Application of deep learning on mammographies to discriminate between low and high-risk DCIS for patient participation in active surveillance trials.

BACKGROUND: Ductal Carcinoma In Situ (DCIS) can progress to invasive breast cancer, but most DCIS lesions never will. Therefore, four clinical trials (COMET, LORIS, LORETTA, AND LORD) test whether active surveillance for women with low-risk Ductal carcinoma In Situ is safe (E. S. Hwang et al., BMJ Open, 9: e026797, 2019, A. Francis et al., Eur J Cancer. 51: 2296-2303, 2015, Chizuko Kanbayashi et al. The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA),  L. E. Elshof et al., Eur J Cancer, 51, 1497-510, 2015). Low-risk is defined as grade I or II DCIS. Because DCIS grade is a major eligibility criteria in these trials, it would be very helpful to assess DCIS grade on mammography, informed by grade assessed on DCIS histopathology in pre-surgery biopsies, since surgery will not be performed on a significant number of patients participating in these trials. OBJECTIVE: To assess the performance and clinical utility of a convolutional neural network (CNN) in discriminating high-risk (grade III) DCIS and/or Invasive Breast Cancer (IBC) from low-risk (grade I/II) DCIS based on mammographic features. We explored whether the CNN could be used as a decision support tool, from excluding high-risk patients for active surveillance. METHODS: In this single centre retrospective study, 464 patients diagnosed with DCIS based on pre-surgery biopsy between 2000 and 2014 were included. The collection of mammography images was partitioned on a patient-level into two subsets, one for training containing 80% of cases (371 cases, 681 images) and 20% (93 cases, 173 images) for testing. A deep learning model based on the U-Net CNN was trained and validated on 681 two-dimensional mammograms. Classification performance was assessed with the Area Under the Curve (AUC) receiver operating characteristic and predictive values on the test set for predicting high risk DCIS-and high-risk DCIS and/ or IBC from low-risk DCIS. RESULTS: When classifying DCIS as high-risk, the deep learning network achieved a Positive Predictive Value (PPV) of 0.40, Negative Predictive Value (NPV) of 0.91 and an AUC of 0.72 on the test dataset. For distinguishing high-risk and/or upstaged DCIS (occult invasive breast cancer) from low-risk DCIS a PPV of 0.80, a NPV of 0.84 and an AUC of 0.76 were achieved. CONCLUSION: For both scenarios (DCIS grade I/II vs. III, DCIS grade I/II vs. III and/or IBC) AUCs were high, 0.72 and 0.76, respectively, concluding that our convolutional neural network can discriminate low-grade from high-grade DCIS.

Clinicopathological Predictors of Positive Resection Margins in Breast-Conserving Surgery.

BACKGROUND: Ductal carcinoma in situ (DCIS) is associated with risk of positive resection margins following breast-conserving surgery (BCS) and subsequent reoperation. Prior reports grossly underestimate the risk of margin positivity with IBC containing a DCIS component (IBC + DCIS) due to patient-level rather than margin-level analysis. OBJECTIVE: The aim of this study was to delineate the relative risk of IBC + DCIS compared with pure IBC (without a DCIS component) on margin positivity through detailed margin-level interrogation. METHODS: A single institution, retrospective, observational cohort study was conducted in which pathology databases were evaluated to identify patients who underwent BCS over 5 years (2014-2019). Margin-level interrogation included granular detail into the extent, pathological subtype and grade of disease at each resection margin. Predictors of a positive margin were computed using multivariate regression analysis. RESULTS: Clinicopathological details were examined from 5454 margins from 909 women. The relative risk of a positive margin with IBC + DCIS versus pure IBC was 8.76 (95% confidence interval [CI] 6.64-11.56) applying UK Association of Breast Surgery guidelines, and 8.44 (95% CI 6.57-10.84) applying the Society of Surgical Oncology/American Society for Radiation Oncology guidelines. Independent predictors of margin positivity included younger patient age (0.033, 95% CI 0.006-0.060), lower specimen weight (0.045, 95% CI 0.020-0.069), multifocality (0.256, 95% CI 0.137-0.376), lymphovascular invasion (0.138, 95% CI 0.068-0.208) and comedonecrosis (0.113, 95% CI 0.040-0.185). CONCLUSIONS: Compared with pure IBC, the relative risk of a positive margin with IBC + DCIS is approximately ninefold, significantly higher than prior estimates. This margin-level methodology is believed to represent the impact of DCIS more accurately on margin positivity in IBC.

