Advances in the Management. of Breast Cancer

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States, an estimated 192,370 women were diagnosed with breast cancer in 2009, accounting for 27% of all new cancer cases.

1 reviews therapy Advances in the Management of Breast Cancer by Rowan T. Chlebowski, MD, PhD, Professor of Medicine, University of California, Los Angeles School of Medicine; Chief, Division of Medical Oncology and Hematology, Harbor-UCLA Medical Center In the United States, an estimated 192,370 women were diagnosed with breast cancer in 2009, accounting for 27% of all new cancer cases. As the second leading cause of cancer deaths in women, an estimated 40,170 deaths were attributable to the disease in The breast cancer death rate has been declining since the 1990s due to screening and early detection and improvement in adjuvant therapy. 2 Etiology, Risk Factors, and Risk Assessment While the etiology of breast cancer is largely unknown, there are identifiable risk factors for developing the disease, including female gender, increasing age, Table 1. Breast Cancer Risk Factors 3 Nonmodifiable Gender (female > male) Increasing age Breast cancer family history Genetic factors (BRCA1 or BRCA2 genes, pten, p53) History of benign breast disease Race/ethnicity Exposure to ionizing radiation Early menarche Late menopause Breast cancer is the most common cancer among women, with one in eight American women at risk for developing invasive disease at some point in their lives. 1 and strong family history (Table 1). A family history of ovarian cancer, a history of breast cancer younger than age 50, and an Ashkenazi Jewish background can identify women more likely to have mutations (BRCA1 or BRCA2) associated with greatly increased breast cancer risk. Several computer models to predict breast cancer risk are in clinical use. Modifiable Use of estrogen plus progestin menopausal hormone therapy Obesity and nonactive lifestyle Alcohol consumption and high-fat diet Nulliparity or first full-term pregnancy at age 30 or older The most commonly used in the United States is the Breast Cancer Risk Assessment Tool, also known as the Gail model. Screening Breast cancer can be detected using several methods for screening, including a clinical breast exam (CBE) and mammography. The most benefit is gained from CBE when used in combination with mammography. Proven to decrease mortality, screening mammography is the mainstay of breast cancer screening and can detect lesions two years prior to discovery by CBE alone. Magnetic resonance imaging (MRI) can be used in conjunction with mammography, but it is recommended only in high-risk patients because it can result in more false-positive findings. 4 14

Controversial recommendations made by the U.S. Preventive Services Task Force (USPSTF) in 2009 encourage women at average risk for breast cancer to start biennial mammography screening at age 50.

These recommendations are not universally accepted, and the American Cancer Society continues to recommend screening mammography yearly beginning at age 40.

2 Controversial recommendations made by the U.S. Preventive Services Task Force (USPSTF) in 2009 encourage women at average risk for breast cancer to start biennial mammography screening at age The USPSTF s argument is that screening before age 50 can contribute to unnecessary psychological burden, physical harm, and medical costs. These recommendations are not universally accepted, and the American Cancer Society continues to recommend screening mammography yearly beginning at age 40. Specific populations recognized to be at higher risk are candidates for more intensive screening programs. Pathophysiology Designed for the production and storage of milk, the breast is composed of lobules and ducts surrounded by a stroma composed of fatty and connective tissue, blood vessels, and lymphatic vessels. Most breast cancers are adenocarcinomas and arise from the granular tissue of either the lobules or the ducts. Noninvasive, in situ tumors are localized to the lobules or ducts, while invasive tumors penetrate into the stroma of the breast and can invade lymphatic and vascular structures. Ductal carcinoma in situ (DCIS) is the most common type of noninvasive breast cancer, while lobular carcinoma in situ (LCIS) is considered a risk factor for developing a future malignancy, rather than a true cancer itself. Infiltrating ductal carcinoma is the most common invasive breast cancer, followed in frequency by infiltrating Table 2. Breast Cancer Staging and Survival 6,7 Clinical Description TNM (Tumor, Node, Metastasis) Five-Year Survival Rate Noninvasive Stage 0 DCIS, LCIS 100% Early invasive Locally advanced Metastatic Stage I, II, and some stage IIIA (T0-3, N0-1, M0, and T3N1M0) lobular carcinoma and mixed infiltrating and lobular carcinoma. Several other types of invasive cancer, such as medullary carcinoma, tubular carcinoma, and mucinous carcinoma, are associated with a somewhat better prognosis. Specific signaling pathways that are activated pathologically or via a mutation in the progression of normal breast cell to invasive tumor remain largely unknown. Estrogen signaling and human epidermal growth factor pathway activation are some of the involved processes. Ninety percent of breast cancers are caused by sporadic mutations. 6 The remaining population of patients has mutations caused by a hereditary link, such as the BRCA1/ BRCA2 mutations. Staging and Workup For women presenting with localized disease, characteristics of the tumor play a major role in the risk of recurrence. Three factors include the histologic grade of the tumor, estrogen receptor (ER) and progesterone receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status. Stage IIIB, IIIC, and some stage IIIA (T0-4, N0-3, M0 but no T3N1M0) Stage IV (any T, any N, M1) % 57% 20% Breast cancer is staged using the American Joint Committee on Cancer TNM (tumor, node, metastasis) system, which takes into account the size and speed of growth of the tumors. After histologic diagnosis, in addition to patient history and physical examination, diagnostic workup can include general laboratory studies (complete blood cell count, liver function tests, platelet count), imaging studies (bilateral mammography, breast ultrasound, MRI), and tumor characteristics (ER, PR, HER2) status. Use of breast MRI for routine staging is controversial. Increasingly, gene pattern expression of tumor samples is being used to provide prognostic and predictive information on potential chemotherapy efficacy. Tests include the 21-gene Oncotype DX and the 70-gene MammaPrint assays. Breast cancer survival is related to stage or extent of disease. Stage 0 refers to noninvasive tumors in the breast. Stages I to IV describe the extent of spread of invasive breast cancers. While five-year relative survival rates are listed in Table 2, note that risk of recurrence and death extends at least 15 years after diagnosis. managedcareoncology.com 15

