by Dr. C.H. Weaver M.d. updated 10/2021
Effective treatment of stage I - III breast cancer requires both local and systemic therapy. Local therapy consists of surgery and/or radiation and is directed at destroying any cancer cells in or near the breast. Systemic therapy is directed at destroying cancer cells throughout the body, and may include chemotherapy, hormonal therapy, and/or precision cancer medicines. Systemic therapy may be administered before or after surgery, which is called neoadjuvant or adjuvant therapy respectively. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
- Local Treatment of Early Stage Breast Cancer
- Adjuvant Therapy and Precision Cancer Medicines
- Endocrine or Hormonal Therapy
Local Treatment of Early Stage Breast Cancer
The primary local treatment of ESBC typically consists of surgery with or without radiation therapy. Surgery and radiation are considered local therapies because they can prevent cancer recurrence in the affected breast and surrounding area but cannot treat cancer that has already spread to other locations in the body.
Surgery: Surgery for ESBC may consist of mastectomy or lumpectomy. A mastectomy involves removal of the entire breast, whereas a lumpectomy involves removal of the cancer and a portion of surrounding tissue. Because a lumpectomy alone is associated with a higher rate of cancer recurrence than mastectomy, patients who elect to have a lumpectomy are also treated with radiation therapy. The combination of lumpectomy and radiation is called breast-conserving therapy. Clinical studies have shown that breast-conserving therapy is associated with a lower risk of local cancer recurrence compared to lumpectomy alone.1,2
Mastectomy or breast-conserving therapy are the current standard of care for the local treatment of ESBC. Both are considered acceptable options and clinical trial have demonstrated they produce similar long-term survival.3
All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy.6 However, the presence of inflammatory breast cancer, multifocal disease in the breast and a history of collagen vascular disease are relative contraindications to breast-conserving therapy.
For patients who opt for a total mastectomy, reconstructive surgery may be performed at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction).7-10
Axillary Lymph Node Management
Surgery for ESBC also involves the evaluation of underarm (axillary) lymph nodes in order to determine whether cancer has spread outside the breast and establish the stage of the cancer. Involvement of lymph nodes with cancer is an important determinant of recurrence risk and whether additional systemic treatment is beneficial.
Sentinel lymph node (SLN) biopsy is the initial standard procedure to evaluate the lymph nodes in women with invasive breast cancer. Prior to surgery, blue dye is injected near the cancer and the dye drains from the area containing the cancer into the nearby lymph nodes, through the sentinel node(s). The sentinel nodes are the first nodes to which cancer is likely to spread and removing these nodes during surgery and evaluation under a microscope allows doctors to determine whether cancer has spread.4
Research indicates that sentinel node biopsy appears to be just as effective in determining cancer spread to axillary lymph nodes as an axillary lymph node dissection, and results in fewer side effects.5, 11-14 Surgery in depth....
Neoadjuvant Therapy is treatment administered before surgery. The purpose of neoadjuvant therapy is to immediately treat and shrink the cancer in order to increase the likelihood that it may be completely removed with surgery. A committee of physicians, called The Consensus Conference Committee, has published treatment guidelines stating that neoadjuvant chemotherapy is “the treatment of choice” for patients with stage III breast cancer and is “worthy of consideration” in patients with stage IIA and IIB breast cancer. Neoadjuvant therapy increases the likelihood of breast conservation without impacting survival or recurrence rates.15,16
Radiation Therapy: If a patient elects to have a mastectomy, radiation therapy is not typically administered; however, patients who undergo a lumpectomy need to receive radiation.
- Radiation therapy for early stage breast cancer.
Systemic Adjuvant Therapy
Despite undergoing local treatment with surgery and radiation, some patients already have small amounts of cancer that have spread outside the breast. These cancer cells are referred to as micrometastases and cannot be detected with any of the currently available tests. The presence of micrometastases causes breast cancer recurrence following local treatment with surgery and/or radiation therapy.
