Treatment of Stage I Breast Cancer

A comprehensive review of stage I breast cancer treatment

Treatment of Stage I Breast Cancer

Medically reviewed by Dr. C.H. Weaver M.D. 10/2018

Patients diagnosed with stage I invasive breast cancer have a single location of cancer less than 2 cm (3/4 inch) in size that has not spread to the axillary lymph nodes or sites distant from the breast. Although the majority of women with stage I breast cancer are cured following treatment with surgery and radiation, some patients may benefit from additional treatment with chemotherapy and/or hormonal therapy. Treatment after surgery is called adjuvant therapy and it may further decrease the risk of cancer recurrence.

The following is a general overview of treatment for Stage I breast cancer. Treatment may consist of surgery, radiation, chemotherapy, hormonal therapy, targeted therapy, or a combination of these treatment techniques. 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.

Primary Treatment of Stage I Breast Cancer

Surgery and Radiation

The primary treatment of stage I breast cancer 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. Systemic treatments, such as chemotherapy and hormonal therapy, can treat cancer that has spread throughout the body and may be administered as adjuvant treatment (after primary treatment) for Stage I breast cancer.

Surgery: Surgery for Stage I breast cancers may consist of mastectomy or lumpectomy. A mastectomyinvolves 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 and breast-conserving therapy are the current standard of care for the local treatment of Stage I breast cancers and both are considered acceptable options. Furthermore, breast-conserving therapy and mastectomy have been shown to produce similar long-term survival.[3]

Surgery for early-stage breast cancer may also involve 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. This is important to determine whether additional treatments beyond local therapies, such as chemotherapy, are required. For over 30 years, the standard of practice for breast cancer staging has included the removal of approximately 10-25 axillary lymph nodes to help determine whether the cancer has spread. This procedure, called an axillary lymph node dissection, can be associated with chronic side effects including pain, limited shoulder motion, numbness, and swelling.

A newer approach for evaluating whether cancer has spread to the lymph nodes is a sentinel lymph node biopsy. The advantage to this procedure is that it involves the removal of only a small number of nodes (or even a single node), called the sentinel nodes, which are the first nodes to which cancer is likely to spread. Prior to surgery, blue dye is injected near the cancer. The dye drains from the area containing the cancer into the nearby lymph nodes, through the sentinel node(s). The nodes containing the dye are removed during surgery and evaluated under a microscope to determine whether cancer has spread. Sentinel lymph node biopsy is becoming the standard approach for determining whether cancer has spread to the lymph nodes in women with localized breast cancer.[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 in patients with early-stage breast cancer.[5]

Radiation therapy: If a patient elects to have a mastectomy, radiation therapy is not typically administered; however, patients who undergo a lumpectomy typically receive radiation. Radiation therapy is often administered using a machine that delivers a beam of radiation deep into the body where the cancer resides, a technique called external beam radiation therapy (EBRT). These treatments are typically administered five days per week for five to six weeks.

Research indicates that radiation reduces the risk of a cancer recurrence in women ages 50 and older when administered after lumpectomy and hormone therapy. This trial included 636 women who were aged 50 years or older. All were treated with a lumpectomy plus the hormone therapy drug tamoxifen. Approximately half of the patients were also treated with radiation therapy to the breast, while the other half did not receive radiation therapy. Women aged 50 to 59 years appeared to benefit the most from the addition of radiation.

Radiation may also be delivered over a shorter time period using a procedure known as breast brachytherapy. Patients should discuss with their doctor whether this is an appropriate approach for them.

For more detailed information, go to Radiation Therapy for Breast Cancer.

Adjuvant Therapy

Adjuvant therapy is additional systemic treatment administered after initial surgery and radiation therapy to eliminate any cancer that remains thereby reducing the risk of cancer recurrence.

Despite undergoing 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. An effective treatment is needed to cleanse the body of micrometastases in order to improve a patient’s duration of survival and potential for cure.

Adjuvant therapy for early-stage breast cancer may include chemotherapy, hormonal therapy, and/or precision cancer medicines. The National Institutes of Health says that all women with node-negative breast cancer have a risk of cancer recurrence and treatment with adjuvant chemotherapy and hormonal therapy should be considered on an individual basis following a discussion of the potential risks and benefits of treatment with their physician.

Clinical trials have demonstrated that treatment of early-stage breast cancer with adjuvant therapy reduces the risk of recurrence and improves survival.[6],[7],[8] Patients that have been identified as having a poorer prognosis are most likely to benefit from adjuvant therapy and should work closely with their doctor to select their optimal adjuvant therapy. This section is a discussion of the potential benefits, as demonstrated in clinical trials, of the following types of adjuvant therapy:

Adjuvant Chemotherapy

Chemotherapy is any treatment involving the use of drugs to kill cancer cells and is a standard adjuvant therapy for early-stage breast cancer. Cancer chemotherapy may consist of single drugs or combinations of drugs and can be administered through a vein or delivered orally in the form of a pill.

