Overview. Executive Summary. DCIS disease state overview

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1 Overview Executive Summary The Oncotype DX Breast Cancer Assay for DCIS patients is the first clinically validated genomic assay for ductal carcinoma in situ (DCIS), a pre invasive form of breast cancer contained within the duct. It generates the DCIS Score an individualized prediction of the 10 year risk of local recurrence (DCIS or invasive carcinoma) in women with DCIS. This can be used to help guide treatment decisions for patients with DCIS who have undergone breast conserving surgery (BCS). The assay differentiates those who may safely avoid radiation therapy and its associated toxicities and costs. DCIS disease state overview This disease accounts for 20% to 25% of all newly diagnosed breast cancers, and 85% of all newly diagnosed in situ breast cancers. 1, 2 The American Cancer Society estimates that approximately 49,000 new cases of DCIS will be diagnosed in the United States in As of January 2005, an estimated 500,000 women were living with DCIS. 3 The goal of DCIS treatment is breast conservation, with optimal cosmesis, and prevention of subsequent invasive or in situ recurrence. A patient diagnosed with DCIS is treated with surgical excision. Radiation therapy is recommended to approximately 60 80% of patients. Even with treatment, there is a risk of local recurrence. In several large randomized trials, patients treated with breast conserving surgery (BCS) alone were shown to have recurrence rates ranging from 14% to 32%; with radiation, the risk of recurrence ranges from 6% to 16%. 4 7 If a patient recurs, it may be with DCIS (50%) or with invasive breast cancer (50%). 8 Radiation therapy is useful to reduce the likelihood of ipsilateral recurrence. Studies suggest a 40% to 60% risk reduction benefit to radiation therapy following BCS in DCIS patients. 4 7, 9, 10 Defining which lesions will lead to a recurrence and which will not recur helps to better inform radiation treatment decisions. Page 1 of 24

2 Treatment guidelines Currently, standardized clinicopathologic variables are lacking to quantify the risk of recurrence. Among the suggested primary treatments for DCIS, the National Comprehensive Cancer Network (NCCN) includes lumpectomy without radiation therapy. 11 Though the NCCN guideline for breast cancer lists some factors that can aid in the determination of local recurrence risk in DCIS patients palpable mass, larger size, higher grade, close or involved margins, and age under 50 years the decision for or against radiation therapy relies largely on the patient s and the physician s view of individual risk. Clear quantitative methods to differentiate high and low risk patients for the consideration of radiation therapy are not available. In a collaborative effort, the American College of Radiology (ACR), the American College of Surgeons (ACS), the College of American Pathologists (CAP), and the Society of Surgical Oncology (SSO) published a practice guideline (revised in 2006) for the management of DCIS of the breast. 12 In the area of radiation therapy decisions, the guideline suggests the value and need for more research. Though randomized studies have shown that radiation therapy reduces the risk of recurrence, the absolute benefit varied across subgroups. While there are patients for whom radiation therapy could be safely omitted, currently there is no way to clearly differentiate them for treatment decision purposes. Radiation therapy risks Radiation therapy for in situ or early stage breast cancer can lead to adverse events. These include late skin toxicity, radio dermatitis, fatigue, and pain. 13, 14 Though it is rare, the adverse events are severe or life threatening. Less than 1% of patients with non metastatic breast cancer who are treated radiation therapy suffer rib fractures or develop radio induced sarcomas. 15, 16 However, over a third those who do develop sarcomas die as a result within 5 years, and over half die within 15 years. 15 Without a way to identify those patients who can safely avoid radiation therapy, treatment in more patients than is beneficial results in unnecessary risks and discomfort. Oncotype DX Breast Cancer Assay for DCIS patients The Oncotype DX Breast Cancer Assay is a tumor gene expression test that has been validated to provide individualized assessments of recurrence risk for patients diagnosed with DCIS who have undergone lumpectomy. The continuous scale DCIS Score is generated based on 7 cancer genes and 5 Page 2 of 24

