Early Stage Breast Cancer Treatments - An overview

Cancer is a condition in which cells escape their normal cycle of life and death. This is achieved through a system of genetic mutations and changes that allow them to become 'immortalised' (or very resistant, but not completely immune to, cell death). They may then alter their structure in a way that functions only to sustain itself and other nearby cancer cells. If this continues over time, cancer cells may form a conglomeration called a tumour, which may cause damage to the surrounding tissue, and possible detriments to the normal function of the organs or structures in which the tumour arose. In advanced cases, it may cause extreme discomfort, illness or death in the affected individual. This is associated with metastasis, which is an invasion of cancer cells from its 'origin' into other nearby organs or tissues.

Breast cancer is a common form of this disorder which may metastasise via the lymphatic system, as many lymph nodes are located in that general area. The disease is strongly associated with mutations in the BRCA-1 and -2 genes.

Breast cancer cells may express receptors for female hormones that regulate many aspects of normal function and development, which is a simple and effective method to help them grow and spread further.

Understanding Early Stage Breast Cancer

Early breast cancer is generally characterised by the detection of cancer cells in the ducts or lobes of the breast. This is known as stage 0 (zero) breast cancer.

Stage 1 (one) involves the appearance of carcinomas (tumours) measuring two centimetres or less.

The presence of these tumours accompanied by invasion into the lymph nodes is termed Stage 2 (two).

In stage 3a (three A), the tumours may be larger, with cancer cells present in up to nine lymph nodes.

These stages are often termed 'early-stage breast cancer'. Due to the pernicious potential effects on health and lifespan associated with this type of cancer, treatment at these stages may be initiated as soon as possible following detection.

Early Stage Breast Cancer Treatments

Effective lines of treatment for early-stage breast cancer are:

Surgery

These are procedures, known as mastectomies, that remove tumours and/or some tissue surrounding them. Procedures to remove small tumours are known as lumpectomies. Quadrantectomies remove more healthy tissue around a tumour. These are known as partial or breast-conserving mastectomies, which may be more appropriate for early-stage cancers. Partial mastectomies are associated with high survival rates and low return of tumours. Another advantage of mastectomy is that the tissue may be analysed in terms of cancer cell spread; i.e. if no cancer cells are found near the edges of excised (removed) tissue, then further surgical procedures are not necessary. Another type of surgery commonly applied to breast cancer treatment removes the lymph nodes most vulnerable to a tumour (i.e. sentinel lymph node biopsy) to eliminate the possibility of progression to the next stage of cancer. 

Radiation Therapy

This is usually administered after surgery, to destroy any remaining cancer cells and to ensure they do not spread to the lymph nodes.

Traditionally, radiation was directed at the whole breast, but more modern methods can target tumours (or areas containing cancer cells) with greater accuracy. Another new option is radiation therapy administered in the course of surgery (intra-operative radiation therapy). 

Radiation therapy is largely safe and effective, but has the disadvantage of the possibility that healthy cells in the vicinity of the target may also die. 

This may result in cosmetic deterioration or discomfort.

Hormone therapy

This is a form of therapy best suited to breast cancer types in which hormone receptors are expressed. It can be used in conjunction with surgery, or as a treatment for breast cancer at stages 0 and 1. Some women may also begin hormone therapy as a prophylactic (prevention) measure, based on their genetic profile. As oestrogen promotes the growth of certain types of breast cancer, hormone therapy focuses on the goal of reducing or inhibiting the release of this hormone in the body.

Oestrogen-blocking drugs include:

• Tamoxifen: Tamoxifen is an oestrogen-receptors antagonist (blocks the action of oestrogen by selectively binding to the receptors without producing the same effect as oestrogen). However, it does not stop the effects of the hormone in the rest of the body. Therefore, it is known as a selective estrogen receptor modulator (SERM). Tamoxifen promotes survival and remission, particularly in women who have had surgery. This drug is also effective in metastatic breast cancer. Tamoxifen is an oral formulation, associated with side-effects such as changes in mood, vaginal dryness, hot flashes and fatigue - similar to the effects of menopause. Tamoxifen is associated with the increased risk of developing uterine cancers in menopausal women. Other severe adverse reactions include deep vein thromboses, pulmonary embolism and stroke.
   
• Aromatase inhibitors (AIs): These drugs inhibit the biological mechanism by which oestrogen is produced in the body. However, they do not significantly reduce the production of this hormone by the ovaries, and are therefore appropriate for treating early-stage cancer in postmenopausal women. AIs tend to be recommended either following or in conjunction with tamoxifen. A recent trial indicates that following two or three years of tamoxifen with up to three years of exemestane may confer a modest increase in survival. AIs are associated with side-effects such as hot flushes, joint stiffness, arthralgia and muscle pain. They are also associated with a higher risk of osteoporosis development. The AIs currently approved for use are: Letrozole, Exemestane and Anastrozole
   
• Fulvestrant: Fulvestrant blocks the oestrogen receptor, but also causes a decrease in the numbers of the receptor. It has shown efficacy in the initial treatment of breast cancer, and in cases resistant to SERM and AI administration. Fulvestrant is most often recommended to treat early-stage breast cancer in post-menopausal women, possibly because it is not selective for receptors found on tumours. This drug has similar side-effects to SERMs, and may also cause joint pain and gastrointestinal disturbances.

Ovarian ablation 

This is the removal or chemical inhibition of the ovaries, in order to restrict the actions of oestrogen in hormone-receptor positive breast cancer. This course of action is extreme, but is associated with increased remission and survival in comparison with the pharmacological options mentioned above. 