Determination of Factors Associated with Upstage in Atypical Ductal Hyperplasia to Identify Low-Risk Patients Where Active Surveillance May be an Alternative.

BACKGROUND: Excision is routinely recommended for atypical ductal hyperplasia (ADH) found on core biopsy given cancer upstage rates of near 20%. Identifying a cohort at low-risk for upstage may avoid low-value surgery. Objectives were to elucidate factors predictive of upstage in ADH, specifically near-complete core sampling, to potentially define a group at low upstage risk. PATIENTS AND METHODS: This retrospective, cross-sectional, multi-institutional study from 2015 to 2019 of 221 ADH lesions in 216 patients who underwent excision or active observation (≥ 12 months imaging surveillance, mean follow-up 32.6 months) evaluated clinical, radiologic, pathologic, and procedural factors for association with upstage. Radiologists prospectively examined imaging for lesional size and sampling proportion. RESULTS: Upstage occurred in 37 (16.7%) lesions, 25 (67.6%) to ductal carcinoma in situ (DCIS) and 12 (32.4%) to invasive cancer. Factors independently predictive of upstage were lesion size ≥ 10 mm (OR 5.47, 95% CI 2.03-14.77, p < 0.001), pathologic suspicion for DCIS (OR 12.29, 95% CI 3.24-46.56, p < 0.001), and calcification distribution pattern (OR 8.08, 95% CI 2.04-32.00, p = 0.003, "regional"; OR 19.28, 95% CI 3.47-106.97, p < 0.001, "linear"). Near-complete sampling was not correlated with upstage (p = 0.64). All three significant predictors were absent in 65 (29.4%) cases, with a 1.5% upstage rate. CONCLUSIONS: The upstage rate among 221 ADH lesions was 16.7%, highest in lesions ≥ 10 mm, with pathologic suspicion of DCIS, and linear/regional calcifications on mammography. Conversely, 30% of the cohort exhibited all low-risk factors, with an upstage rate < 2%, suggesting that active surveillance may be permissible in lieu of surgery.

Tumor microenvironment and immune system preservation in early-stage breast cancer: routes for early recurrence after mastectomy and treatment for lobular and ductal forms of disease.

BACKGROUND: Intra-ductal cancer (IDC) is the most common type of breast cancer, with intra-lobular cancer (ILC) coming in second. Surgery is the primary treatment for early stage breast cancer. There are now irrefutable data demonstrating that the immune context of breast tumors can influence growth and metastasis. Adjuvant chemotherapy may be administered in patients who are at a high risk of recurrence. Our goal was to identify the processes underlying both types of early local recurrences. METHODS: This was a case-control observational study. Within 2 years of receiving adjuvant taxan and anthracycline-based chemotherapy, as well as modified radical mastectomy (MRM), early stage IDC and ILC recurred. Vimentin, α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF), matrix metalloproteinase (MMP1), and clustered differentiation (CD95) were investigated. RESULTS: Of the samples in the ductal type group, 25 showed local recurrence, and 25 did not. Six individuals in the lobular-type group did not experience recurrence, whereas seven did. Vimentin (p = 0.000 and 0.021), PDGF (p = 0.000 and 0.002), and CD95 (p = 0.000 and 0.045) expressions were significantly different in ductal and lobular carcinoma types, respectively. Measurement of ductal type was the sole significant difference found in MMP1 (p = 0.000) and α-SMA (p = 0.000). α-SMA and CD95 were two variables that helped the recurrence mechanism in the ductal type according to the pathway analysis. In contrast, the CD95 route is a recurrent mechanism for the lobular form. CONCLUSIONS: While the immune system plays a larger role in ILC, the tumor microenvironment and immune system both influence the recurrence of IDC. According to this study, improving the immune system may be a viable cancer treatment option.

ASO Author Reflections: Toward Individualized Management of Heterogenous Mixed Invasive Ductolobular Breast Cancers.