A pivotal National Cancer Institute sponsored clinical trial initiated in 1981 illustrates the benefit of adjuvant chemotherapy treatment of women with node-negative breast cancer. In this study, 536 women with node negative breast cancer were treated with surgical mastectomy alone or with surgical mastectomy plus adjuvant chemotherapy. Ten years following treatment, 73% of women treated with mastectomy and adjuvant 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%.[9]

Chemotherapy options: 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.[10] 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.[11]

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.

The taxanes are a class of chemotherapy drug that have been shown to improve cancer-free survival of women with Stage II-III breast cancer and are typically combined with AC chemotherapy in the treatment of breast cancer.[12] They may also provide benefit in the adjuvant treatment of node-negative disease. Of the taxanes that are used in the treatment of breast cancer, Taxotere® (docetaxel) appears to be more effective than Taxol® (paclitaxel) in the treatment of patients with advanced breast cancer[13] and is FDA-approved for the treatment of patients with locally advanced (Stage II and III) and metastatic (Stage IV) breast cancer.[14]

Adjuvant Hormonal Therapy

Estrogen causes some cancers to grow. 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 hormonal therapy for breast cancer. Hormonal therapy drugs include tamoxifen as well as a newer of drugs known as aromatase inhibitors. Aromastase inhibitors include Femara® (letrozole), Arimidex® (anastrazole), and Aromasin® (exemestane). In premenopausal women, surgical removal of the ovaries or suppression of ovarian activity may also be used to reduce estrogen exposure.

For more in-depth information about hormonal therapy, 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.

Adjuvant hormonal therapy and chemotherapy in the treatment of women with node-negative ER-positive breast cancer

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.[15]

Targeted Therapy With Precision Cancer Medicines

Targeted therapies are anticancer drugs that interfere with specific pathways involved in cancer cell growth or survival. Some targeted therapies block growth signals from reaching cancer cells; others reduce the blood supply to cancer cells; and still others stimulate the immune system to recognize and attack the cancer cell. Depending on the specific “target,” targeted therapies may slow cancer cell growth or increase cancer cell death.

Herceptin® (trastuzumab): Herceptin is a targeted therapy that binds to a protein known as HER2. Twenty to thirty percent of breast cancers overexpress (make too much of) HER2, and could potentially respond to treatment with Herceptin. Results from an important clinical trial indicate that adding Herceptin to chemotherapy improves survival for patients with advanced HER2-positive breast cancer.[16] Herceptin has also been shown to improve survival among women with early-stage HER2-positive breast cancer that is node-positive or high-risk node-negative.[17] Among women with early-stage breast cancer, Herceptin is part of a treatment regimen that also includes chemotherapy and newer medicines that target HER2 are also available.

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.

In the case of node-negative breast cancer, 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. Women with very small node-negative breast cancers, for example, have a low risk of recurrence and may not require adjuvant therapy 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 can help guide decisions about the need for adjuvant therapy in women with node-negative breast cancer, researchers have been interested in developing more accurate approaches to the assessment of recurrence risk. One such approach involves genomic testing of tumor tissue. The expression, or activity, of certain genes has been linked with the likelihood of cancer recurrence; testing tumor tissue for the expression of these genes may provide important information about prognosis and likely response to treatment.

Oncotype DX is a test that measures the expression of 21 genes in a sample of early-stage breast cancer cells. The test is used to calculate a Recurrence Score, which indicates the likelihood of cancer recurrence. Studies have reported that among women with node-negative, estrogen receptor-positive breast cancer treated with tamoxifen, the Recurrence Score is a better predictor of recurrence than standard measures such as patient age, tumor size, and tumor grade.[18] The Recurrence Score was also linked with the response to chemotherapy among women with node-negative, hormone receptor-positive breast cancer,[19] and can help guide decisions about the need for chemotherapy.

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 stage I breast cancer include the following:

Additional Approaches to Personalized Medicine

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.[20]

Neoadjuvant Chemotherapy

Neoadjuvant therapy is treatment administered before surgery. The purpose of neoadjuvant chemotherapy is to treat the cancer immediately and shrink the tumor in order to increase the likelihood that the cancer may be completely removed with surgery. Patients with large Stage I breast cancer may benefit most from neoadjuvant chemotherapy.