3 reference genes. The assay cut offs divide the scale into risk groups to provide context for an individual score to aid in treatment decisions. Analytical validation The Oncotype DX Breast Cancer Assay is conducted in Genomic Health s (Redwood City, CA) Clinical Laboratory Improvement Amendments (CLIA) certified, CAP accredited reference laboratory. Using testing methods optimized to minimize variability, the laboratory analyzes the expression of a panel of 7 cancer related genes and 5 reference genes in formalin fixed, paraffin embedded tumor tissue by real time reverse transcriptase polymerase chain reaction (RT PCR). The RT PCR technique in general and in the Oncotype DX assay specifically has been proven to be sensitive, specific, highly reproducible, and have a wide dynamic range when analyzing tumor tissue preserved in this manner. 17, 18 The DCIS Score is continuous on a scale of 0 to 100. Risk group cut offs provide context to an individual DCIS Score to aid in treatment decisions. These cut offs are based on population averages from a prospective validation study that used 327 archived tumor specimens from the Eastern Cooperative Oncology Group (ECOG) 5149 clinical trial. 19 Clinical validity The DCIS Score result of the Oncotype DX Breast Cancer Assay has been proven to predict the likelihood of local recurrence, whether with DCIS or with invasive carcinoma. 19 Beyond predicting the general risk of recurrence, the DCIS Score also predicts the likelihood of recurrence with invasive carcinoma. In a prospective retrospective validation study, Solin et al. demonstrated that the results of the Oncotype DX Breast Cancer Assay for DCIS patients were statistically significantly associated with rates of any ipsilateral breast event (IBE; defined as recurrence with DCIS or invasive breast cancer) and with rates of invasive IBE (Figure 1). DCIS Scores were obtained for 327 patients who had been enrolled in the Eastern Cooperative Oncology Group (ECOG) 5149 clinical trial using formalin fixed, paraffin embedded tumor specimens. These patients had all undergone surgical excision but no subsequent radiation therapy, and any IBEs were recorded. Page 3 of 24

4 Figure year recurrence risks by DCIS Score A. Any IBE B. Invasive IBE Abbreviations: IBE ipsilateral breast event, HR hazard ratio per 50 units, CI confidence interval. Benefit beyond standard clinicopathologic characteristics Multivariate analyses demonstrate that the DCIS Score was the strongest predictor of the risk of local recurrence in the validation study. 19 Among standard clinical and pathologic characteristics, only tumor size (HR = 1.54; 95% CI: 1.14, 2.02; p = 0.01) and postmenopausal status (HR = 0.49; 95% CI: 0.27, 0.90; p = 0.02) were significant predictors of local recurrence when the DCIS Score was excluded from Page 4 of 24

5 the analysis. A subsequent analysis of tumor size, postmenopausal status, and the DCIS Score together showed the DCIS Score to be the strongest predictor (Table 1). Table 1. Results of a multivariate analysis of predictors of any IBE Variable HR 95% CI p value DCIS Score 2.41 (1.15, 4.89) 0.02 Tumor size 1.52 (1.11, 2.01) 0.01 Postmenopausal status 0.49 (0.27, 0.90) 0.02 Abbreviations: IBE ipsilateral breast event, HR hazard ratio, CI confidence interval. Clinical utility Prior experience with the Oncotype DX Breast Cancer Assay in invasive breast cancer shows that physicians respond to a well validated assay with confidence and changed treatment decisions. 20 The decision impact of the DCIS Score by risk group was conservatively estimated based on the observed decision impact of the Recurrence Score in invasive breast cancer patients and validated by clinical expert opinion (Table 2). Radiation use in low risk patients is expected decrease by 30%. Among intermediate and high risk patients, an approximate 5% increase in radiation use is expected. Table 2. Change in therapy use due to the Oncotype DX Breast Cancer Assay* Risk group Observed change in adjuvant chemotherapy use due to the Recurrence Score 20 Estimated change in radiation therapy use due to the DCIS Score Low 52% 30% Intermediate 27% 5% High 13% 5% * These are absolute changes. Health economics The Oncotype DX Breast Cancer Assay for DCIS patients differentiates patients by risk of local recurrence. By identifying those who can safely be treated with excision alone, it reduces the overuse of radiation therapy, leading to savings in radiation therapy costs. A financial impact model estimates the overall cost of adopting this test to a Medicare plan with 2 million female members to be $110,484 annually, or less than half a cent per member per month (PMPM). To a similar private payer plan, adopting the test results in an overall savings of $88,598 (less than half a cent PMPM saved). Figure 2 below shows the model s user interface with inputs and results given a 10% Medicare, 90% Private payer mix. Page 5 of 24