Mixed invasive ductolobular breast cancer (MIDLC) is a rare breast cancer with varying lobular and ductal components. Characteristics, management, and outcomes of MIDLC are not well understood due to the rarity of the cancer and the lack of uniform diagnostic criteria and reporting. There is a need for better understanding and individualized management of this heterogeneous spectrum of breast cancers.

The impact of histologic subtype on primary site surgery in the management of metastatic lobular versus ductal breast cancer: a population based study from the National Cancer Database (NCDB).

PURPOSE: Primary site surgery for metastatic breast cancer improves local control but does not impact overall survival. Whether histologic subtype influences patient selection for surgery is unknown. Given differences in surgical management between early-stage lobular versus ductal disease, we evaluated the impact of histology on primary site surgery in patients with metastatic breast cancer. METHODS: The National Cancer Database (NCDB, 2010-2016) was queried for patients with stage IV HR-positive, HER2-negative invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC). We compared clinicopathologic features, primary site surgery rates, and outcomes by histologic subtype. Multivariable Cox proportional hazard models with and without propensity score matching were used for overall survival (OS) analyses. RESULTS: In 25,294 patients, primary site surgery was slightly but significantly less common in the 6,123 patients with ILC compared to the 19,171 patients with IDC (26.9% versus 28.8%, p = 0.004). Those with ILC were less likely to receive chemotherapy (41.3% versus 47.4%, p < 0.0001) or radiotherapy (29.1% versus 37.9%, p < 0.0001), and had shorter OS. While mastectomy rates were similar, those with ILC who underwent lumpectomy had significantly higher positive margin rates (ILC 15.7% versus IDC 11.2%, p = 0.025). In both groups, the odds of undergoing surgery decreased over time, and were higher in younger patients with T2/T3 tumors and higher nodal burden. CONCLUSION: Lobular histology is associated with less primary site surgery, higher positive margin rates, less radiotherapy and chemotherapy, and shorter OS compared to those with HR-positive HER2-negative IDC. These findings support the need for ILC-specific data and treatment approaches in the setting of metastatic disease.

The Effect of Intraoperative Margin Assessment During Breast Conserving Surgery for Breast Cancer in a Dutch Cohort.

INTRODUCTION: Intraoperative specimen radiography is a routinely used procedure to ensure adequate resection of non-palpable breast tumors. Intraoperative digital specimen mammography (IDSM) is an alternative to conventional specimen radiography (CSR) which provides immediate specimen evaluation and can potentially decrease operation time. IDSM may also result in lower positive margin and re-excision rates. IDSM was implemented in our hospital in 2018. The objective of this study was to evaluate the effect of using IDSM versus CSR on operation time, margin status and re-excision rates in breast conserving surgery. METHODS: The present study is a single-center retrospective cohort study with 2 patient cohorts: one which underwent CSR (n = 532) and one which underwent IDSM (n = 475). The primary outcome was the operation time. Secondary outcomes were the margin status of the primary surgery, the cavity shaving rate, and the re-excision rate. Differences between cohorts were compared using univariate statistics and multiple regression analyses to adjust for variables that were significantly different between the groups. RESULTS: IDSM use was associated with an 8-minute reduction in surgery time (B = -8.034, 95% CI [-11.6, -4.5]; P < .001). Treatment variables independently associated with the operation time included use of IDSM, type of surgery, and performance of cavity shaving. Cavity shaves were more often performed when IDSM was used (24% for IDSM vs. 14% for CSR, P < .001), while the proportion of negative margin rates (93% for IDSM vs. 96% for CSR, P = .070) was comparable. CONCLUSION: IDSM was associated with a modest reduction in operation time. Surgeons performed more cavity shaves since the introduction of IDSM, but this increase was not reflected by difference in negative margin rates.

Immune system and tumor microenvironment in early-stage breast cancer: different mechanisms for early recurrence after mastectomy and chemotherapy on ductal and lobular types.