Systemic therapy is any treatment involving the use of medications that circulate in the blood to kill cancer cells. Systemic adjuvant therapy is routinely used in early-stage breast cancer to reduce the risk of cancer recurrence throughout the body and may consist of chemotherapy or precision cancer medicines used alone or in combination. Systemic therapy can be administered through a vein or delivered orally in the form of a pill. All women with ESBC have a risk of cancer recurrence and treatment with adjuvant therapy reduces the risk of recurrence and improves survival.17-19
Sequence of Adjuvant Therapy for Early Stage Breast Cancer
Adjuvant therapy is typically administered after surgery and before radiation because this sequence produces superior survival when compared to giving radiation first. It is much easier to treat a local recurrence of cancer than a systemic recurrence and this may explain why patients treated with chemotherapy followed by radiation have improved survival compared to patients treated with radiation followed by chemotherapy. An additional explanation is that delivering radiation therapy before chemotherapy treatment of systemic disease may adversely affect the doctor’s ability to deliver the chemotherapy treatment. Hormone therapy can begin during or following radiation therapy. One notable exception to this sequence is patients with locally advanced breast cancer. In these patients, administration of chemotherapy prior to surgery (neoadjuvant) may allow for greater breast conservation.
The optimal time to initiate adjuvant systemic therapy is uncertain however a retrospective, observational study has reported that delays in initiation of adjuvant chemotherapy do adversely affected survival outcomes.20
Choice of Adjuvant Therapy & Precision Cancer Medicines
Adjuvant therapy should be considered on an individual basis based on the ability of the treatment to reduce the risk of cancer recurrence and prolong survival. The stage of the cancer and the presences of specific biomarkers help determine the risk of recurrence and the optimal adjuvant treatment to reduce that risk.
- Estrogen hormone receptor status
- HER2 over expression
- Oncotype Dx
Genetic Mutations – Not all breast cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular biomarker testing is performed to test for certain genetic mutations or the proteins they produce because the results can help select treatment including newer precision cancer medicines designed to attack cancer cells with specific genetic mutations. Molecular testing helps further define specific groups of patients that can benefit from more personalized treatment options with precision cancer medicines.
HER2-neu positive Breast Cancer: The HER2 pathway is a biological pathway involved in cellular replication and growth. Approximately 20-25% of breast cancers over express the HER2 protein and are referred to as HER2-positive. Several precision Cancer medicines target and block the HER2-protein and are used for the treatment early-stage HER2-positive breast cancer. Herceptin (trastuzumab) was the first precision cancer medicine developed to target HER2-positive breast cancer however several newer medications are now available.
HER2/neu–negative breast cancer: For HER2/neu–negative breast cancer, there is no single adjuvant chemotherapy regimen that is considered standard or superior to another.
Chemotherapy is the standard treatment to reduce cancer recurrence risk and prolong survival for the majority of patients who do not have a specific biomarker identified that can be targeted with a precision cancer medicine. A pivotal National Cancer Institute sponsored clinical trial illustrates the benefit of adjuvant chemotherapy treatment of women with node-negative breast cancer. In this study, 536 women were treated with surgical mastectomy alone or with surgical mastectomy plus adjuvant chemotherapy. Ten years following treatment, 73% of women treated with mastectomy and chemotherapy were alive without evidence of cancer recurrence, compared to only 58% of women treated with mastectomy alone. Chemotherapy reduced the risk of recurrence by 37% and the chance of dying from breast cancer by 34%.21
There are many different chemotherapy drugs and combinations of drugs (regimens). The regimen consisting of cyclophosphamide, methotrexate and fluorouracil (CMF) was the first standard combination used to treat individuals with node-negative breast cancer and has been in use for many years. CMF chemotherapy is typically administered for 6 cycles over a period of approximately 4-6 months. Some clinical studies in women with more advanced breast cancer have suggested that including the chemotherapy drug doxorubicin in chemotherapy regimens may improve an individual’s outcome with breast cancer.22,23
Research shows that the inclusion of the chemotherapy drug doxorubicin in adjuvant chemotherapy increases the number of women that can expect to survive without evidence of cancer compared to combination chemotherapy without doxorubicin. CAF (cyclophosphamide, doxorubicin, and fluorouracil) and AC (doxorubicin and cyclophosphamide) are also considered standard chemotherapy regimens for use in node-negative breast cancer; however, these regimens are associated with more side effects than CMF.24-26
The taxanes are a class of chemotherapy drug that have been shown to improve cancer-free survival of women with ESBC and are typically combined with AC chemotherapy.23 They may also provide benefit in the adjuvant treatment of node-negative disease. Taxol (paclitaxel) and Taxotere® (docetaxel) and the two main taxanes used for the treatment of ESBC.27,28
Dose Dense Therapy
Multiple studies and long-term follow-up data confirm the benefit of dose dense therapy for treatment of ESBC. Breast cancer is known to have a “dose response” effect meaning that higher doses of chemotherapy tend to destroy more breast cancer cells than lower doses.