6 Figure 2. Financial impact model user interface Summary The Oncotype DX Breast Cancer Assay DCIS Score is a clinically validated test to predict local recurrence risk in general, and with invasive breast cancer specifically, in patients with DCIS treated with surgical excision. It stratifies patients by risk of recurrence and aids in treatment decision making by identifying those who can safely avoid radiation therapy and its associated risks. This assay addresses the unmet need for guidelines to help select patients for radiation therapy. The economic implications have applicability to commercial health plans, and the Centers for Medicare and Medicaid Services (CMS). Approximately 20% of newly diagnosed breast cancers are in situ an early, pre invasive, form of breast cancer. 2 In women with ductal carcinoma in situ (DCIS), the cancerous cells are confined to the breast ducts and have not invaded the adjacent stromal tissue beyond the basement membrane. 21 Most women with DCIS undergo breast conserving surgery (BCS) in combination with radiation therapy to prevent local recurrence of DCIS or progression to IBC. Some of these women also undergo adjuvant hormonal therapy. 22 Page 6 of 24

7 Although use of radiation treatment is common for DCIS, not all of these women need radiation therapy in addition to BCS; some might be managed successfully through monitoring alone. Although radiation therapy has minimal adverse effects in women with DCIS, avoiding the treatment in women who would not benefit from it is critical because of its high cost. According to an unpublished analysis of the 2009 Medicare SAF carrier claims file, radiation therapy costs approximately $19,752 on average per patient with DCIS (adjusted to 2011 US dollars) given a 43% Medicare : 57% private payer mix. 23 Until now, no validated molecular markers have clearly differentiated cases of DCIS with a low risk of recurrence, which are less likely to require radiation therapy, from high risk cases. Without such information, choosing the most cost effective treatment for each patient is challenging. On December 28, 2011, Genomic Health launched the Oncotype DX Breast Cancer Assay for DCIS patients. Oncotype DX, the first clinically validated genomic assay for DCIS patients, provides an individualized prediction of the 10 year risk of local recurrence (DCIS or IBS). Oncotype DX generates the DCIS Score, which clinicians can use to help determine which women may safely avoid radiation therapy and its associated costs. This overview summarizes the epidemiology and pathology of DCIS, as well as current diagnostic and treatment approaches. This section also provides information on the development of the Oncotype DX Breast Cancer Assay for DCIS patients and its utility for managing this disease. Epidemiology Rates of DCIS diagnosis are increasing, with an estimated 49,000 cases of DCIS expected in Based on the 2011 US female population projections by the US Census Bureau, this is an incidence rate of 30.9 per 100, The age adjusted incidence of DCIS in the United States was 5.8 per 100,000 women in 1975, compared to 32.5 per 100,000 women in 2004 (Figure 3). 25 Before the 1980s, when the use of screening mammography first became widespread, the diagnosis of DCIS was rare; less than 1% of newly diagnosed breast cancers were DCIS and most of these cases were found through removal of a suspicious mass. National Cancer Institute records from show that DCIS accounted for 20% to 25% of newly diagnosed breast cancers. 2 As of January 2005, an estimated 500,000 women were living with DCIS. 3 The incidence of DCIS increases with age, with a peak incidence rate of 97 per 100,000 women aged years. 25 According to a case control study of 657 women, DCIS in younger women is more Page 7 of 24

8 likely to be symptomatic and involve the presence of DCIS cells in the lobules and stromal desmoplasia than in older women. 26 The study also found that DCIS tends to be more extensive in younger than in older women, but that hormone receptor status of DCIS does not vary by age. Figure 3: Changes in age adjusted incidence of DCIS, Invasive Breast Cancer, and mammography, Source: AHRQ Publication No. 09 E DCIS now represents 20 25% of newly diagnosed breast cancers in populations with good access to mammography. 2 Women with DCIS who are treated with excision alone have a 10 year recurrence rate of 30%; 38% of these recurrences are with invasive breast cancer. 27 With excision and radiation therapy, the 10 year recurrence rate drops to 18%, but 50% of these recurrences are with invasive breast cancer. Despite the high frequency of IBC in women with DCIS, 98 99% of women treated for DCIS survive for at least 10 years. 28 The normal female human breast contains tens of thousands of lobules, which are small grapelike clusters of milk producing glands lined with epithelial cells. 29 The lobules are interconnected by small ducts, which jointly form larger ducts that transmit milk through the nipple. Together, the lobule and associated duct are known as the terminal ductal lobular unit. DCIS is one of several types of intraductal proliferative lesions that originate from the terminal ductal lobular unit and that are confined to the mammary duct lobular system. Page 8 of 24

