Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial

Jayant S Vaidya , Max Bulsara , Michael Baum  et AL. J Clin Oncol 2020 Sep 20;38(27):3138-3149.
Objective: To determine whether risk adapted intraoperative radiotherapy, delivered as a single dose during lumpectomy, can effectively replace postoperative whole breast external beam radiotherapy for early breast cancer.

Design: Prospective, open label, randomised controlled clinical trial.
Setting: 32 centres in 10 countries in the United Kingdom, Europe, Australia, the United States, and Canada.
Participants: 2298 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, cN0-N1, eligible for breast conservation and randomised before lumpectomy (1:1 ratio, blocks stratified by centre) to either risk adapted targeted intraoperative radiotherapy (TARGIT-IORT) or external beam radiotherapy (EBRT).

Interventions: Random allocation was to the EBRT arm, which consisted of a standard daily fractionated course (three to six weeks) of whole breast radiotherapy, or the TARGIT-IORT arm. TARGIT-IORT was given immediately after lumpectomy under the same anaesthetic and was the only radiotherapy for most patients (around 80%). TARGIT-IORT was supplemented by EBRT when postoperative histopathology found unsuspected higher risk factors (around 20% of patients).

Main outcome measures: Non-inferiority with a margin of 2.5% for the absolute difference between the five year local recurrence rates of the two arms, and long term survival outcomes.

Results: Between 24 March 2000 and 25 June 2012, 1140 patients were randomised to TARGIT-IORT and 1158 to EBRT. TARGIT-IORT was non-inferior to EBRT: the local recurrence risk at five year complete follow-up was 2.11% for TARGIT-IORT compared with 0.95% for EBRT (difference 1.16%, 90% confidence interval 0.32 to 1.99). In the first five years, 13 additional local recurrences were reported (24/1140 v 11/1158) but 14 fewer deaths (42/1140 v 56/1158) for TARGIT-IORT compared with EBRT. With long term follow-up (median 8.6 years, maximum 18.90 years, interquartile range 7.0-10.6) no statistically significant difference was found for local recurrence-free survival (hazard ratio 1.13, 95% confidence interval 0.91 to 1.41, P=0.28), mastectomy-free survival (0.96, 0.78 to 1.19, P=0.74), distant disease-free survival (0.88, 0.69 to 1.12, P=0.30), overall survival (0.82, 0.63 to 1.05, P=0.13), and breast cancer mortality (1.12, 0.78 to 1.60, P=0.54). Mortality from other causes was significantly lower (0.59, 0.40 to 0.86, P=0.005).

Conclusion: For patients with early breast cancer who met our trial selection criteria, risk adapted immediate single dose TARGIT-IORT during lumpectomy was an effective alternative to EBRT, with comparable long term efficacy for cancer control and lower non-breast cancer mortality. TARGIT-IORT should be discussed with eligible patients when breast conserving surgery is planned.

Effect of Delayed Targeted Intraoperative Radiotherapy vs Whole-Breast Radiotherapy on Local Recurrence and Survival: Long-term Results From the TARGIT-A Randomized Clinical Trial in Early Breast Cancer

Jayant S Vaidya , Max Bulsara , Christobel Saunders  et AL. –  JAMA Oncol. 2020 Sep 1;6(9):1410-1415.

Importance: Conventional adjuvant radiotherapy for breast cancer given daily for several weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed.

Objective: To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control.

Design, setting, and participants: In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019.

Interventions: The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound.

Main outcomes and measures: A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes.

Results: Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P = .80).

Conclusions and relevance: These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival.

A prospective cohort study to analyze the interaction of tumor-to-breast volume in breast conservation therapy versus mastectomy with reconstruction

Utku Dolen , Melissa Thornton, Marissa M Tenenbaum et Al. – Ann Surg Oncol 2020 Sep 12. 

Purpose: We explored the impact of the relative volume of a tumor versus the entire breast on outcomes in patients undergoing breast conservation therapy (BCT) versus mastectomy and reconstruction (M + R). We hypothesized that there would be a threshold tumor:breast ratio (TBR) below which patient-reported outcomes (PRO) would favor BCT and above which would favor M + R.

Methods: We conducted a prospective cohort study of patients with ductal carcinoma in situ (DCIS) or invasive breast cancers undergoing BCT or M + R. A prerequisite for inclusion, analysis of tumor and breast volumes was conducted from three-dimensional magnetic resonance imaging reconstructions to calculate the TBR. Three-dimensional photography was utilized to calculate pre- and postoperative volumes and assess symmetry. Oncologic, surgical, and patient-reported outcome data were obtained from relevant BREAST-Q modules administered pre- and postoperatively.