Adjuvant chemotherapy for ESBC is often delivered every 3 weeks. One way to increase dose intensity is to use the same chemotherapy at the same doses but administer treatment every two weeks instead of every three weeks. The average weekly dose is therefore 50% higher with treatment every 2 weeks compared to every 3-weeks. The delivery of chemotherapy every 2 weeks to increase the “dose intensity” is referred to as “dose-dense therapy.” Another way of increasing the dose intensity of chemotherapy was to give the drugs individually in sequence rather than administering all the drugs together at the same time. According to the National Cancer Institute the overall results of studies designed to compare dose dense therapy to every 3 – week chemotherapy support the use of dose-dense chemotherapy for women with HER2-negative ESBC.19
Triple-negative breast cancer (TNBC): TNBC is defined as the absence of staining for estrogen or progesterone receptors (ER, PR), and HER2/neu. TNBC is insensitive to some of the most effective therapies available for breast cancer treatment including HER2-directed therapies and endocrine therapies. Combination cytotoxic and dose dense chemotherapy remains the standard therapy for early-stage TNBC.19,29
Endocrine or Hormonal Therapy
The breasts, uterus and other female organs are composed of cells that contain estrogen receptors. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer’s growth. Cancer cells that have estrogen receptors are referred to as estrogen receptor-positive (ER-positive) cancers.
The growth of ER-positive breast cancer cells can be prevented or slowed by reducing the exposure to estrogen. This is the goal of endocrine therapy for breast cancer. Clinical trials have demonstrated that five years of adjuvant endocrine therapy substantially reduce the risk of locoregional and distant recurrence, as well as the development of contralateral breast cancer, and death from breast cancer. Research shows that even in women who are disease free after 5 years of endocrine therapy there remains a steady risk of late recurrence 5 to 20 years after diagnosis.30-34
There are four main types of endocrine therapy - each type stops hormone-related growth by a different method. Options for endocrine therapy are partly based on menopausal status because estrogen and progesterone levels remain low after menopause starts. In premenopausal women, surgical removal of the ovaries or suppression of ovarian activity is often used to reduce estrogen exposure. Aromatase inhibitor drugs and tamoxifen are more commonly recommended for postmenopausal women.
- Ovarian ablation is a surgical procedure called bilateral oophorectomy where the ovaries are removed from the body and permanently stops the ovaries from making hormones.
- Ovarian suppression temporarily stops the ovaries from making hormones. It is achieved with drugs called LHRH (luteinizing hormone- releasing hormone) agonists. These drugs stop LHRH from being made, which stops the ovaries from making hormones. LHRH agonists include Zoladex (goserelin) and Lupron(leuprolide).
- Aromatase inhibitors stop a hormone called androgen from changing into estrogen. They do not affect estrogen made by the ovaries. Non-steroidal aromatase inhibitors include Arimidex (anastrozole) and Femara (letrozole). Aromasin (exemestane) is a steroidal aromatase inhibitor.
- Antiestrogens block estrogen from attaching to hormone receptors and tamoxifen is the most common.
Inhibitors of cyclin-dependent kinases (CDK) 4 & 6 block the activity of these enzymes that help to regulate cell division. CDK inhibitors when combined with endocrine therapy more effectively prevent hormones from binding with their respective receptors on the cancer cells than does traditional hormone therapy alone.
The CDK inhibitor Verzenio in combination with standard endocrine therapy administered to patients with high-risk, hormone receptor-positive, HER2-negative ESBC results in a 28% reduction in the risk of developing a recurrence of invasive disease.
Each treatment option is associated with side effects and the choice of endocrine therapy should be tailored to each individual taking into consideration their risk of recurrence, menopausal status and impact of each treatments associated side effects.
- For more in-depth information go to Hormonal Therapy for Breast Cancer.