9 DCIS involves a proliferation of epithelial cells in the breast duct. Myoepithelial cells and an intact basement membrane usually surround the duct. 21 The outside layer of the basement membrane interacts with connective tissue stroma, immune cells, lymphatics, and blood vessels. By definition, the neoplastic epithelial cells have not invaded beyond the duct, and they might never spread to neighboring tissues. Thus, the cancerous cells remain in their normal place in the duct, i.e., in situ (Figure 4). Figure 4: Ductal carcinoma in situ Cross section of a breast duct with proliferation of carcinomatous cells within the normal duct (i.e., in situ). The cancerous cells are proliferating within the intact myoepithelial and peripheral basement membrane. The normal duct is made up of a single epithelial layer, whereas the DCIS lesion has several layers of cells that collect inwards into the lumen. Outside the basement membrane, the breast stroma contains the extracellular matrix (ECM); lymphatics; blood vessels; and stromal, immune, and fat cells. All of these components play a role in carcinogenesis by promoting or suppressing malignant progenitor cells that can accumulate in the duct. 21 Most if not all IBCs apparently initiate from in situ carcinomas like DCIS. 21, 30 These lesions can progress sequentially from usual ductal hyperplasia to hyperplastic enlarged lobular units, atypical ductal hyperplasia, DCIS, and then IBC (Figure 5). 30 At each step in this progression, the tumors acquire more genetic abnormalities and lose more normal cell cycle regulation. Most of these changes occur by the time the woman develops DCIS, and a majority of the clinical features of the IBC are in place by the time the woman has DCIS. 30, 31 Furthermore, with the progression from usual ductal hyperplasia to DCIS, the risk of IBC increases. 31 Page 9 of 24

10 Unlike in IBC, the basement membrane is intact in DCIS and the myoepithelial cell layer is circumferential and intact (Figure 5). 30 Once the DCIS progresses to IBC, the malignant cells invade tissue and changes take place in the tumor microenvironment. Figure 5: Proliferative lesions of mammary duct epithelium The normal breast duct has two cell layers, the outer, contractile ring of myoepithelial cells and the inner epithelial cell layer that produces colostrum (A). In usual ductal hyperplasia (called benign proliferative changes in this figure), the lumen is filled with many cell layers, resulting in only slit like luminal spaces (B). In atypical hyperplasia, the breast duct has many more cells than the normal two layers and the lumens have become more rounded or punched out than the slit like luminal spaces in usual ductal hyperplasia (C). In DCIS, the duct s lumen has developed comedo necrosis (intraluminal accumulation of necrotic debris) and is now comprised of malignant cells with more than two cell layers (D). In invasive carcinoma, the malignant cells have gained function and normal cells have lost function (E). 30 DCIS lesions can be high, intermediate, and low grade. 30 High grade lesions have more genetic changes from normal breast tissue and are associated with a greater risk of recurrence after BCS than lower grade lesions. 30 High grade DCIS is associated with a breakdown in the layer of myoepithelial cells and the basement membrane around the lumen of the duct. Other features of high grade DCIS include growth in fibroblasts, infiltration of lymphocytes, and the formation of new blood vessels in the stromal tissues surrounding the duct. Without treatment, 14 60% of women with low grade DCIS develop IBC in the affected breast within 10 years. 30 The risk factors for DCIS include older age, high mammographic density, history of benign breast disease, family history of breast cancer, late age at menopause, postmenopausal use of hormone replacement therapy, and reproductive factors (such as nulliparity and older age at the time of first Page 10 of 24