Results: The BCT cohort had significantly smaller tumor volumes (p = 0.001) and lower TBRs (p = 0.001) than patients undergoing M + R overall. The M + R group, however, comprised a broader range of TBRs, characterized at lower values by patients opting for contralateral prophylactic mastectomy. Postoperative satisfaction with breasts, psychosocial, and sexual well-being scores were significantly higher in the BCT cohort, while physical well-being significantly favored the M + R cohort 480.2 ± 286.3 and 453.1 ± 392.7 days later, respectively.

Conclusions: Relative to BCT, M + R was used to manage a broad range of TBRs. The relative importance of oncologic and surgical risk reduction, symmetry, and number of procedures can vary considerably and may limit the utility of TBR as a guide for deciding between BCT and M + R. Clinical Trial StatementThis study was registered with clinicaltrials.gov as “A Prospective Trial to Assess Tumor:Breast Ratio and Patient Satisfaction Following Lumpectomy Versus Mastectomy With Reconstruction”

Prospective Multicenter Study Validate a Prediction Model for Surgery Uptake Among Women with Atypical Breast Lesions

Catherine Uzan, Chafika Mazouni , Caroline Rossoni  et Al – JAMA Intern Med. 2020 Jun 1;180(6):831-842. 

Background: Diagnosis of atypical breast lesions (ABLs) leads to unnecessary surgery in 75-90% of women. We have previously developed a model including age, complete radiological target excision after biopsy, and focus size that predicts the probability of cancer at surgery. The present study aimed to validate this model in a prospective multicenter setting. Women with a recently diagnosed ABL on image-guided biopsy were recruited in 18 centers, before wire-guided localized excisional lumpectomy. Primary outcome was the negative predictive value (NPV) of the model.

Results: The NOMAT model could be used in 287 of the 300 patients included (195 with ADH). At surgery, 12 invasive (all grade 1), and 43 in situ carcinomas were identified (all ABL: 55/287, 19%; ADH only: 49/195, 25%). The area under the receiving operating characteristics curve of the model was 0.64 (95% CI 0.58-0.69) for all ABL, and 0.63 for ADH only (95% CI 0.56-0.70). For the pre-specified threshold of 20% predicted probability of cancer, NPV was 82% (77-87%) for all ABL, and 77% (95% CI 71-83%) for patients with ADH. At a 10% threshold, NPV was 89% (84-94%) for all ABL, and 85% (95% CI 78–92%) for the ADH. At this threshold, 58% of the whole ABL population (and 54% of ADH patients) could have avoided surgery with only 2 missed invasive cancers.

Conclusion: The NOMAT model could be useful to avoid unnecessary surgery among women with ABL, including for patients with ADH

A single-center, randomized, non-inferiority study evaluating seroma formation after mastectomy combined with flap fixation with or without suction drainage: protocol for the Seroma reduction and drAin fRee mAstectomy (SARA) trial

Lisa de Rooij , Sander M J van Kuijk Et Al. –

Background: Seroma formation is a common complication after breast cancer surgery and can lead to delayed wound healing, infection, patient discomfort and repeated visits to the outpatient clinic. Mastectomy combined with flap fixation is becoming standard practice and is currently combined with closed-suction drainage. There is evidence showing that closed-suction drainage may be insufficient in preventing seroma formation. There is reasonable doubt whether there is still place for closed-suction drainage after mastectomy when flap fixation is performed. We hypothesize that mastectomy combined with flap fixation and closed suction drainage does not cause a significant lower incidence of seroma aspirations, when compared to mastectomy and flap fixation alone. Furthermore, we expect that patients without drainage will experience significantly less discomfort and comparable rates of surgical site infections.

Methods: This is a randomized controlled trial in female breast cancer patients undergoing mastectomy and flap fixation using sutures with or without sentinel lymph node biopsy (SLNB). Patients will be eligible for inclusion if they are older than 18 years, have an indication for mastectomy with or without sentinel procedure. Exclusion criteria are modified radical mastectomy, direct breast reconstruction, previous history of radiation therapy of the unilateral breast, breast conserving therapy and inability to give informed consent. A total of 250 patients will be randomly allocated to one of two groups: mastectomy combined with flap fixation and closed-suction drainage or mastectomy combined with flap fixation without drainage. Follow-up will be conducted up to six months postoperatively. The primary outcome is the proportion of patients undergoing one or more seroma aspirations. Secondary outcome measures consist of the number of invasive interventions, surgical site infection, quality of life measured using the SF-12 Health Survey, cosmesis, pain and number of additional outpatient department visits.

Discussion: To our knowledge, no randomized controlled trial has been conducted comparing flap fixation with and without closed-suction drainage with seroma aspiration as the primary outcome. This study could result in finding evidence that supports performing mastectomy without closed-suction drainage.

