Pamela Benitez

Accelerated Treatment of Breast Cancer

PURPOSE Radiation therapy (RT) restricted to the tumor bed, by means of an interstitial implant, and lasting 4 to 5 days after lumpectomy was prospectively evaluated in early-stage breast cancer patients treated with breast-conserving therapy (BCT). The goals of the study were to determine whether treatment time can be reduced and whether elective treatment of the entire breast is necessary. MATERIALS AND METHODS Between January 1993 and January 2000, 174 cases of early-stage breast cancer were managed with lumpectomy followed by RT restricted to the tumor bed using an interstitial implant. Each brachytherapy patient was matched with one external-beam RT (ERT) patient derived from a reference group of 1,388 patients treated with standard BCT. Patients were matched for age, tumor size, histology, margins of excision, absence of an extensive intraductal component, nodal status, estrogen receptor status, and tamoxifen use. Median follow-up for both the ERT and brachytherapy groups was 36 months. RESULTS No statistically significant differences were noted in the 5-year actuarial rates of ipsilateral breast treatment failure or locoregional failure between ERT and brachytherapy patients (1% v 0%, P =.31 and 2% v 1%, P =.63, respectively). In addition, there were no statistically significant differences noted in rates of distant metastasis (6% v 3%, P =.24), disease-free survival (87% v 91%, P =.55), overall survival (90% v 93%, P =.66), or cause-specific survival (97% v 99%, P =.28). CONCLUSION Accelerated treatment of breast cancer using an interstitial implant to deliver radiation to the tumor bed alone over 4 to 5 days seems to produce 5-year results equivalent to those achieved with conventional ERT. Extended follow-up will be required to determine the long-term efficacy of this treatment approach.

Differences in patterns of failure in patients treated with accelerated partial breast irradiation versus whole-breast irradiation: a matched-pair analysis with 10-year follow-up.

PURPOSE To examine 10-year results of a single institutions experience with radiotherapy limited to the region of the tumor bed (i.e., accelerated partial breast irradiation, [APBI]) in selected patients treated with breast-conserving therapy (BCT) and compare them with results of matched BCT patients who underwent whole-breast irradiation (WBI). PATIENTS AND METHODS A total of 199 patients with early-stage breast cancer were treated prospectively with BCT and APBI using interstitial brachytherapy. To compare potential differences in local recurrence rates on the basis of the volume of breast tissue irradiated, patients in the APBI group were matched with 199 patients treated with WBI. Match criteria included tumor size, nodal status, age at diagnosis, margins of excision, estrogen receptor status, and use of adjuvant tamoxifen therapy. Local-regional control, disease-free survival, and overall survival were analyzed between treatment groups. RESULTS Median follow-up for surviving patients was 9.6 years (range, 0.3-13.6 years). Eight ipsilateral breast tumor recurrences (IBTRs) were observed in patients treated with APBI. The cumulative incidence of IBTR at 10 years was 5%. On matched-pair analysis, the rate of IBTR was not statistically significantly different between the patient groups (4%, 95% confidence interval [CI] 1.3-6.7% for WBI therapy patients vs. 5%, 95% CI 1.5-8.5% for APBI patients; p = 0.48). CONCLUSIONS Radiation therapy limited to the region of the tumor bed (APBI) produced 10-year local control rates comparable to those from WBI in selected low-risk patients.

Irradiation of the tumor bed alone after lumpectomy in selected Patients with early-stage breast cancer treated with breast conserving therapy

We present the interim findings of our in‐house protocol treating the tumor bed alone after lumpectomy with low‐dose‐rate (LDR) interstitial brachytherapy in selected patients with early‐stage breast cancer treated with breast conserving therapy (BCT).

Low-dose-rate brachytherapy as the sole radiation modality in the management of patients with early-stage breast cancer treated with breast-conserving therapy: Preliminary results of a pilot trial