11 pregnancy). 28, 30 The risk factors for DCIS are similar to those for IBC, suggesting that the two diseases share a common etiology. Diagnosis According to the breast cancer guidelines published by the National Comprehensive Cancer Network (NCCN ) and by coalition of the American College of Radiology (ACR), the American College 11, 12 of Surgeons (ACS), CAP, and the Society of Surgical Oncology (SSO), a diagnosis of DCIS involves: History and physical exam Diagnostic mammogram Pathology review Assessment of the tumor s estrogen receptor (ER) status Mammography Patients rarely suspect that they have DCIS because the condition does not usually produce palpable lesions or symptoms. As a result, about 90% of cases of DCIS are identified when a screening mammography detects small areas of calcification in the breast. 12, 32 The calcifications in DCIS usally vary in size, shape, and density and they are usually grouped in clusters. 12 Follow up mammography using magnification views to examine the calcifications is required to better assess size and morphology. 12 The size of the lesion is often difficult to estimate with screening mammography, and the magnification views can yield more precise information. The remainder of the breast is also examined to help assess the feasibility of BCS. Because patients with DCIS can have bilateral involvement, the contralateral breast is also closely examined. The appearance of the calcifications on mammography correlates with the DCIS grade: linear, branching microcalcifications are typically associated with high grade DCIS with necrosis, whereas fine granular microcalcifications are often associated with lower grade lesions. However, these findings are not absolute, and biopsy is required to establish a histologic diagnosis. 33 A disadvantage of mammography for DCIS diagnosis is that it often leads to underestimates of both the pathologic extent of DCIS and the number of tumor foci. 30 The likelihood of mammographic Page 11 of 24

12 underestimation of DCIS extent increases with lesion size. 12 Furthermore, mammography cannot reliably reveal whether the tumor cells have invaded the basement membrane. Biopsy A DCIS diagnosis requires a histologic assessment of formalin fixed, paraffin embedded needlecore or excisional biopsies after visualization of suspicious calcifications by mammography. Accurately diagnosing DCIS requires successfully distinguishing it from other forms of benign hyperplasia (requiring no further treatment) and IBC (which might require chemotherapy, hormonal therapy, or both). The components of the complete pathological evaluation of DCIS are summarized in Figure 6 below. Figure 6. Pathological evaluation of DCIS Exclusion of invasive breast cancer Diagnosis of DCIS Presence or absence of comedo necrosis ER status Characterization of: o Nuclear grade (low, intermediate, or high) o Tumor size o Extent of tumor The College of American Pathologists (CAP) has developed a grading system based on nuclear cytology features alone, such as nuclear size and the presence, size, and number of nucleoli (Table 3). 34 Clinicians who use the CAP grading system assess histologic subtype and the presence of comedo necrosis (or necrosis in the central portion of involved ductal space) separately from the CAP grade. Thus, grading of DCIS is based on a very different approach than IBC grading, which involves an assessment of histologic features and mitotic index, as well as nuclear morphology. 35 Page 12 of 24

13 Table 3: College of American Pathology grading system for DCIS 34 Description LOW GRADE NUCLEI (Nuclear Grade 1) HIGH GRADE NUCLEI (Nuclear Grade 3) Appearance Monotonous (monomorphic). Markedly pleomorphic. Size Features normal red blood cell or duct epithelial cell nucleus dimensions. Usually exhibit diffuse, finely dispersed chromatin, only occasional nucleoli and mitotic figures. Usually associated with polarization of constituent cells. Nuclei usually >2.0 red blood cell or duct epithelial cell nuclear dimensions. Usually vesicular and exhibit irregular chromatin distribution and prominent, often multiple nucleoli. Mitoses may be conspicuous. The presence of nuclei that are of similar size but are pleomorphic precludes a low grade classification. Treatment The goal of DCIS treatment is breast conservation, with optimal cosmesis, and prevention of subsequent invasive or in situ recurrence. The most common treatment for DCIS is BCS with radiation therapy. Women with ER positive DCIS are sometimes treated with tamoxifen. However, chemotherapy does not play a role in the treatment of pure DCIS. In its guidelines, the NCCN suggests lumpectomy with or without whole breast radiation or total mastectomy with or without reconstruction as primary treatments for DCIS. 11 In patients who have had BCS alone or BCS and radiation therapy, especially if their DCIS is ER positive, the NCCN recommends considering tamoxifen for 5 years to reduce recurrence risk. The NCCN notes that the benefits of tamoxifen for DCIS that is ER negative are unknown. The ACR ACS CAP SCO guidelines recommend mastectomy only for women with at least two primary tumors in the breast, who have diffuse microcalcifications that look malignant, or who continue to have positive margins after BCS. 12 According to these experts, BCS with radiation therapy is appropriate for localized DCIS, and some women can be safely treated with BCS alone. Surgery In the past, mastectomy was the primary therapy for DCIS. 8 Mastectomy is highly effective, with local recurrence rates in the range of 1 2% at 10 years. 8, 36 The rate of second tumors in the contralateral breast in patients who have undergone mastectomy for DCIS, 0.5% to 1% per year, is Page 13 of 24