Breast Cancer and Secondary Cancer Recurrences After Autologous Tissue Reconstruction. Amy P Early , Wong Moon ²et AL. – Clin Breast Cancer 2020 Aug 3;S1526-8209(20)30181-6.

Background: The medical literature defining breast cancer recurrence and secondary cancers after autologous tissue reconstruction for breast cancer is sparse. We sought to identify and analyze occurrences at our institution.

Patients and methods: A 20-year retrospective review of cancer recurrences and atypical breast neoplasms after autologous tissue breast reconstruction at Roswell Park Comprehensive Cancer Center was conducted after being granted a waiver from the institutional review board.

Results: Eighteen locoregional recurrences among 337 cases were identified and analyzed. Overall recurrence rate was 5.3%. Four secondary cancers (1.2%) were radiation-induced angiosarcoma, undifferentiated pleomorphic sarcoma, and metaplastic carcinoma. One case of flat epithelial atypia was identified.

Conclusion: Our retrospective review found incidence and survival after treatment of breast cancer concordant with reports in the literature. We also identified and analyzed secondary neoplasms, including a unique case of undifferentiated pleomorphic sarcoma and metachronous recurrence of breast carcinoma. A case of recurrence as metaplastic carcinoma was identified.

Adjuvant and neoadjuvant radiotherapy in breast cancer: A literaure review and update on the state of the evidence in 2020. Y Belkacemi^, K Debbi , G Loganadane et Al – Cancer Radiother 2020 Oct;24(6-7):482-492.

Radiation therapy has benefited from many developments over the past 20 years. These developments are mainly linked to the technology, imaging and informatics evolutions which allow better targets definitions, ensure better organs-at-risk sparing and excellent reproducibility of treatments, with a perfect control of patient positioning. In breast cancer radiotherapy, the evolution was marked by the possibility of reducing the duration of treatments from 6-7 to 3-4 weeks by using hypofractionated regimens, or by further reducing the irradiation to one week when treatment is solely focalised to the tumour bed. This concept of accelerated partial breast irradiation has challenged the paradigm of the obligation to irradiate the whole breast after conservative surgery in all patients. In addition, the technical mastery of accelerated partial breast irradiation and the development of stereotactic radiotherapy techniques are currently contributing to the development of research projects in neoadjuvant settings. Thus, numerous ongoing studies are evaluating the impact of high-dose preoperative tumour irradiation, alone or in combination with systemic treatments, on biological tumor changes, on anti-tumour immunity, and on the pathologic complete response, which is considered as predictive of better long-term survival in some molecular breast cancer subtypes. In this review, we discuss all these developments which allow breast radiation therapy to enter the era of personalisation of treatments in oncology.

Changes in breast cancer management during the Corona Virus Disease 19 pandemic: An international survey of the European Breast Cancer Research Association of Surgical Trialists (EUBREAST).  Maria Luisa Gasparri ¹, Oreste Davide Gentilini Et Al – ^– Breast 2020 Aug;52:110-115.

Background: Corona Virus Disease 19 (COVID-19) had a worldwide negative impact on healthcare systems, which were not used to coping with such pandemic. Adaptation strategies prioritizing COVID-19 patients included triage of patients and reduction or re-allocation of other services. The aim of our survey was to provide a real time international snapshot of modifications of breast cancer management during the COVID-19 pandemic.

Methods: A survey was developed by a multidisciplinary group on behalf of European Breast Cancer Research Association of Surgical Trialists and distributed via breast cancer societies. One reply per breast unit was requested.

Results: In ten days, 377 breast centres from 41 countries completed the questionnaire. RT-PCR testing for SARS-CoV-2 prior to treatment was reported by 44.8% of the institutions. The estimated time interval between diagnosis and treatment initiation increased for about 20% of institutions. Indications for primary systemic therapy were modified in 56% (211/377), with upfront surgery increasing from 39.8% to 50.7% (p < 0.002) and from 33.7% to 42.2% (p < 0.016) in T1cN0 triple-negative and ER-negative/HER2-positive cases, respectively. Sixty-seven percent considered that chemotherapy increases risks for developing COVID-19 complications. Fifty-one percent of the responders reported modifications in chemotherapy protocols. Gene-expression profile used to evaluate the need for adjuvant chemotherapy increased in 18.8%. In luminal-A tumours, a large majority (68%) recommended endocrine treatment to postpone surgery. Postoperative radiation therapy was postponed in 20% of the cases.

Conclusions: Breast cancer management was considerably modified during the COVID-19 pandemic. Our data provide a base to investigate whether these changes impact oncologic outcomes.