Background: The most common type of breast cancer is the ductal type (IDC), followed by lobular type (ILC). Surgery is the main therapy for early-stage breast cancer. Adjuvant chemotherapy might be given to those at high risk of recurrence. Recurrence is still possible after mastectomy and chemotherapy and most often occurs in the first two years. We aimed to determine the mechanisms in early local recurrence in both types. Methods: We used an observational method with a cross-sectional study design. The samples were patients with early-stage IDC and ILC, who underwent modified radical mastectomy (MRM) and got adjuvant chemotherapy with taxan and anthracycline base, and experienced recurrence in the first two years after surgery. The materials in this study were paraffin blocks from surgical specimens; we examined vimentin, α-SMA and MMP1, PDGF and CD95 by immunohistochemistry (IHC). Data analysis was done using OpenEpi 3.0.1 and EZR. We used pathway analysis with linear regression. Results: There were 25 samples with local recurrence and 25 samples without recurrence in the ductal type group. The lobular type group consisted of six subjects without recurrence and seven with recurrence. There were significant differences in the expression of vimentin (p=0.000 and 0.021, respectively), PDGF (p=0.000 and 0.002) and CD95 (p=0.000 and 0.045) in ductal and lobular cancer types, respectively. MMP1 (p=0.000) and α-SMA (p=0.000) only showed a significant difference in the ductal type. The pathway analysis showed that in the ductal type, the mechanism of recurrence was enabled by two factors: α-SMA and CD95. Meanwhile, for the lobular type, the recurrence mechanism was through the CD95 pathway. Conclusions: Local recurrence in early-stage IDC and ILC had different mechanisms.  These findings are expected to make cancer treatment in both types more focused and efficient.

A case report of a patient with ductal carcinoma and a malignant phyllodes tumor in situ in 2 separate breasts.

RATIONALE: Breast malignant phyllodes tumors (MPT) are quite uncommon. It is rarely reported that they occur in conjunction with breast cancer. We detailed a case in which an MPT and ductal carcinoma in situ carcinoma occurred simultaneously in 2 different breasts. PATIENT CONCERNS: A 79-year-old female patient was seen for a rapidly growing lump in the upper left quadrant of her breast. The lump was described as huge, hard, irregular, and palpable. MRI of the breasts revealed a big mass in the left breast and a smaller lump in the right. DIAGNOSIS: Ductal carcinoma in situ with breast MPT. INTERVENTIONS: We performed a double mastectomy. Post-operative endocrine treatment was suggested. OUTCOMES: During the 18-month follow-up period, no signs of recurrence or metastasis were seen. The ultrasound examination of the chest wall showed no abnormality. Bilateral axillary and supraclavicular ultrasonography showed no lymphadenectasis and a CT scan of the lungs showed no suspicious cancer nodules. LESSONS: It is possible for MPT and ductal carcinoma in situ to occur simultaneously in different breasts. Surgeons need to integrate clinical observations, imaging tools, and patient history to make an early diagnosis. Before undergoing surgery, a thorough examination of both breasts is required.

Perioperative care of nipple-areola complex-sparing mastectomy and one-stage breast reconstruction via endoscopic axillary approach for ductal carcinoma in situ: A case report.

RATIONALE: Breast cancer represents a prevalent malignancy that primarily impacts women, with pronounced consequences on their overarching health. The major therapeutic approach, encompassing surgical procedures, can often culminate in mastectomy, potentially inciting psychological turmoil and disorders. PATIENT CONCERNS: A patient was admitted to our facility on May 5, 2023, precipitated by the discovery of bilateral breast masses during a routine physical examination conducted 3 days before admission. DIAGNOSIS: The breasts were symmetric, with the right nipple inverted and a palpable mass in the upper outer quadrant of the right breast, measuring approximately 5 cm × 4 cm. The mass was firm with indistinct borders, relatively regular morphology, poor mobility, and no tenderness. Outpatient color Doppler ultrasound revealed heterogeneous echogenicity in the right breast, classified as Breast Imaging Reporting and Data System (BI-RADS) category 0, along with multiple ductal dilatations. The left breast exhibited a hypoechoic area (BI-RADS 3), indicative of proliferative changes. Radiographic mammography confirmed diffuse changes in the right breast (BI-RADS 0) and proliferative signs in the left breast (BI-RADS 2). Biopsy results reveal significant atypical ductal hyperplasia consistent with intermediate-grade ductal carcinoma in situ. This patient was diagnosed as ductal carcinoma in situ of the right breast (cTisN0M0 and Stage 0), accompanied by a left breast mass. INTERVENTIONS: On May 15, 2023, the patient was readmitted for further surgical intervention. Following relevant auxiliary examinations, the patient underwent nipple-areola complex-sparing radical mastectomy for the right breast, sentinel lymph node biopsy in the right axillary area, prosthesis-based breast reconstruction for the right breast, and microrotatotomy of the left breast mass on the left side on May 17. OUTCOMES: The patient made a successful recovery under scrupulous perioperative supervision and was discharged 7 days post-surgery. LESSONS: The axillary approach for endoscopic mammary gland excision and immediate implant reconstruction permits patients to preserve the esthetics of the female form while undergoing conventional medical treatment. This methodology considerably enhances the psychophysical health of the patients, thereby marking it as an advantageous practice worthy of broad dissemination in the medical community.