Adjuvant Chemotherapy plus Hormonal Therapy
Researchers with the National Surgical Adjuvant Breast and Bowel Project (NSABP) have reported that the combination of adjuvant chemotherapy and hormonal therapy appears to increase survival over adjuvant hormonal therapy alone and may be the optimal treatment for women with node-negative, ER-positive breast cancer.
In a clinical trial involving over 1,500 women with node-negative, ER-positive breast cancer, patients underwent surgical removal of the cancer and half of the patients then received 5 years of hormonal therapy and the other half received 5 years of hormonal therapy plus chemotherapy. More of the women who were treated with the combination of chemotherapy and hormonal therapy lived cancer-free for 12 years or more. The 12- year cancer free survival was 89% in women receiving endocrine and chemotherapy compared to 79% for those treated with endocrine therapy alone.
Women aged 49 years or younger derived the most benefit in terms of cancer-free and overall survival from the addition of chemotherapy, while women over the age of 60 did not achieve a benefit from the addition of chemotherapy. The study results also suggested that women with a lower degree of estrogen receptor expression benefited more from chemotherapy than those with higher receptor expression.35
The Era of Personalized Medicine
An important advance in the treatment of cancer is the development of more individualized cancer therapy. Information provided by genomic tests or from analysis of other characteristics of cancer cells can often help guide the selection of treatments that have the best chance of success for a particular patient. The Oncotype DX genomic test can identify many women with hormone positive breast cancer that can avoid chemotherapy treatment altogether.42
In the case of node-negative breast cancer and some early stage node positive cancers, adjuvant hormonal therapy and/or chemotherapy has been shown to benefit many, but the extent of the benefit varies by the likelihood of cancer recurrence. Some women with small node-negative and positive breast cancer, for example, have a low risk of recurrence and may not require adjuvant chemotherapy to further reduce recurrence risk. In contrast, women with larger tumors – or other poor prognostic factors, such as high tumor grade – are more likely to benefit from adjuvant therapy.
Although factors such as tumor size and lymph node involvement have been used to guide decisions about the need for adjuvant therapy genomic testing of tumor tissue may be more accurate. The expression, or activity, of certain genes has been linked with the likelihood of cancer recurrence and testing tumor tissue for the expression of these genes provides important information about prognosis and likely response to treatment.
The Oncotype DX Test:
The Oncotype DX Breast Recurrence Score test provides a genomic-based, individualized risk assessment for invasive breast cancer that individuals can use to personalize a treatment plan. The test measures the expression of 21 genes: 16 cancer-related genes and five reference genes - in a breast tumor sample after it has been removed by surgery or biopsy to calculate a Recurrence Score that can predict the likely benefit of chemotherapy as well as the risk of distant recurrence in women with ER positive breast cancers.36,37,42
Many women with HR positive HER2 negative early stage breast cancer can avoid receiving chemotherapy and be treated with endocrine therapy alone. All patients should discuss the role of Oncotype DX testing in the management of their cancer. (42)
Deciding whether adjuvant therapy is right for you?
Before deciding to receive adjuvant treatment, patients should ensure they understand whether the benefits outweigh the risks for their particular cancer and circumstances. Understanding the answers to 3 questions will help determine if adjuvant therapy is a viable option:
- What is my prognosis (risk of cancer recurrence) without adjuvant treatment?
- How will my prognosis be improved with adjuvant treatment?
- What are the risks of adjuvant treatment?
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Areas of active investigation aimed at improving the treatment of early stage breast cancers include the following:
Novel HER2neu Therapies: The development of stronger more precise medications that target HER2 is ongoing. Novel anti-HER2neu therapies are developed in patients with more advanced disease before being used in ESBC. Treatment of HER2 + Breast Cancer in Depth….
Immunotherapy: In the I-SPY clinical trial 181 women were treated with standard neoadjuvant chemotherapy and 69 were treated with 4 cycles of Keytruda plus weekly paclitaxel followed by adjuvant chemotherapy.