Occult Breast Carcinoma Is More Common in Women Undergoing Breast Reduction after Contralateral Cancer: A Systematic Review and Meta-Analysis.  Siobhan E Fitzpatrick ¹, Thomas C Lam lEt Al. – ast Reconstr Surg. 2020 Aug;146(2):117e-126e.

Background: Occult breast carcinoma is occasionally found in breast reduction specimens. Although its incidence varies widely, there is a trend toward an increased incidence for women with a history of breast cancer. The authors performed a systematic review and meta-analysis of occult carcinoma incidence in breast reduction specimens.

Methods: The MEDLINE and Embase databases were searched for peer-reviewed studies with no language restrictions for studies that recorded the incidence of occult carcinoma in breast reduction specimens. Cancer incidence per specimen was pooled for women with and without a history of breast cancer.

Results: Forty-two studies were eligible for inclusion, of which 29 were quantitatively analyzed. The pooled incidence of carcinoma was higher within specimens from women with breast cancer (3.4 percent; 95 percent CI, 2.2 to 5.3 percent) than without (0.6 percent; 95 percent CI, 0.4 to 0.8 percent), and this increased likelihood was significant when populations were compared directly (OR, 6.02; 95 percent CI, 3.06 to 11.86; p < 0.0001).

Conclusions: Women with a history of breast cancer have an increased incidence of occult breast carcinoma within their breast reduction specimens compared with women with no breast cancer history. There is a need for preoperative radiology screening, counseling, and histopathology guidelines to ensure adequate diagnosis and management of these women.

Utility of the periareolar incision technique for breast reconstructive surgery in patients with breast cancer.  Hirohito Seki , Takashi Sakurai , Yuka Maeda  Et Al – Surg Today 2020 Sep;50(9):1008-1015.

Purpose: Periareolar incisions for nipple-sparing mastectomy offer the advantages of smaller inconspicuous wounds and easier resection below the nipple-areolar complex. However, they provide a narrow surgical field, which complicates the procedure and carries a risk of nipple necrosis. This study evaluated the clinical outcomes and safety of periareolar incisions for breast reconstructive surgery in patients with breast cancer.

Methods: The study included 181 patients with primary operable breast cancer who underwent nipple-sparing mastectomy for reconstructive breast procedures without intraoperative nipple-areolar complex resection. The clinical outcomes and complications were retrospectively evaluated. The recurrence-free survival was compared using Kaplan-Meier curves.

Results: Nipple-sparing mastectomy was performed via inframammary fold and periareolar incisions in 31 and 150 patients, respectively. There were no significant differences in clinical outcomes related to surgery, frequency of complications, nipple necrosis (inframammary fold incision vs. periareolar incision: 0% vs. 3.3%, P = 0.590), or the recurrence-free survival (P = 0.860) between the 2 groups.

Conclusion: Our results showed that the clinical outcomes and complication rates of periareolar incisions for breast reconstruction were equivalent to those of inframammary fold incisions, suggesting that the periareolar incision technique for breast reconstructive surgery may safely improve cosmetic outcomes if done with adequate care.

Radiotherapy after breast-conserving surgery for elderly patients with early-stage breast cancer: A national registry-based study. Fei Wang , Ingrid Meszoely , Tuya Pal  et Al. – Int J Cancer. 2020 Aug 24PMID: 32838477

Considerable controversies exist regarding whether elderly patients with early-stage breast cancer receiving breast-conserving surgery (BCS) should forgo radiotherapy. We utilized the National Cancer Database to analyze data of 115 516 women aged ≥70 years, treated with BCS for T1-2N0-1M0 breast cancer between 2004 and 2014. Multivariable Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for mortality 3, 5 and 10 years after 90 days of BCS associated with radiotherapy. Patients who received no radiotherapy had a higher mortality rate than those who received radiotherapy (5-year survival rate: 71.2% vs 83.8%), with multivariable-adjusted HRs of 1.65 (95% CI: 1.57-1.72) for 3-year mortality, 1.53 (1.47-1.58) for 5-year mortality and 1.43 (1.39-1.48) for 10-year mortality. The association held even for patients ≥90 years. This association was observed in all strata by reasons for radiotherapy omission, receipt of endocrine therapy or chemotherapy, calendar period and other clinical characteristics, with 40% to 65% increased 5-year mortality for patients without radiotherapy. This positive association persisted when analyses were restricted to patients with T1N0 and estrogen-receptor-positive disease who had received endocrine therapy (5-year mortality: HR 1.47 [1.39-1.57]) and in propensity score weighted analyses. Our study shows, in routine practice, elderly patients who received no post-BCS radiotherapy had higher total mortality than those who received radiotherapy. These findings suggest that the current recommendation of omission of post-BCS radiotherapy for elderly women with early-stage breast cancer may need to be reconsidered, particularly for those without contraindication