3 Treatment Options The treatment of breast cancer involves a multimodal approach that may include surgery, radiation, and systemic therapy. Systemic therapies include hormonal therapy, chemotherapy, and biological or targeted therapy. Noninvasive Breast Cancer The goal of treating in situ disease is to prevent either recurrence of in situ disease and/or development of invasive breast cancer. After initial surgical resection, observation alone is often preferred in patients with LCIS because of the low risk of developing invasive cancer (approximately 21% over 15 years). 8 Treatment options available to patients with DCIS include lumpectomy plus radiation, total mastectomy with or without reconstruction, and lumpectomy alone followed by clinical observation. Endocrine therapy with tamoxifen, an estrogen receptor antagonist, can be considered in ER+ or PR+ cases of DCIS. 9 Invasive Breast Cancer Primary surgical management of localized, invasive breast cancer can include lumpectomy plus radiation or mastectomy. Radiation after mastectomy is dependent on the stage of the disease, with women with four or more lymph positive nodes being offered the treatment. Neoadjuvant chemotherapy (chemotherapy prior to surgery) is often employed to shrink large tumors, making the patient eligible for breast-conserving surgery. These neoadjuvant preoperative treatment regimens are similar to the recommended adjuvant therapies that are employed after surgical resection. An area of active investigation is the incorporation of biologic agents, such as vascular endothelial growth factor Table 3. Preferred Adjuvant Chemotherapy Regimens 7 HER2- Disease TAC (docetaxel/doxorubicin/cyclophosphamide) AC T (doxorubicin/cyclophosphamide followed by paclitaxel) TC (docetaxel/cyclophosphamide) HER2+ Disease AC TH (doxorubicin/cyclophosphamide followed by paclitaxel + trastuzumab) TCH (docetaxel, carboplatin, trastuzumab) (VEGF) receptor inhibitor therapy, into the neoadjuvant setting. If the tumor is ER+ or PR+, adjuvant endocrine therapy should be considered. 10,11 Options include tamoxifen, regardless of menopausal status, or aromatase inhibitors (AI), such as anastrozole, letrozole, or exemestane, for postmenopausal women. The optimal agent, sequence of administration, and duration of treatment are under investigation, but use of an AI is especially favored as an initial approach. Depending on risk of recurrence, cytotoxic chemotherapy is often utilized as an adjuvant to surgery. 12 Common adjuvant regimens are included in Table 3. Trastuzumab, a monoclonal antibody that targets the HER2 receptor, should be used in conjunction with chemotherapy in patients who are HER2+. 7 Questions remain regarding optimal adjuvant therapy for patients with HER2+ invasive disease. A phase 3 study awaiting publication, BCIRG-006, compared the disease-free survival (DFS) and overall survival (OS) after treatment of patients with HER2+ resected earlystage disease with an anthracyclinebased regimen (AC T ± H) and a nonanthracycline-containing regimen (TCH). The study resulted in no statistical advantage of DFS favoring the anthracycline regimen; however, the anthracycline arm was associated with more grade 3/4 congestive heart failure and greater loss of left ventricular ejection fraction. The results suggest a nonanthracycline-containing regimen is noninferior and may be an option if cardiotoxicity is an issue. 13 The optimal adjuvant anti-her2 regimen and duration (one year vs. two years) is presently under investigation The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, which investigates the optimal administration of adjuvant therapy with anti-her2 agents, is ongoing. The study compares the effects of trastuzumab and lapatinib, alone or in combination, on breast cancer recurrence risk and OS. 14 Lapatinib, a small molecule kinase inhibitor targeting both endothelial growth factor receptor and HER2, has previously been approved in combination with capecitabine for patients in the metastatic setting who are refractory to therapy with an anthracycline, a taxane, and a trastuzumab. Metastatic Disease Systemic treatment of metastatic breast cancer (MBC) is intended to prolong survival and enhance quality of life but is not curative. Therefore, for initial recurrence, endocrine treatments are often favored over chemotherapy because they are associated with lower toxicity. 16 Women with ER/PR- tumors or ER/PR+ tumors who are refractory to endocrine therapy are candidates 16