PURPOSE We present the preliminary findings of our in-house protocol treating the tumor bed alone after lumpectomy with low-dose-rate (LDR) interstitial brachytherapy in selected patients with early-stage breast cancer treated with breast-conserving therapy (BCT). METHODS AND MATERIALS Since March 1, 1993, 60 women with early-stage breast cancer were entered into a protocol of tumor bed irradiation only using an interstitial LDR implant with iodine-125. Patients were eligible if the tumor was < or = 3 cm, margins were > or = 2 mm, there was no extensive intraductal component, the axilla was surgically staged, and a postoperative mammogram was performed. Implants were placed using a standardized template either at the time of reexcision or shortly after lumpectomy. A total of 50 Gy was delivered at 0.52 Gy/h over a period of 96 h to the lumpectomy bed plus a 2-cm margin. Perioperative complications, cosmetic outcome, and local control were assessed. RESULTS The median follow-up for all patients is 20 months. Three patients experienced minimal perioperative pain that required temporary nonnarcotic analgesics. There have been four postoperative infections which resolved with oral antibiotics. No significant skin reactions related to the implant were noted and no patient experienced impaired would healing. Early cosmetic results reveal minimal changes consisting of transient hyperpigmentation of the skin at the puncture sites and temporary induration in the tumor bed. Good to excellent cosmetic results were noted in all 19 patients followed up a minimum of 24 months posttherapy. To date, 51 women have obtained 6-12-month follow-up mammograms and no recurrences have been noted. All patients currently have no physical signs of recurrence, and no patient has failed regionally or distantly. CONCLUSION Treatment of the tumor bed alone with LDR interstitial brachytherapy appears to be well tolerated, and early results are promising. Long-term follow-up of these patients is necessary to establish the equivalence of this treatment approach compared to standard BCT, however.

Phase I/II Study Evaluating Early Tolerance in Breast Cancer Patients Undergoing Accelerated Partial Breast Irradiation Treated With the MammoSite Balloon Breast Brachytherapy Catheter Using a 2-Day Dose Schedule

PURPOSE Initial Phase I/II results using balloon brachytherapy to deliver accelerated partial breast irradiation (APBI) in 2 days in patients with early-stage breast cancer are presented. MATERIALS AND METHODS Between March 2004 and August 2007, 45 patients received adjuvant radiation therapy after lumpectomy with balloon brachytherapy in a Phase I/II trial delivering 2800 cGy in four fractions of 700 cGy. Toxicities were evaluated using the National Cancer Institute Common Toxicity Criteria for Adverse Events v3.0 scale and cosmesis was documented at >or=6 months. RESULTS The median age was 66 years (range, 48-83) and median skin spacing was 12 mm (range, 8-24). The median follow-up was 11.4 months (5.4-48 months) with 21 patients (47%) followed >or=1 year, 11 (24%) >or=2 years, and 7 (16%) >or=3 years. At <6 months (n = 45), Grade II toxicity rates were 9% radiation dermatitis, 13% breast pain, 2% edema, and 2% hyperpigmentation. Grade III breast pain was reported in 13% (n = 6). At >or=6 months (n = 43), Grade II toxicity rates were: 2% radiation dermatitis, 2% induration, and 2% hypopigmentation. Grade III breast pain was reported in 2%. Infection was 13% (n = 6) at <6 months and 5% (n = 2) at >or=6 months. Persistent seroma >or=6 months was 30% (n = 13). Fat necrosis developed in 4 cases (2 symptomatic). Rib fractures were seen in 4% (n = 2). Cosmesis was good/excellent in 96% of cases. CONCLUSIONS Treatment with balloon brachytherapy using a 2-day dose schedule resulted acceptable rates of Grade II/III chronic toxicity rates and similar cosmetic results observed with a standard 5-day accelerated partial breast irradiation schedule.

Hormone Replacement Therapy in Breast Cancer Survivors

Abstract: The use of hormone replacement therapy (HRT) in postmenopausal breast cancer survivors is controversial. This report describes the symptomatic benefit of HRT and the subsequent risk of recurrent breast cancer in a group of postmenopausal women with a prior history of locally treated breast cancer.

Mutational landscape of radiation-associated angiosarcoma of the breast

Purpose Radiation-associated breast angiosarcomas are a rare complication of radiation therapy for breast carcinoma. With relatively little is known about the genetic abnormalities present in these secondary tumors, we examined genomic variation in biospecimens from radiation-associated breast angiosarcomas. Experimental Design Patients were identified that had a previous breast cancer diagnosis, received radiation therapy, and developed angiosarcoma in the ipsilateral breast as the earlier cancer. Tumor regions were isolated from archival blocks using subsequent laser capture microdissection. Next generation sequencing was performed using a targeted panel of 160 cancer-related genes. Genomic variants were identified for mutation and trinucleotide-based mutational signature analysis. Results 44 variants in 34 genes were found in more than two thirds of the cases; this included 12 variants identified as potentially deleterious. Of particular note, the BRCA1 DNA damage response pathway was highly enriched with genetic variation. In a comparison to local recurrences, 14 variants in 11 genes were present in both the primary and recurrent lesions including variants in genes associated with the DNA damage response machinery. Furthermore, the mutational signature analysis shows that a previously defined IR signature is present in almost all of the current samples characterized by predominantly C→T substitutions. Conclusions While radiation-associated breast angiosarcomas are relatively uncommon, their prognosis is very poor. These data demonstrate a mutational pattern associated with genes involved in DNA repair. While important in revealing the biology behind these tumors, it may also suggest new treatment strategies that will prove successful.

