Is it Time to Retire the Term of Low-Grade Ductal Carcinoma in Situ and Replace it With Ductal Neoplasia?

As the leading cause of cancer morbidity and the second leading cause of cancer mortality among women, breast cancer continues to remain a major global public health problem. Consequently, significant attention has been directed toward early breast cancer detection and prevention. As a result, the number of image-detected biopsies has increased, and minimally invasive diagnostic procedures have almost replaced open surgical biopsies. Therefore, pathologists are expected to provide more information with less tissue and diagnose increasing numbers of atypical proliferative breast lesions, in situ lesions, and small breast carcinomas. This is a difficult task, as reflected by continuous reports highlighting the challenges associated with morphologic distinction between atypical ductal hyperplasia and low-grade ductal carcinoma in situ. The current interobserver variability among pathologists to accurately define these two entities often leads to silent overdiagnosis and overtreatment. Up to now, there are no reproducible morphologic features and/or any reliable biomarkers that can accurately separate the above-mentioned entities. Despite these reports, patients diagnosed with low-grade ductal carcinoma in situ are subject to cancer therapy regardless of the fact that low-grade ductal carcinoma in situ is known to be an indolent lesion. Studies have shown that low and high-grade ductal carcinoma in situ are genetically different forms of breast cancer precursors; however, the term ductal carcinoma in situ is followed by cancer therapy regardless of the grade and biology of the tumor. In contrast, patients with the diagnoses of atypical ductal hyperplasia do not undergo cancer therapy. In the current article, attempts are made to highlight the continuous dilemma in distinction between atypical ductal hyperplasia and low-grade ductal carcinoma in situ. Going forward, we suggest that low-grade ductal carcinoma in situ be referred to as ductal neoplasia. This alternative terminology allows for different management and follow-up strategies by eliminating the word carcinoma.

Risk-Adapted Intraoperative Radiation Therapy (IORT) for Breast Cancer: A Novel Analysis.

BACKGROUND: Randomized trials have shown that risk-adapted intraoperative radiation therapy (IORT) after breast-conserving surgery for low-risk breast cancer patients is a safe alternative to whole-breast radiation therapy (WBRT). The risk-adapted strategy allows additional WBRT for predefined high-risk pathologic characteristics discovered on final histopathology. The greater the percentage of patients receiving WBRT, the lower the recurrence rate. The risk-adapted strategy, although important and necessary, can make IORT appear better than it actually is. METHODS: Risk-adapted IORT was used to treat 1600 breast cancers. They were analyzed by the intention-to-treat method and per protocol to better understand the contribution of IORT with and without additional whole-breast treatment. Any ipsilateral breast tumor event was considered a local recurrence. RESULTS: During a median follow-up period of 63 months, local recurrence differed significantly between the patients who received local treatment and those who received whole-breast treatment. For 1393 patients the treatment was local treatment alone. These patients experienced 79 local recurrences and a 5-year local recurrence probability of 5.95 %. For 207 patients with high-risk final histopathology, additional whole-breast treatment was administered. They experienced two local recurrences and a 5-year local recurrence probability of 0.5 % (p = 0.0009). CONCLUSIONS: Whole-breast treatment works well at reducing local recurrence, and it is a totally acceptable and necessary addition to IORT as part of a risk-adapted program. However, the more whole-breast treatment that is given, the more it dilutes the original plan of simplifying local treatment and the less we understand exactly what IORT contributes to local control as a stand-alone treatment.

Recurrence and Survival Rates for 1400 Early Breast Tumors Treated with Intraoperative Radiation Therapy (IORT).