14 similar to the rate for women with primary breast cancer. Currently, NCCN recommends total mastectomy, without lymph node dissection, for women with evidence of widespread DCIS. 11 BCS has become the most common surgical procedure for women with DCIS in the United States. 37 According to NCCN, BCS and total mastectomy are both appropriate for the vast majority of patients with DCIS whose disease is not widespread. 11 As many as 70% of DCIS patients now undergo BCS, although BCS rates differ by region. 38 Survival rates are similar with BCS and mastectomy, but the risk of local recurrence is higher after local excision and radiation therapy than after mastectomy. 11 Radiation therapy According to a chart review study on almost 3,000 women with DCIS who underwent BCS, the use of radiation therapy has increased substantially over time. 38 Among women in the study, 61% underwent radiation therapy given BCS in compared to 26% in Currently, several different types of radiation therapy are options for DCIS treatment, including external whole breast radiation, and internal or external partial breast radiation. 39 External whole breast radiation is usually given 5 days a week over 5 to 7 weeks. Partial breast radiation treatment is much shorter (spanning only 5 to 10 days) and side effects occur in a smaller part of the breast. However, the effectiveness of partialbreast radiation therapy is still being studied. Several large randomized trials showed that BCS plus radiation therapy reduces the risk of local recurrence by approximately 50% compared to BCS alone. 4 7 Recurrence rates for BCS plus radiation therapy were 6 16% (compared to 14% to 32% for BCS alone). Data from two international registries indicate that the recurrence rate at 15 years of follow up is 16 19%, which is generally consistent with data from randomized trials. 9, 10 These results suggest that radiation therapy reduces the risk of ipsilateral recurrence by approximately 40 60%. However, evidence also suggests that some women, especially those with low grade DCIS, are unlikely to have an ipsilateral recurrence after BCS without radiation treatment. 11 For example, a nonrandomized prospective study found that the 5 year risk of ipsilateral recurrence was 6% in women with low or intermediate grade DCIS and a median tumor size of 6 mm, compared to 15% in women with high grade DCIS and a median tumor size of 5 mm. 40 Page 14 of 24

15 Hormonal treatment About 70 85% of DCIS cases are ER positive. 41 For these women, tamoxifen is the only Food and Drug Administration approved systemic agent for preventing local recurrence. A chart review study involving almost 3,000 women with DCIS found that only about 2% of DCIS patients underwent BCS and tamoxifen therapy in , but this proportion had grown to 34% in Tamoxifen use with BCS and radiation therapy is much more common (11.2% of women in the chart review study) than tamoxifen with BCS alone (4.3%). 22 Randomized trials comparing tamoxifen to no tamoxifen in patients treated with BCS plus radiation therapy found that recurrence rates were 2 3% lower in women treated with tamoxifen, BCS, and radiation therapy than in women treated with BCS and radiation therapy alone (approximately 15 30% relative risk reduction). 4 However, clinical trials have not shown that tamoxifen increases survival in women with DCIS who have undergone BCS and radiation therapy. A large clinical trial found that the raloxifene had lower activity against DCIS than tamoxifen. 6, 42 Trials of aromatase inhibitors in women with DCIS are ongoing, but results are not yet available. Although immunohistochemical evaluation of ER status is frequent in women with DCIS, the Update Committee of the American Society of Clinical Oncology concluded that existing data are insufficient to recommend using ER status to guide decisions regarding tamoxifen treatment in patients with DCIS. 43 Treatment of recurrence Positive surgical margins, or evidence of tumor tissue in the edge of the resected sample, are a strong predictor of recurrence, particularly of DCIS. 9, 44, 45 Other predictors of recurrence include comedo type or high grade histologic classification of the DCIS lesion and younger age. 46, 47 Studies have not yet shown whether validated markers for prognosis in IBC, including ER and HER2, reflect risk of recurrence in DCIS. Treatment for local recurrence of DCIS or IBC following BCS plus radiation therapy typically involves mastectomy. 41 Excision with local radiation therapy might be used if the patient has not previously received radiation treatment. Only 1% of patients with recurrent DCIS experience a second Page 15 of 24