4 Table 4. Preferred Chemotherapy Regimens for Metastatic Breast Cancer 7 Single Agents Combinations Anthracyclines Taxanes doxorubicin, epirubicin, pegylated liposomal doxorubicin paclitaxel,* docetaxel, nab-paclitaxel AC CAF/FAC (cyclophosphamide/doxorubicin/fluorouracil) FEC (fluorouracil/epirubicin/cyclophosphamide) Antimetabolites capecitabine, gemcitabine AT (doxorubicin/docetaxel; doxorubicin/paclitaxel) EC (epirubicin/cyclophosphamide) Other microtubule inhibitors vinorelbine CMF (cyclophosphamide/methotrexate/fluorouracil) GT (gemcitabine/paclitaxel) docetaxel/capecitabine *Preferred agent with bevacizumab for chemotherapy (Table 4). Women with HER2+ tumors benefit from use of anti-her2 therapy (trastuzumab or lapatinib) in their treatment regimens (Table 5). The approach of complete HER2 blockade is also being studied in patients with metastatic HER2+ disease who progress on trastuzumab. Results from a phase 3 trial comparing lapatinib alone to lapatinib plus trastuzumab after progression on trastuzumab indicated an OS benefit of 14.0 vs. 9.5 months for patients being treated with the combination. 19,20 Clinical trials have demonstrated efficacy of other biologic agents in the management of metastatic breast cancer. Bevacizumab, a monoclonal antibody targeting VEGF, has been approved as a first-line agent in combination with paclitaxel for treatment-naïve HER2- patients. The optimal use of bevacizumab in combination with chemotherapy is under investigation (Table 6). (Shortly before press time, a federal health scientist said on July 16 that follow-up studies of Roche s breast cancer drug, bevacizumab, failed to extend the lives of patients, opening the door for it to be withdrawn for use in treating locally recurrent or HER2- metastatic breast cancer in woman who have not previously received chemotherapy.) In addition to new agents targeting extracellular receptors, research in the field of breast cancer is beginning to focus on the complex intracellular signaling pathways. These biologic pathways play a major role in initial cancer development and later in drug resistance (Table 7). The PI3K/Akt/ mtor pathway and poly (ADP-ribose) polymerase (PARP) will be important drug targets in the future. Table 5. Preferred First-Line Agents for HER2+ Metastatic Breast Cancer 7 Trastuzumab-Naïve Patients In combination with trastuzumab: paclitaxel ± carboplatin docetaxel vinorelbine capecitabine Trastuzumab-Exposed Patients lapatinib + capecitabine trastuzumab + other first-line agents trastuzumab + capecitabine trastuzumab + lapatinib (without cytotoxic therapy) Table 6. Results of Key Trials for the Use of Bevacizumab as First-Line Agent in Metastatic Breast Cancer Trial Regimen N Outcome ORR (%) Median PFS (months) Median OS (months) E2100 Paclitaxel vs. paclitaxel + bevacizumab * * AVADO Docetaxel Docetaxel + low-dose bevacizumab Docetaxel + high-dose bevacizumab * * 10.1* RIBBON-1 Capecitabine +/- bevacizumab Taxane +/- bevacizumab Anthracycline +/- bevacizumab vs. 24* 50 vs. 35* 52 vs vs. 5.7* 9.2 vs. 8.0* (pooled analysis) 29 vs vs (pooled analysis) ORR = objective response rate; PFS = progression-free survival; OS = overall survival; *statistically significant managedcareoncology.com 17