INTRODUCTION: Intraoperative radiotherapy (IORT) permits accurate delivery of radiation therapy directly to the tumor bed. We report local, regional, and distant recurrence data along with overall and breast cancer-specific survival for 1400 tumors treated with x-ray IORT. METHODS: A total of 1367 patients with 1400 distinct tumors were enrolled in a registry trial. All received breast conservation surgery and low-energy 50 kV x-ray IORT. To be eligible for excision plus IORT as the only local treatment, histopathology had to confirm tumor size ≤30 mm, margins ≥2 mm, negative lymph nodes, and no extensive lymphovascular invasion. Patients who failed any parameters were referred for additional surgery and/or whole breast radiation therapy (WBRT). RESULTS: There were 64 ipsilateral local recurrences, 60 were in the IORT only group, 7 axillary recurrences, and 7 distant recurrences. Forty-one local recurrences were within the same quadrant as the index cancer. Twenty-three were in different quadrants. With 62 months of median follow-up, the 5-year Kaplan-Meier probability of any event for all 1400 tumors was 5.27%. For 1175 patients who received IORT only, it was 5.98%. For favorable subtypes, it ranged from 2.41 to 4.31%. Multivariate analysis revealed that biologic subtype luminal A and the addition of WBRT significantly reduced the risk of local recurrence. CONCLUSIONS: The local, regional, and distant recurrence rates observed were comparable to those reported in the literature for IORT but higher than those reported for standard forms of WBRT, hypofractionated treatment, or APBI. IORT benefits include convenience, decreased exposure to medical environments, and low complication rates.

Elevating your breast program to the next level.

This paper describes a series of steps taken to elevate the Hoag Breast Program to the next level. The hope is that some of our ideas will be useful to you and your breast program.

Intraoperative Radiation Therapy (IORT): A Series of 1000 Tumors.

BACKGROUND: Two prospective, randomized trials, TARGIT-A and ELIOT, have shown intraoperative radiation therapy to be a safe alternative, with a low-risk of local recurrence, compared with whole breast radiation therapy, following breast-conserving surgery, for selected low-risk patients. We report the first 1000 tumors treated with this modality at our facility. METHODS: A total of 1000 distinct breast cancers in 984 patients (16 bilateral) were treated with breast conserving surgery and X-ray IORT from June 2010 to August 2017. Patients were enrolled in an IORT registry trial. Local recurrence was the primary endpoint. RESULTS: There have been 28 ipsilateral local recurrences, ten DCIS and 18 invasive. Four local recurrences were within the IORT field, 13 outside of the IORT field but within the same quadrant as the index cancer, and 11 were new cancers in different quadrants. There have been four regional nodal recurrences and one distant recurrence. There have been no breast cancer related deaths and 14 non-breast cancer deaths. With a median follow-up of 36 months, Kaplan-Meier analysis projects 3.9% of patients will recur locally at 4 years. This includes all ipsilateral events in all quadrants. CONCLUSIONS: The local, regional, and distant recurrence rates observed in this trial were comparable to those of the prospective randomized TARGIT-A and ELIOT trials. The low complication rates previously reported by our group as well as the low recurrence rates reported in this study support the cautious use and continued study of X-ray IORT in women with low-risk breast cancer.

Intraoperative Radiation Using Low-Kilovoltage X-Rays for Early Breast Cancer: A Single Site Trial.

INTRODUCTION: Two prospective, randomized trials, TARGIT-A and ELIOT, have shown intraoperative radiation therapy (IORT) to be a safe alternative to whole breast radiation therapy following breast-conserving surgery for selected low-risk patients. However, minimal data are available about the clinical effectiveness of this modality of treatment using the Xoft® Axxent® Electronic Brachytherapy (eBx®) System®. METHODS: A total of 201 patients with 204 early-stage breast cancers were enrolled in a prospective X-ray IORT trial from June 2010 to September 2013. All tumors were treated with breast-conserving surgery and IORT. Data were collected at 1 week, 1 month, 6 months, 1 year, and yearly thereafter. RESULTS: With a median follow-up of 50 months, there have been seven ipsilateral breast tumor events (IBTE), no regional or distant recurrences, and no breast cancer-related deaths. One IBTE was within the IORT field, four outside of the IORT field but within the same quadrant as the index cancer, and two were new biologically different cancers in different quadrants. Three events were in patients who deviated from the protocol criteria. Kaplan-Meier analysis projects that 2.9% of patients will recur locally at 4 years. CONCLUSIONS: Recurrence rates observed in this trial were comparable to those of the TARGIT-A and ELIOT trials as well as the retrospective TARGIT-R trial. The low complication rates previously reported by our group as well as the low recurrence rates reported in this study support the cautious use and continued study of IORT in selected women with low-risk breast cancer.