Ablation can be permanent, i.e. a surgical removal of the ovaries (oophorectomy) or alternatively by irradiation of the ovaries.

Chemical ablation, achieved using drugs such as luteinizing hormone-releasing hormone analogues, e.g leuprolide or goserelin, may be reversable.
In these cases, tamoxifen and AIs may be added to therapy for pre-menopausal women.

Ovarian ablation alone has been found to significantly improve survival, and to be comparable in effect to tamoxifen therapy.

References

1. Ergul N, Kadioglu H, Yildiz S, et al. Assessment of multifocality and axillary nodal involvement in early-stage breast cancer patients using 18F-FDG PET/CT compared to contrast-enhanced and diffusion-weighted magnetic resonance imaging and sentinel node biopsy. Acta radiologica (Stockholm, Sweden : 1987).2014.
2. Werner-Lin A, Ratner R, Hoskins LM, Lieber C. A Survey of Genetic Counselors About the Needs of 18-25 Year Olds from Families with Hereditary Breast and Ovarian Cancer Syndrome. Journal of genetic counseling.2014.
3. Sayed S, Moloo Z, Wasike R, et al. Is breast cancer from Sub Saharan Africa truly receptor poor? Prevalence of ER/PR/HER2 in breast cancer from Kenya. Breast (Edinburgh, Scotland).2014.
4. Rugo HS. Hormone therapy in premenopausal women with early-stage breast cancer. The New England journal of medicine.2014;371(2):175-176.
5. Mandala M, Moro C, Ferretti G, et al. Effect of tamoxifen on GH and IGF-1 serum level in stage I-II breast cancer patients. Anticancer research.2001;21(1b):585-588.
6. Lehman M, Hickey BE, Francis DP, See AM. Partial breast irradiation for early breast cancer. The Cochrane database of systematic reviews.2014;6:Cd007077.
7. Kim Z, Min SY, Yoon CS, et al. The basic facts of korean breast cancer in 2011: results of a nationwide survey and breast cancer registry database. Journal of breast cancer.2014;17(2):99-106.
8. Pesce CE, Liederbach E, Czechura T, Winchester DJ, Yao K. Changing surgical trends in young patients with early stage breast cancer, 2003 to 2010: a report from the national cancer data base. Journal of the American College of Surgeons.2014;219(1):19-28.
9. Sakakibara M, Yokomizo J, Shiina N, et al. MRI-Guided Quadrantectomy in Patients with Ductal Carcinoma in Situ Detected Preoperatively by Mammographic Calcifications. Journal of the American College of Surgeons.2014.
10. Deneve JL, Hoefer RA, Jr., Harris EE, Laronga C. Accelerated partial breast irradiation: a review and description of an early North American surgical experience with the intrabeam delivery system. Cancer control : journal of the Moffitt Cancer Center.2012;19(4):295-308.
11. Olivotto IA, Whelan TJ, Parpia S, et al. Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology.2013;31(32):4038-4045.
12. De Sousa JA, Facina G, da Silva BB, Gebrim LH. Effects of low-dose tamoxifen on breast cancer biomarkers Ki-67, estrogen and progesterone receptors. International seminars in surgical oncology : ISSO.2006;3:29.
13. Sikora MJ, Cooper KL, Bahreini A, et al. Invasive lobular carcinoma cell lines are characterized by unique estrogen-mediated gene expression patterns and altered tamoxifen response. Cancer research.2014;74(5):1463-1474.
14. MacNab MW, Tallarida RJ, Joseph R. An evaluation of tamoxifen as a partial agonist by classical receptor theory--an explanation of the dual action of tamoxifen. European journal of pharmacology.1984;103(3-4):321-326.
15. Burstein HJ, Temin S, Anderson H, et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology.2014.
16. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet.2007;369(9561):559-570.
17. Henry NL. Endocrine therapy toxicity: management options. American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting.2014:e25-30.
18. Committee Opinion No. 601: Tamoxifen and uterine cancer. Obstetrics and gynecology.2014;123(6):1394-1397.
19. Abramson N, Costantino JP, Garber JE, Berliner N, Wickerham DL, Wolmark N. Effect of Factor V Leiden and prothrombin G20210-->A mutations on thromboembolic risk in the national surgical adjuvant breast and bowel project breast cancer prevention trial. Journal of the National Cancer Institute.2006;98(13):904-910.
20. Mouridsen HT. Incidence and management of side effects associated with aromatase inhibitors in the adjuvant treatment of breast cancer in postmenopausal women. Current medical research and opinion.2006;22(8):1609-1621.
21. Ciruelos E, Pascual T, Arroyo Vozmediano ML, et al. The therapeutic role of fulvestrant in the management of patients with hormone receptor-positive breast cancer. Breast (Edinburgh, Scotland).2014;23(3):201-208.
22. Shah PD, Dickler MN. Endocrine therapy for advanced breast cancer. Clinical advances in hematology & oncology : H&O.2014;12(4):214-223.
23. Al-Mubarak M, Sacher AG, Ocana A, Vera-Badillo F, Seruga B, Amir E. Fulvestrant for advanced breast cancer: a meta-analysis. Cancer treatment reviews.2013;39(7):753-758.
24. Singh G. Oophorectomy in breast cancer-controversies and current status. The Indian journal of surgery.2012;74(3):210-212.
25. Prowell TM, Davidson NE. What is the role of ovarian ablation in the management of primary and metastatic breast cancer today? The oncologist.2004;9(5):507-517.
26. Ovarian ablation in early breast cancer: overview of the randomised trials. The Lancet.1996;348(9036):1189-1196.
27.