Successful Breast Conservation After Neoadjuvant Chemotherapy in Lobular Breast Cancer: The Role of Menopausal Status in Response to Treatment.

BACKGROUND: While neoadjuvant chemotherapy (NAC) has been shown to increase rates of breast conservation surgery (BCS) for breast cancer, response rates in invasive lobular carcinoma (ILC) appear lower than other histologic subtypes. Some data suggest higher response rates to NAC in premenopausal versus postmenopausal patients, but this has not been studied in ILC. We evaluated the rates of successful BCS after NAC in patients with ILC stratified by menopausal status. PATIENTS AND METHODS: We analyzed data from a single-institution cohort of 666 patients with stage I-III hormone receptor positive HER-2 negative ILC. We used t-tests, chi-squared tests, and multivariable logistic regression to investigate rates of NAC use, attempted BCS, and associations between NAC and successful BCS by menopausal status. RESULTS: In 217 premenopausal and 449 postmenopausal patients, NAC was used more often in the premenopausal group (15.2% vs. 9.8%, respectively, p = 0.041). Among those who attempted breast conservation (51.3% of pre- and 64.8% of postmenopausal cohorts), NAC was not associated with successful BCS in either group. Interestingly, for postmenopausal patients, receipt of NAC was significantly associated with increased rates of completion mastectomy in those who had positive margins at the first attempt at BCS. CONCLUSION: NAC was not associated with successful BCS in either premenopausal or postmenopausal patients with ILC. Although premenopausal patients were more likely to receive NAC, these data suggest that menopausal status may not be a good predictor of response to chemotherapy. Better predictors of response and more efficacious treatment for patients with ILC are needed.

Does Preoperative MRI Reduce Positive Margins after Breast-Conserving Surgery?

BACKGROUND: Breast-conserving surgery (BCS) is a mainstay for breast cancer management, and obtaining negative margins is critical. Some have advocated for the use of preoperative magnetic resonance imaging (MRI) in reducing positive margins after BCS. We sought to determine whether preoperative MRI was associated with reduced positive margins. PATIENTS AND METHODS: The SHAVE/SHAVE2 trials were multicenter trials in ten US centers with patients with stage 0-3 breast cancer undergoing BCS. Use of preoperative MRI was at the discretion of the surgeon. We evaluated whether or not preoperative MRI was associated with margin status prior to randomization regarding resection of cavity with shave margins. RESULTS: A total of 631 patients participated. Median age was 64 (range 29-94) years, with a median tumor size of 1.3 cm (range 0.1-9.3 cm). Patient factors included 26.1% of patients (165) had palpable tumors, and 6.5% (41) received neoadjuvant chemotherapy. Tumor factors were notable for invasive lobular histology in 7.0% (44) and extensive intraductal component (EIC) in 32.8% (207). A preoperative MRI was performed in 193 (30.6%) patients. Those who underwent preoperative MRI were less likely to have a positive margin (31.1% versus 38.8%), although this difference was not statistically significant (p = 0.073). On multivariate analysis, controlling for patient and tumor factors, utilization of preoperative MRI was not a significant factor in predicting margin status (p = 0.110). Rather, age (p = 0.032) and tumor size (p = 0.040) were the only factors associated with margin status. CONCLUSION: These data suggest that preoperative MRI is not associated margin status; rather, patient age and tumor size are the associated factors.

Is Choosing Wisely Wise for Lobular Carcinoma in Patients Over 70 Years of Age? A National Cancer Database Analysis of Sentinel Node Practice Patterns.