Are We Overtreating Ductal Carcinoma in Situ (DCIS)?

OBJECTIVE: During 2015, the media was flooded with the issue of whether ductal carcinoma in situ (DCIS) was being overtreated and whether favorable cases could be simply watched (core biopsy only followed by surveillance). To answer this question, we looked at DCIS patients treated with excision alone with margin width <1 mm as inadequate and a surrogate for no treatment (surveillance group) and margin ≥1 mm as adequate surgical excision (excision group). METHODS: A total of 720 patients with pure DCIS treated with excision alone were stratified into two groups based on margin width and further subdivided by nuclear grade. Kaplan-Meier analysis was used to determine local recurrence-free survival. Differences in outcome were analyzed using the log-rank test. RESULTS: The 10-year local recurrence probabilities are statistically significant for low-grade versus high-grade and surveillance alone versus excision alone. The comparison of excision alone group with margins ≥1 mm for low-grade DCIS versus high-grade DCIS shows a 10-year local recurrence-free survival rate of 13 versus 35 % (p < 0.0001). The surveillance group had (margins <1 mm) had higher rates of recurrence in both the low-grade group (51 %) and high-grade group (70 %) (p < 0.001). CONCLUSIONS: This study indicates that there is not an acceptable level of local control in DCIS patients with tumor margins <1 mm that undergo active surveillance, regardless of tumor grade. Leaving even low-grade DCIS untreated would lead to local recurrence in more than half the patients in 10 years. Needle biopsy and surveillance for DCIS, regardless of grade, is just not adequate at this time.

Acute and Chronic Complications in Patients with Ductal Carcinoma in Situ Treated with Intraoperative Radiation Therapy.

Intraoperative radiation therapy (IORT) delivers radiation therapy directly to the tumor bed at the time of surgery. Minimal data are available regarding IORT complications in patients diagnosed with ductal carcinoma in situ (DCIS) using the Xoft® Axxent eBx® System. 146 patients with pure DCIS received X-ray based IORT therapy using the Xoft® Axxent eBx® System at Hoag Memorial Hospital Presbyterian between June 2010 to April 2016 and were accrued to an IORT data registry study. The protocols were approved by the institutional review board and met the guidelines of their responsible governmental agency. Data were collected at 1 week, 1 month, 6 months, 1 year, and thereafter yearly. Acute complications were defined as those occurring within the first month. Chronic complications were those that persisted beyond 6 months. Acute complications were observed in 18% of patients and included hematomas that required drainage, an infection treated with antibiotics, and erythema. Chronic complications were observed in 12% of patients and included a seroma, fibrosis and hyperpigmentation. The majority of acute and chronic problems were mild (Grade I). If Grade I erythema, fibrosis, and hyperpigmentation are not included, only 11/146 patients (7.5%) had significant complications. The rate of acute and chronic complications from X-ray IORT in DCIS patients was low compared to historical toxicity rates observed in DCIS patients treated with whole breast irradiation. Our data indicate that X-ray IORT can be utilized safely in patients diagnosed with DCIS.

Oncoplastic breast reconstruction: Patient selection and surgical techniques.

Standard breast conserving techniques often fail to achieve the desired goal of tumor extirpation with adequate margins while preserving breast cosmesis. The emergence of oncoplastic breast reconstruction addresses these limitations and also allows breast conservation in women who would not have met traditional criteria. Using various volume displacing oncoplastic techniques, tumors can be successfully resected from any quadrant of the breast, while maintaining or improved breast cosmesis, diminishing post-radiation deformities, and providing breast symmetry. J. Surg. Oncol. 2016;113:875-882. © 2016 Wiley Periodicals, Inc.

Extreme oncoplasty: breast conservation for patients who need mastectomy.