5 Table 7. Novel Therapies Under Investigation in Breast Cancer 24 Biologic Target HER Multikinase VEGF PARP PI3K/Akt/mTOR pathway Agent HER3 antibodies HSP90 inhibitors neratinib pertuzumab PI3k inhibitors trastuzumab DM-1 aflibercept axitinib pazopanib sorafenib sunitinib vandetanib ABT-888 AG BSI-201 olaparib PF deforolimus everolimus References 1. National Institutes of Health. Cancer: breast. Surveillance epidemiology and end results (SEER) fact sheet. National Cancer Institute website. Available at: html/breast.html. Accessed March 16, Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin. 2009;59: American Cancer Society. Detailed guide: breast cancer. American Cancer Society website. Available at: factors_for_breast_cancer_5.asp?sitearea=. Accessed March 16, The National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology TM for Breast Cancer Screening and Diagnosis Available at: org/professionals/physician_gls/pdf/breast-screening.pdf. Accessed March 16, U.S. Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151: American Cancer Society. Detailed guide: breast cancer. American Cancer Society website. Available at: cancer_5.asp?sitearea=. Accessed March 16, The National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology TM for Breast Cancer Available at: physician_gls/pdf/breast.pdf. Accessed March 16, Haagensen CD, Bodian C, Haagensen DE Jr., eds. Breast Carcinoma: Risk and Detection. Philadelphia, PA: W.B. Saunders; Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 randomised controlled trial. Lancet. 1999;353: Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs. raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA. 2006;295: Early Breast Cancer Trialists Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet. 1198;351: Hortobagyi GN, Singletary SE, Strom EA. Locally advanced breast cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; Slamon D, Eiermann W, Robert N, et al. Phase 3 trial comparing AC-T with AC-TH with TCH in the adjuvant treatment of HER2+ early breast cancer patients: second interim efficacy analysis [abstract]. San Antonio Breast Cancer Symposium Abstract Clinical trials (PDQ). National Cancer Institute website. Available at: hid= Accessed March 17, Tykerb [package insert]. Research Triangle Park, NC: GlaxoSmithKline; Accessed March 17, Higgins MJ, Wolff AC. Therapeutic options in the management of metastatic breast cancer. Oncology. 2008;22: ; discussion 623, Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2+ breast cancer. N Engl J Med. 2005;353: Smith I, Procter M, Gelber RD, et al. Two-year follow-up of trastuzumab after adjuvant chemotherapy in HER2+ breast cancer: a randomized controlled trial. Lancet. 2007;369: O Shaughnessy J, Blackwell KL, Burstein H, et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy [abstract]. In: General Session 6 of the 44th Annual ASCO Meeting; 2008 May 30-Jun 3; Chicago, IL. Abstract Blackwell KL, Burnstein HJ, Sledge GW, et al. Updated survival analysis of a randomized study of lapatinib alone or in combination with trastuzumab in women with HER2+ metastatic breast cancer progressing on trastuzumab therapy [abstract]. In: General Session 5 of the 32nd Annual San Antonio Breast Cancer Symposium; 2009 Dec 9-13; San Antonio, TX. Abstract Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357: Miles DW, Chan A, Romieu G, et al. Final overall survival (OS) results from the randomised, double-blind, placebo-controlled, phase 3 AVADO study of bevacizumab (BV) plus docetaxel (D) compared with placebo (PL) plus D for the first-line treatment of locally recurrent (LR) or metastatic breast cancer (MBC) [abstract]. In: General Session 4 of the 32nd Annual San Antonio Breast Cancer Symposium; 2009 Dec 9-13; San Antonio, TX. Abstract Robert N, Dieras V, Glaspy J, et al. Clinical benefit rate and time to response in RIBBON-1, a randomized, double-blind, phase 3 trial of chemotherapy with or without bevacizumab (B) for the first-line treatment of HER2- locally recurrent or metastatic breast cancer (MBC) [abstract]. In: Poster Session 6 of the 32nd Annual San Antonio Breast Cancer Symposium; 2009 Dec 9-13; San Antonio, TX. Abstract Clinical trials (PDQ). National Cancer Institute website. Available at: Accessed March 17,

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