When added to standard neoadjuvant chemotherapy, Keytruda more than doubled the estimated complete response rates assessed at surgery for both HR-positive/ERBB2-negative and triple-negative breast cancer. The research suggests that adding the Keytruda checkpoint inhibitor in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to provide additional benefit and will be studied in a phase 3 comparative clinical trial. (38)
Triple Negative Breast Cancer
Poly (ADP-ribose) polymerase (PARP) inhibitor agents. The PARP inhibitors are being evaluated in clinical trials for patients with BRCA mutations and in TNBC.39
Who benefits from tamoxifen? Pharmacogenomics refers to the study of how inherited genetic variation influences drug response. As this field progresses, it is likely to lead to more individualized cancer therapy. For example, a gene known as CYP2D6 plays a role in tamoxifen metabolism (the processing of tamoxifen by the body). Most people have two functional versions of this gene and are able to effectively process tamoxifen. Some people, however, have versions of this gene that are less effective at processing tamoxifen. Testing patients for these gene variants could eventually help doctors identify patients who are less likely to respond to tamoxifen.40
- Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. The New England Journal of Medicine. 2002;347:1233-1241.
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- Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. The New England Journal of Medicine. 2002;347;1227-1232.
- Edge SB, Niland JC, Bookman MA, et al. Emergence of sentinel node biopsy in breast cancer as standard-of care in academic comprehensive cancer centers. Journal of the National Cancer Institute. 2003;95:1514-1521.
- Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. The New England Journal of Medicine. 2003;349:546-553.
- Weiss MC, Fowble BL, Solin LJ, et al.: Outcome of conservative therapy for invasive breast cancer by histologic subtype. Int J Radiat Oncol Biol Phys 23(5): 941-7, 1992.
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- Veronesi U, Paganelli G, Galimberti V, et al.: Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 349 (9069): 1864-7, 1997.
- Albertini JJ, Lyman GH, Cox C, et al.: Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276 (22): 1818-22, 1996.
- Krag D, Weaver D, Ashikaga T, et al.: The sentinel node in breast cancer--a multicenter validation study. N Engl J Med 339 (14): 941-6, 1998.
- Veronesi U, Paganelli G, Viale G, et al.: Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 91 (4): 368-73, 1999.
- Schwartz GF, Hortobagyi GN and the Consensus Conference Committee. Proceedings of the Consensus Conference on Neoadjuvant Chemotherapy in Carcinoma of the Breast, Philadelphia PA. Cancer. 2004;100:2512-2532.
- Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. Journal of Clinical Oncology. 1997;15:2483-2493.
- Amadori D, Nanni O, Marangolo M, et al. Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study. Journal of Clinical Oncology. 2000;18:3125-3134.
- Mansour EG, Gray R, Shatila AH, et al. Survival advantage of adjuvant chemotherapy in high-risk node-negative breast cancer: ten-year analysis–an intergroup study. Journal of Clinical Oncology. 1998;16:3486-3492.
- Breast Cancer Treatment (Adult) (PDQ®)–Health Professional Version
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- Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. New England Journal of Medicine. 1976;294:405-410.
- Nabholtz J-M, Pienkowski T, Mackey J, et al. Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. Proceedings from the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:Abstract 141.
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- Thor AD, Berry DA, Budman DR, et al.: erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90 (18): 1346-60, 1998.
- Paik S, Bryant J, Park C, et al.: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90 (18): 1361-70, 1998.
- Ravdin P, Erban J, Overmoyer B, Budd GT, et al. Phase III comparison of docetaxel and paclitaxel in patients with metastatic breast cancer. Proceedings from the 12th European Conference on Clinical Oncology, Sept 21-25, 2003, Copenhagen Denmark.
- Food and Drug Administration. Approval Summary for Taxotere® For the treatment of locally advanced or metastatic breast cancer. FDA Oncology Tools. Accessed Sept. 28, 2004.
- Mehta RS: Dose-dense and/or metronomic schedules of specific chemotherapies consolidate the chemosensitivity of triple-negative breast cancer: a step toward reversing triple-negative paradox. J Clin Oncol 26(19): 3286-8; author reply 3288, 2008.
- Pan H, Gray R, Braybrooke J, et al.: 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med 377 (19): 1836-1846, 2017.
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- Gnant M. Mlineritsch B, Schippinger W, et al. Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-response, stage I and II breast cancer: first efficacy results from ABCSG-12. Journal of Clinical Oncology, May, 2008; Vol. 26 (15S). Abstract LBA4.