Extreme oncoplasty is a breast conserving operation, using oncoplastic techniques, in a patient who, in most physicians' opinions, requires a mastectomy. These are generally large, greater than 5 cm multifocal or multicentric tumors. Many will have positive lymph nodes. Most will require radiation therapy, even if treated with mastectomy. Sixty-six consecutive patients with multifocal, multicentric, or locally advanced tumors that spanned more than 50 mm were studied (extreme cases). All patients underwent excision and oncoplastic reconstruction using a standard or split wise pattern reduction and immediate contralateral surgery for symmetry. All received postexcisional standard whole breast radiation therapy with a boost to the tumor bed. The extreme cases were compared with 245 consecutive patients with unifocal or multifocal tumors that spanned 50 mm or less (standard cases). All extreme patients were advised to have a mastectomy; all sought a breast conserving second opinion. Diagnostic evaluation included digital mammography, ultrasound, MRI, and PET-CT (if invasive). Standard cases did extremely well. No ink on tumor was achieved 96% of the time among 245 patients. The median tumor size was 21 mm (mean 23 mm). Margins equal or greater than 1 mm were achieved in 88.6% of patients. Seventeen (6.9%) standard patients underwent re-excision to achieve wider margins and only one patient (0.4%) was converted to mastectomy. With 24 months of median follow-up, three patients (1.2%) experienced local recurrence. For extreme cases, no ink on tumor was achieved 83.3% of the time, which is comparable to published positive margin rates after standard lumpectomy. The median tumor size was 62 mm (mean 77 mm). Margins equal or greater than 1 mm were achieved in 54.5% of patients. Six (9.1%) extreme patients underwent re-excision to achieve wider margins and four patients (6.1%) were converted to mastectomy. With a follow-up of 24 months, one patient (1.5%) experienced a local recurrence. Extreme oncoplasty is a promising new concept. It allows successful breast conservation in selected patients with greater than 5 cm multifocal/multicentric tumors. It may be useful in patients with locally advanced tumors following neo-adjuvant chemotherapy. From a quality of life point of view, it is a better option than the combination of mastectomy, reconstruction, and radiation therapy. Long-term data on recurrence and survival are not available, using this approach. Based on historical data, it is expected the local recurrence will be somewhat higher but that there will be little or no impact on survival.

Treatment selection for patients with ductal carcinoma in situ (DCIS) of the breast using the University of Southern California/Van Nuys (USC/VNPI) prognostic index.

The University of Southern California/Van Nuys Prognostic Index (USC/VNPI) is an algorithm that quantifies five measurable prognostic factors known to be important in predicting local recurrence in conservatively treated patients with ductal carcinoma in situ (DCIS) (tumor size, margin width, nuclear grade, age, and comedonecrosis). With five times as many patients since originally developed, sufficient numbers now exist for analysis by individual scores rather than groups of scores. To achieve a local recurrence rate of less than 20% at 12 years, these data support excision alone for all patients scoring 4, 5, or 6 and patients who score 7 but have margin widths ≥3 mm. Excision plus RT achieves the less than 20% local recurrence threshold at 12 years for patients who score 7 and have margins <3 mm, patients who score 8 and have margins ≥3 mm, and for patients who score 9 and have margins ≥5 mm. Mastectomy is required for patients who score 8 and have margins <3 mm, who score 9 and have margins <5 mm and for all patients who score 10, 11, or 12 to keep the local recurrence rate less than 20% at 12 years. DCIS is a highly favorable disease. There is no difference in mortality rate regardless of which treatment is chosen. The USC/VNPI is a numeric tool that can be used to aid the treatment decision-making process.

Ductal carcinoma in situ: recent history and areas of controversy.

The authors provide a perspective on the rapidly evolving field of prognostic analyses designed to quantify the risk of local recurrence in conservatively treated ductal carcinoma in situ (DCIS). These include morphologic features variously defined, nomograms, algorithms and multi-gene expression assays-all of which have completed against the perceived conclusions of the randomized trials of irradiation and Tamoxifen for DCIS: "all subsets benefit". At present the majority of newly diagnosed DCIS can be adequately treated with surgery alone. A number will require irradiation to achieve acceptable local control, and a minority will require mastectomy regardless of adjuvant treatments. Differences in the definition of prognostic factors and in the methods used to establish them is a major reason for the lack of consensus in treatment recommendation.