Researchers affiliated with the National Surgical Adjuvant Breast and Bowel Project have reported that neoadjuvant chemotherapy that includes the drug Taxotere® produces more anti-cancer responses than neoadjuvant chemotherapy without Taxotere® or neoadjuvant chemotherapy plus adjuvant Taxotere®. This trial involved over 2,000 women who were randomly assigned to three different groups and treated with one of the following:

  • AC (doxorubicin plus cyclophosphamide) before surgery
  • AC (doxorubicin plus cyclophosphamide) plus Taxotere® before surgery
  • AC (doxorubicin plus cyclophosphamide) before surgery plus Taxotere® after surgery

Approximately 91% of the patients treated with neoadjuvant chemotherapy including Taxotere® had an anti-cancer response, compared to 85% of patients in the other two groups.[21] A later report from this same study, however, indicated that the addition of Taxotere did not improve overall survival.[22]

Adjuvant Bisphosphonate Therapy

Bisphosphonates are a class of drugs that inhibit bone resorption. They are used to treat osteoporosis, as well as hypercalcemia (high levels of calcium in the blood) and bone metastases in patients with cancer.

Research suggests that the bisphosphonate drug Zometa® (zoledronic acid) may also have a role in improving outcomes among women with early-stage breast cancer.[23] A phase III clinical trial by the Austrian Breast Cancer Study Group enrolled 1,803 premenopausal women with Stages I-II, hormone receptor-positive breast cancer. Following surgery, all patients were treated with hormonal therapy; this consisted of Zoladex® (goserelin) for ovarian suppression, plus tamoxifen or Arimidex® (anastrozole). In addition to hormonal therapy, some patients were also treated with Zometa.

Compared with hormonal therapy alone, the combination of hormonal therapy and Zometa reduced the risk of cancer recurrence by 35%. The researchers concluded that the addition of Zometa to hormone therapy among premenopausal women with hormone receptor-positive breast cancer may improve recurrence-free survival.

Newer Approaches to Radiation

Brachytherapy: Advances in radiation therapy have led to the development of an alternative to external beam radiation therapy (EBRT) called brachytherapy. Brachytherapy is a technique for delivering radiation internally by implanting a radioactive material directly into or near the cancer. An advantage of brachytherapy is that the total delivery time is reduced to several days (as opposed to several weeks with whole-breast external beam radiation therapy).

Radiation “boost” therapy: Standard radiation therapy following a lumpectomy consists of a limited dose of radiation (50 Gy) to the entire affected breast. While this treatment leads to long-term outcomes similar to those from mastectomy, women under age 50 experience higher rates of local recurrences following this treatment regimen compared to their elder counterparts. Researchers have theorized that an additional boost of radiation aimed only at the area from which the cancer was removed would reduce the rates of local recurrences, especially in younger patients.[24]

To evaluate the benefits and side effects of boost radiation, researchers affiliated with the European Organisation for Research and Treatment of Cancer (EORTC) conducted a study among 5,318 women with early breast cancer.[25] After breast-conserving surgery, all patients received 50 Gy of radiation to the entire breast. Half the patients also received a 16 Gy radiation boost to the area of the cancer. The remaining patients received no further radiation therapy.

  • Ten-year survival was 82% in both study groups (the group that received boost radiation and the group that did not receive boost radiation).
  • The ten-year risk of cancer recurrence within the breast was 6.2% in patients who received boost radiation and 10.2% in patients who did not receive boost radiation.
  • Young women (those under the age of 40) experienced the greatest reduction in recurrence risk following boost radiation.
  • Severe fibrosis occurred in 4.4% of patients treated with boost radiation, compared with only 1.6% of patients who did not receive boost radiation.

The researchers concluded that the addition of boost radiation reduced the risk of cancer recurrence within the breast, particularly in younger patients, but did not improve 10-year survival.

Shorter-course radiation therapy: The current approach to radiation therapy involves several consecutive weeks of daily treatment. For many women, particularly those who have to travel long distances to reach a radiation therapy facility, this can interfere greatly with work and other activities of daily life.

A possible alternative approach is hypofractionated radiation therapy. Hypofractionation involves fewer radiation treatments with a higher dose of radiation at each treatment. Hypofractionated radiation therapy was compared to conventional radiation therapy in two clinical trials conducted in the U.K.[26] Women treated with hypofractionated radiation therapy received a total radiation dose of 39 to 41.6 Gy administered over 13 to 15 visits. Women treated with conventional radiation therapy received a total radiation dose of 50 Gy administered over 25 visits. Risk of cancer recurrence was low with both approaches, and there was a suggestion that hypofractionation may result in better breast appearance. The long-term effects of hypofractionation remain unknown, however.