Propensity-score matched pair comparison of brachytherapy-based accelerated partial breast irradiation versus whole breast Canadian hypofractionation.

65 Background: Given the initial report of the RAPID trial with greater morbidity for 3-D conformal external beam APBI [3D-APBI] vs. Canadian Hypofractionation [CHfx], a propensity-score matched-pair analysis of brachytherapy-based APBI [B-APBI] vs. CHfx was performed to assess efficacy, toxicities, and cosmesis. METHODS Early-stage breast cancer patients treated with B-APBI or CHfx were reviewed. With ≥ 1y follow-up [FU], B-APBI (n=108) pts were matched 1:1 to CHfx (n=108) by age, T-stage, nodal/ER status, endocrine or chemotherapy and laterality. Ipsilateral breast tumor recurrence (IBTR), regional recurrence (RR), distant metastasis (DM), contralateral breast cancer (CLBC), cause-specific survival (CSS), overall survival (OS) and disease-free survival (DFS) were compared by Kaplan-Meier (log-rank test). Toxicities were graded per CTCAE v3 and comesis per Harvard criteria. RESULTS Median FU was 5.7 y (1.0-17.8) for B-APBI and 2.1 y (1.0-5.7) for CHfx [p < 0.001]. Patients did not differ by match criteria. In comparing B-APBI to CHfx, median age was 69.0 vs. 70.0 [p = 0.72]; for laterality, T-stage, nodal/ER status, endocrine or chemotherapy, no significance [NS] was noted between the 2 groups [p = 0.79, 1.0, 0.60, 0.09, 0.15, and 0.16 respectively]. Comparing B-APBI to CHfx, NS was seen in 5-y actuarial rates of IBTR [1% vs. 0% p = 0.35], RR [0% both], DM [3.4% vs. 0% p = 0.25], CLBC [2.3% vs. 2% p = 0.63], CSS [94.3% vs. 100% p = 0.47], OS [87.7% vs. 88.3% p = 0.71] & DFS [97.5% vs. 100% p = 0.52]. The majority of maximal late toxicities were Gr 1-2. Of toxicities analyzed, including pigmentary changes, edema, pain, induration, volume reduction, telangiectasia, fat necrosis and seroma, only Gr 2-3 hyperpigmentation was significantly higher in the CHfx [8% B-APBI vs. 22% CHfx p = 0.017]. Good/excellent cosmesis was seen in > 93% in both groups. CONCLUSIONS With FU of >5 yrs, B-APBI has similar efficacy and cosmesis but less morbidity vs. CHfx; the lesser toxicity of B-APBI vs. CHfx is in contradistinction to the RAPID results comparing 3D-APBI vs. CHfx. Further FU and more patients are needed to substantiate these findings.

Clinical efficacy of 2-day versus 5-day accelerated partial breast irradiation delivered via balloon-based brachytherapy: Results of a matched pair analysis.