BACKGROUND: Controversy continues in the treatment of breast cancer in women over 70 years of age. In 2016, the Society of Surgical Oncology recommended against routine use of sentinel lymph node biopsy (SLNBx) as part of the 'Choosing Wisely Campaign'. This study examines the oncologic safety of avoidance of routine SLNBx in patients over 70 years of age with invasive lobular carcinoma (ILC). METHODS: The National Cancer Database was used to identify women with invasive ductal carcinoma (IDC) and ILC diagnosed between 2012 and 2020. Clinical and pathological staging, axillary staging, surgery type, and lymph node positivity between patients with IDC or ILC were compared. RESULTS: Among women with T1 tumors, 85,949 (79.6%) patients with IDC and 12,761 (81.5%) patients with ILC underwent SLNBx (p < 0.001). Among patients who underwent SLNBx, those with IDC were more likely to have positive nodes (n = 7535, 8.8%) than those with ILC (n = 1041, 8.2%; p = 0.02). During the time interval of interest, for both IDC and ILC patients, the rate of axillary lymph node dissection decreased and rates of SLNBx or no axillary staging increased. On multivariate analysis, ILC histology was associated with use of SLNBx, but without nodal positivity. CONCLUSION: A trend de-escalation of axillary staging was identified in this study, however the majority of patients meeting the 'Choosing Wisely' criteria are still undergoing SLNBx. No increased risk of nodal positivity was identified among patients with ILC, suggesting that surgeons can continue to choose wisely and limit the use of SLNBx in women over 70 years of age with T1 ILC tumors.

Effectiveness of Carbon Localization for Invasive Breast Cancer: An Institutional Experience.

Introduction: The final oncological and aesthetic results of breast-conserving surgery (BCS) are influenced by the precise localization of breast cancer (BC) tumors and by the quality of the intraoperative margin assessment technique. This study aimed to assess the effectiveness of the carbon localization (CL) technique by determining the success rate of BC identification and the proportion of adequate complete resection of BC lesions. Methods: We conducted a cross-sectional retrospective study of patients treated with primary BCS for invasive BC who underwent CL of their BC lesion at the Jules Bordet Institute between January 2015 and December 2017. Descriptive statistics with categorical and continuous variables were used. The success rate of tumor identification and the rate of adequate excision were calculated using the test of percentages for independent dichotomous data. Results: This study included 542 patients with 564 nonpalpable BC lesions. The median pathological tumor size was 12 mm. Of these, 460 were invasive ductal carcinomas. Most of the tumors were of the luminal subtype. CL was performed using ultrasound guidance in 98.5% of cases. The median delay between CL and surgery was 5 days, with 46% of the patients having CL one day before surgery. The lumpectomy weighed 38 g on average, with a median diameter of the surgical sample at 6 cm and a median volume of 44 cm3 (6-369). One-stage complete resection was successfully performed in 93.4% of cases. In 36% of cases, an intraoperative re-excision was performed, based on intraoperative macroscopic pathological margin evaluation. The tumor was identified in 98.9% of cases in the breast surgical specimen. Conclusion: This study demonstrated high success rates for BC tumor identification (99%) and one-stage complete resection (93.4%) after BCS and CL. These results show that CL is an effective, simple, and inexpensive localization technique for successful excision of BC lesions during BCS.

Mastectomy margins for ductal carcinoma-in-situ (DCIS): 18 Years of follow-up.

BACKGROUND: In patients undergoing mastectomy for ductal carcinoma in situ (DCIS), the significance of a positive or close (<2 mm) margin and associated recurrence risk is unclear. The study sought to evaluate risk of recurrence in relation to the mastectomy surgical margin. METHODS: A single institution retrospective review of patients with DCIS who underwent mastectomy between 2000 and 2010 was performed. Patient demographics, tumor biology, margin status and adjuvant therapy were recorded. The incidence of local recurrence (LR), distant metastasis were analyzed. RESULTS: A total of 282 patients with DCIS were identified. Overall, 12.3% of patients had a pathological positive/close margin (n = 9 tumor on ink and n = 36 <2 mm). Adjuvant radiation was administered to 11 patients with a positive or close margin. At a median follow-up of 12 years, LR was 3.4% (n = 10). None of the patients with LR had a positive or close margin. Additionally, none of the patients who received radiation developed LR. CONCLUSION: Risk of recurrence after mastectomy for DCIS is low and appears to be unrelated to margin status or the use of radiation therapy.