Radiofrequency Ablation

Radiofrequency ablation (RFA) involves the use of high-energy radio waves that can be administered through the skin using a probe that is about the size of a needle. During RFA, a physician uses an imaging technique to visualize the cancer, such as an ultrasound or a computerized tomography (CT) scan. The physician then guides the probe to the correct spot(s) in the breast to deliver the high-energy radio waves that heat and ultimately destroy the cancer cells. The radio waves can also be delivered into the cancer during a surgical procedure. Researchers have been investigating RFA in liver cancer and have now extended the investigation of this technique to small breast cancers.

Researchers from Italy and the MD Anderson Cancer Center have conducted two clinical trials evaluating RFA in patients with early-stage breast cancer and have found the technique to be safe and effective.

The first trial involved 26 patients with either Stage I or II breast cancer that was 1.8 centimeters in diameter or smaller[27] and the second trial included 20 patients with breast cancer that was 2 centimeters or smaller in diameter.[28] RFA was performed for 15 minutes to destroy the breast cancer, then patients immediately underwent surgery to remove the treated tissue in order to determine whether all cancer cells had been destroyed. The cancer was completely destroyed in 45 of the 46 patients involved in both studies. Only a microscopic amount of cancer cells were left in one patient involved in the first trial and only one patient had any complications from RFA: a burn of the skin directly over the cancer site.

Researchers have initiated a clinical trial in Europe further evaluating RFA in early-stage breast cancer patients. However, long-term outcomes will be necessary to truly determine the efficacy of RFA compared to standard treatment.

References:

[1] 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.

[2] Lichter AS, Lippman ME, Jr Danforth DN, et al. Mastectomy versus breast-conserving therapy in the treatment of Stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. Journal of Clinical Oncology, Classic Papers and Current Comments. 1996;1:2-10.

[3] 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.

[4] 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.

[5] 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.

[6] 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.

[7] 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.

[8] Treatment of Early-Stage Breast Cancer. NIH Consensus Statement 1990 Jun 18-21;8(6)1-19.

[9] 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.

[10] 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.

[11] Cummings SR, Norton L, Eckert S, et al. Raloxifene reduces the risk of breast cancer and may decrease the risk of endometrial cancer in post-menopausal women. Two-year findings from the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial. Proceedings of American Society of Clinical Oncology 1998;17:Abstract 3.

[12] 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.

[13] 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.

[14] 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.

[15] Fisher B, Jeong J-H, Bryant J, et al. Treatment of lymph-node-negative, estrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. The Lancet. 2004;364:858-868.

[16] Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of Medicine. 2001;344:783—792.

[17] Smith, I, Proctor M, Gelber RD et al. 2-year Follow-up of Trastuzumab after Adjuvant Chemotherapy in HER2-positive Breast Cancer: A Randomised Controlled Trial. Lancet. 2007;369:29-36.

[18] Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. New England Journal of Medicine. 2004;351:2817-26.

[19] Paik S, Tang G, Shak S et al. Gene Expression and Benefit of Chemotherapy in Women with Node-Negative, Estrogen Receptor-Positive Breast Cancer. Journal of Clinical Oncology. 2006; 24:3726-34.

[20] Goetz MP, Knox SK, Suman VJ et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Research and Treatment. 2007;101:113-21.

[21] Bear HD, Anderson S, Brown A, et al. The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Cyclophosphamide: Preliminary Results From National Surgical Adjuvant Breast And Bowel Project Protocol B-27. Journal of Clinical Oncology. 2003;21:4165-4174.

[22] Bear HD, Anderson S, Smith RE et al. Sequential Preoperative or Postoperative Docetaxel Added to Preoperative Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. Journal of Clinical Oncology. 2006; 24: 2019-2027.

[23] 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.

[24] Bartelink H, Horiot J-C, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. New England Journal of Medicine. 2001;345:1378-1387.

[25] Bartelink H, Horiot J, Poortmans P, et al. Impact of radiation dose on local control, fibrosis and survival after breast conserving treatment: 10-year results of the EORTC trial 22881-10882. Proceedings from the 2006 annual San Antonio Breast Cancer Symposium. Oral presentation December 14, 2006. Abstract #10.

[26] Dewar JA, Haviland JS, Agrawal RK et al. Hypofractionation for early breast cancer: First results of the UK standardization of breast radiotherapy (START) trials. Proceedings of the 43rd Annual Meeting of the American Society of Clinical Oncology. Chicago, IL. June 1-5, 2007. Abstract #LBA518.

[27] Izzo F, Thomas R, Delrio P, et al. Radiofrequency ablation in patients with primary breast carcinoma: A pilot study in 26 patients. Cancer. 2001;92:2036-2044.

[28] Bruno F, Sneige N, Ross M, et al. Small ( 2-cm) Breast Cancer Treated with US-guided Radiofrequency Ablation: Feasibility Study 1. Radiology. 2004; 231:215-224.

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