148 Background: This analysis compares the efficacy of a 2-day vs. 5-day accelerated partial breast irradiation (APBI) schedule in treatment of early-stage breast cancer. METHODS Patients were treated between 6/2000 and 1/2011 with balloon-based brachytherapy using a 2-day (700 cGy x 4 BID) or a 5-day (340 cGy x 10 BID) fractionation. The CTV was a 1cm expansion from the balloon surface with a single-lumen device used in all cases. To compare efficacy between the two treatment groups, a matched-pair analysis was performed using a 1:2 ratio which paired 38 two-day with 76 five-day patients. Match criteria included minimal follow-up (FU) > 1.0 yr, clinical stage, age (+/- 3 yrs), and ER status. Clinical outcomes analyzed include local-regional recurrence [LR, RR] distant metastases (DM), disease-free, cause-specific and overall survival [DFS, CSS, and OS]. RESULTS No significant differences were noted for age (p=0.838), clinical stage (p=1.000), ER (p=1.000), tumor size (p=0.236), margin status (p=0.556), nodal stage (p=0.381), PR (p=0.749), use of chemotherapy (p=0.927) or endocrine therapy (p=0.129). Per the ASTRO Consensus Guidelines, no differences were noted in the clinical groups between the 2-and 5-day treatments with the majority categorized as suitable or cautionary (2-day: 92% vs. 5-day: 87% p=0.436). With a mean FU of 4.7 yrs (4.9 yrs for 2-day vs. 4.5 yrs for 5-day, p=0.279), no differences were seen in the 5-year actuarial rates of LR (0.0% vs. 2.6%, p=0.359), DFS (94.4% vs. 96.1%, p=0.618), CSS (100% vs. 94.9 %, p=0.207), or OS (97.3% vs. 92.5%, p=0.811) between the 2-and 5-day groups, respectively. There was no RR in either group. DM rates were similar for both (5.6% vs. 1.3 %, p=0.456). CONCLUSIONS With near 5-year FU for the 2-day schedule, APBI with the 2-day regimen yielded outcomes equivalent to the 5-day schema. Reduced on-treatment days by such hypofractionation offers flexibility in clinical and patient scheduling. Further FU and more patients will be needed to substantiate equivalence of hypofractionated APBI. An HIC-approved protocol randomizing patients between the 2 vs. 5-day treatments is currently open for accrual at our institution.

3-Year Follow-Up of the Partial Breast Irradiation Trial for DCIS Using the MammoSite® Brachytherapy Balloon Catheter.

Purpose: To report the 3-year median follow-up of a prospective Phase II partial breast irradiation (PBI) trial utilizing the MammoSite® interstitial balloon as the sole radiation therapy treatment after lumpectomy for ductal carcinoma in situ (DCIS).Materials and Methods: One hundred and thirty-three patients were enrolled from May 2003 through January 2006 to reach the 100-patient partial breast irradiation (PBI) target goal of 34 Gy in 10 fractions, 1 cm peripheral to the MammoSite® balloon surface, b.i.d. with Iridium 192 HDR brachytherapy. The eligibility criteria were age 45, unicentric pure DCIS, mammographic size ≤3cm, negative margin of ≥1 mm, gross pathology size ≤5 cm, clinically node negative, post-lumpectomy mammogram absent of residual microcalcificaion. A USC/VNPI score was then calculated based on age, tumor size, margin width, and nuclear grade [ref: Silverstein MJ, Am J Surg 2003;186(4):337-343]. Placement of the balloon was performed at the time of lumpectomy or post-lumpectomy with a required minimum distance of the balloon surface to skin (skin bridge) of 5 mm. Data was collected at enrollment, at implant, 3 and 6-months, then yearly for local control, cosmesis (Harvard Scale), toxicity, adverse events, disease-free survival, cause-specific survival, and contralateral breast failure. Local recurrence is defined as either invasive or non-invasive within the target volume. Ipsilateral elsewhere recurrence (IER) is defined as invasive or non-invasive outside of the target volume.Results: Of the 133 patients enrolled, thirty-three were not treated for the following reasons: less than 5 mm skin bridge (n=13), poor cavity conformance (n=10), positive margin (n=3), microinvasion (n=3), MD decision (n=2), patient request (1), and other (1). The nuclear grade distribution of the tumors were: NG1(17%), NG2(44%), and NG3(39%). The mean age was 60.8 years. The mean tumor size was 10.6 mm; mean closest surgical margin was 6.8 mm (R=0.1-40mm); post-lumpectomy placement in 72%; mean skin bridge distance was 13 mm with 89% ≥7mm. No patients have been lost to follow-up, and at a median 3-year follow-up, the cosmetic results have been rated as excellent/good in 94 and fair in 6 patients. There have been only four recurrences, all non-invasive with the following histological patterns listed in the table below. One was an IER.No serious adverse events were reported with an infection rate of 9% (7 breast infections; 2 cellulitis).Conclusion: This is the longest reported prospective Phase II study using a PBI technique for pure DCIS patients, and continues to demonstrate the efficacy of the MammoSite® balloon for treating pure DCIS breast tumors, with no new recurrences since our last report at SABCS 2007. All the recurrences were noninvasive, and had at least one or more risk factors of a high USC/VNPI score, high nuclear tumor grade, or had a comedo necrosis pattern. There have been no recurrences in nuclear grade 1 or 2 patients in the absence of a comedo necrosis pattern. The cosmesis also continues to be excellent or good long-term in 96% patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 952.