systems

• TNM Staging: Tumor size (T), lymph node involvement (N), metastasis (M) combined.
• AJCC 8th Edition: Includes PR status in staging for more accurate prognosis.

Treatment: Hormone Therapy and Emerging Therapies

Hormone Therapy

Hormone therapy is the mainstay for PR+ breast cancer. Options include:

1. Selective Estrogen Receptor Modulators (SERMs): Tamoxifen blocks ER activity, reduces recurrence risk.
2. Aromatase Inhibitors (AIs): Letrozole and anastrozole blocks estrogen synthesis, more effective in postmenopausal women.
3. Selective Estrogen Receptor Degraders (SERDs): Fulvestrant degrades ER and is used more in advanced disease.

Emerging Therapies

• Targeted Therapies: PR specific pathways being investigated.
• CDK4/6 Inhibitors: Agents like palbociclib add to hormone therapy in metastatic setting.
• PI3K/AKT/mTOR Inhibitors: Target resistance mechanisms by blocking downstream signaling.

Case Studies: Clinical Scenarios to Illustrate Decision-Making

Case 1: Early-Stage Progesterone Receptor Positive Breast Cancer

• Patient: 45 yo premenopausal woman with stage II ER+/PR+ IDC.
• Result: Excellent response, no recurrence at 5 years.

Case 2: Advanced PR+ Breast Cancer with Resistance

• Patient: 62 yo postmenopausal woman with metastatic PR+ breast cancer on AIs.
• Treatment: Switch to fulvestrant with palbociclib.
• Result: Stable disease and improved QOL for 18 months.

Patient Care: Psychosocial Considerations and Survivorship

Psychosocial Support

• Address anxiety and depression common in breast cancer patients.
• Provide resources for counseling and support groups.

Survivorship

• Monitoring: Follow-ups for recurrence and treatment side effects.

• Lifestyle Interventions: Diet, exercise and weight management reduces recurrence risk.

Challenges and Future Directions

• Hormone Therapy Risks: Menopausal hormone therapy carries breast cancer risk so need personalized counseling.
• Therapy Resistance: Resistance mechanisms need to be understood especially in advanced and metastatic disease.
• New Therapies: Trials are ongoing to develop PR specific agents to change the treatment landscape.
• Prognostic Biomarkers: Need biomarkers to predict response and resistance for precision medicine.

Closing Thoughts

PR+ breast cancer is a clinically relevant subtype that responds well to hormone therapy. PR+ tumors have better PFS and OS than PR- tumors so PR is a prognostic biomarker. But hormone therapy risks and resistance need to be addressed. Research targeting PR specific pathways and resistance mechanisms will help improve patient care.

References

^{[1] 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}

^{[2] 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.}

^{[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] Salagame, U., Banks, E., O’Connell, D. L., Egger, S., & Canfell, K. (2018). Menopausal Hormone Therapy use and breast cancer risk by receptor subtypes: Results from the New South Wales Cancer Lifestyle and EvaluAtion of Risk (CLEAR) study. PloS one, 13(11), e0205034. https://doi.org/10.1371/journal.pone.0205034}

^{[5] Li, Z., Wei, H., Li, S., Wu, P., & Mao, X. (2022). The Role of Progesterone Receptors in Breast Cancer. Drug design, development and therapy, 16, 305–314. https://doi.org/10.2147/DDDT.S336643}