16 recurrence after mastectomy. Patients whose DCIS recurs as IBC have a similar prognosis to patients with early stage IBC. Predicting recurrence risk in DCIS Radiation therapy decreases the risk of local recurrence in patients with any subtype of DCIS. However, some women with DCIS have such a low risk of local recurrence that they might not benefit from radiotherapy therapy. In addition, it might be possible to manage a subset of women with DCIS by simply monitoring them after biopsy in lieu of surgery, radiation treatment, or other therapies. Although the adverse effects of radiation therapy in women with DCIS are minimal, using this treatment only in women who would benefit from it is crucial because of the associated costs. An unpublished analysis based on Current Procedural Terminology code level procedure volumes and costs, a targeted health economic literature review, and Medicare claims and costs found that the cost of radiation therapy per DCIS patient is approximately $12,968 under Medicare and $24,870 under a private payer (all costs adjusted to 2011 US dollars. 23 Assuming that 10% of patients in a given DCIS population are covered by Medicare and 90% by a private payer, the cost per patient is approximately $23,680. Unlike in IBC, where molecular markers such as ER, progesterone receptor (PR), and HER2 have been in longstanding clinical use, markers in DCIS have been limited to clinical and pathologic parameters. For example, DCIS patients with any of the following features might have a high risk of local 9, 11, recurrence. Palpable DCIS Large DCIS lesions High nuclear grade Presence of comedo necrosis Positive surgical margins Most of these parameters are qualitative and they all lack reproducibility. These parameters do not provide useful information for determining the risk of recurrence in patients with DCIS. Page 16 of 24

17 Therefore, predictive and prognostic biomarkers based on tumor biology are needed to inform therapeutic decision making. Such biomarkers could help guide clinicians decisions about which women with DCIS need treatment. For the women with DCIS who do need treatment, such biomarkers could also inform such decisions as whether these patients require BCS combined with radiation treatment or whether BCS alone would be sufficient. Finally, biomarker discovery could be useful for discovering novel, less toxic, targeted agents for patients with low risk DCIS. Oncotype DX Breast Cancer Assay for DCIS Patients The Oncotype DX Breast Cancer Assay for DCIS patients is the first clinically validated genomic assay for ductal carcinoma in situ (DCIS). It provides an individualized prediction of the 10 year risk of local recurrence (DCIS or invasive carcinoma) in women with DCIS. Oncotype DX generates the DCIS Score, which clinicians can use to help guide treatment decisions for patients who have undergone breast conserving surgery (BCS) for their DCIS by determining which women may safely avoid radiation therapy and its associated toxicities and costs. The DCIS Score is based on a multi gene diagnostic assay created by Genomic Health, Inc. (Redwood City, CA). The assay is conducted in Genomic Health s Clinical Laboratory Improvement Amendments (CLIA) certified, CAP accredited reference laboratory. The laboratory analyzes the expression of a panel of 21 cancer related genes using real time reverse transcriptase polymerase chain reaction (RT PCR) and calculates the DCIS Score based on the results. The RT PCR technique is sensitive, specific, highly reproducible, and has a wide dynamic range. The assay s testing methods are optimized to minimize variability. Development of the Oncotype DX Breast Cancer Assay To develop the Oncotype DX Breast Cancer Assay, Genomic Health completed the following steps: Step 1. Optimization of methods for quantifying gene expression in formalin fixed, paraffinembedded tissue In the United States, tumor tissues are typically preserved and stored in formalin fixed, paraffinembedded samples. When tissue is preserved in paraffin, its RNA becomes fragmented, although the relative ratio of RNA between genes is unchanged. RT PCR techniques can be used Page 17 of 24

18 to measure the expression of most genes relative to a set of reference genes. 17 To develop the Oncotype DX Breast Cancer Assay, Genomic Health researchers optimized RT PCR technology for high throughput, real time quantitation of specific RNA in formalin fixed, paraffin embedded tissue. 18 The company also optimized the technique to be reproducible, regardless of the variability inherent in tumor blocks. Step 2. Selection of 250 candidate genes from the human genome (Figure 7). Genomic Health researchers studied the published literature, a genomics database, and experiments based on DNA arrays performed on fresh frozen tissue. They used these data to identify 250 candidate genes that might be associated with breast cancer tumor behavior from among the approximately 25,000 genes in the human genome. Figure 7: Candidate Gene Selection Step 3. Testing of candidate genes to identify an optimal gene panel for clinical validation Genomic Health researchers analyzed the 250 candidate genes in 447 patients from three independent clinical studies to identify a panel of 16 genes that strongly correlated with distant recurrence free survival to create the Recurrence Score. The researchers identified five reference genes to normalize the expression of these cancer related genes. The gene expression data from this gene panel are the basis for the DCIS Score result (7 cancer genes, 5 reference genes). Step 4. Development and prospective clinical validation of the DCIS Score Page 18 of 24

19 Genomic Health developed the DCIS Score algorithm based on published results for Oncotype DX that showed a similarity in the expression profiles of the Recurrence Score genes between DCIS and IBC when both are present within the same patient tumor. Genomic Health developed the DCIS Score algorithm from published data obtained from Kaiser Permanente and National Surgical Adjuvant Breast and Bowel Project B 14, which indicated that the progesterone receptor (PR), glutathlone s transferase M1 (GSTM1), and genes in the proliferation group (cyclin B1, survivin, Ki 67, STK15, MYBL2) predict distant recurrence regardless of whether adjuvant tamoxifen therapy was given. 49 This DCIS Score was subsequently validated as a predictor of local recurrence in patients from the Eastern Cooperative Group (ECOG) E5194 study. 19 These results were presented at the San Antonio Breast Conference DCIS Score The DCIS Score is obtained by performing the Oncotype DX Breast Cancer Assay, using a distinct DCIS algorithm and coefficients that was pre specified because of its ability to predict recurrence in patients with DCIS regardless of whether they underwent adjuvant tamoxifen therapy. The likelihood of local recurrence at 10 years increases continuously with an increase in the DCIS Score. The use of PCR for quantitation results in a continuous score, as opposed to a binary result (low vs. high only). The detailed Oncotype DX DCIS Score report (Figure 8) that is generated for each patient provides assay results as a continuous DCIS Score result (0 100). The report also provides quantitative ER and PR single gene scores. Page 19 of 24

20 Figure 8: Sample Oncotype DX Breast Cancer Assay for DCIS patients report More than 90% of Oncotype DX Assay results are available within 7 to 10 days from the date laboratory processing begins. Reports can be delivered by fax, overnight mail, or secure online transfer to the treating physician, submitting pathologist, and/or other authorized healthcare providers. All healthcare providers who order the Oncotype DX Breast Cancer Assay can also view patient test results online at no charge. Page 20 of 24

21 References 1. American Cancer Society. Cancer Facts and Figures. Atlanta, GA: American Cancer Society; Ernster VL, Ballard Barbash R, Barlow WE, et al. Detection of ductal carcinoma in situ in women undergoing screening mammography. J Natl Cancer Inst 2002;94: Allegra CJ, Aberle DR, Ganschow P, et al. National Institutes of Health State of the Science Conference statement: Diagnosis and Management of Ductal Carcinoma In Situ September 22 24, J Natl Cancer Inst 2010;102: Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 1993;328: Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B 24 randomised controlled trial. Lancet 1999;353: Houghton J, George WD, Cuzick J, Duggan C, Fentiman IS, Spittle M. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 2003;362: Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 2000;355: Fonseca R, Hartmann LC, Petersen IA, Donohue JH, Crotty TB, Gisvold JJ. Ductal carcinoma in situ of the breast. Ann Intern Med 1997;127: Solin LJ, Fourquet A, Vicini FA, et al. Mammographically detected ductal carcinoma in situ of the breast treated with breast conserving surgery and definitive breast irradiation: long term outcome and prognostic significance of patient age and margin status. Int J Radiat Oncol Biol Phys 2001;50: Solin LJ, Kurtz J, Fourquet A, et al. Fifteen year results of breast conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol 1996;14: NCCN Clinical Practice Guidelines in Oncology(TM): Breast Cancer (Accessed December 16, 2011, at American College of Radiology, American College of Surgeons, College of American Pathologists, Society of Surgical Oncology. Practice guideline for the management of ductal carcinoma in situ of the breast (DCIS). J Am Coll Surg 2007;205: Page 21 of 24

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