Increased Risk for Ipsilateral Breast Tumor Recurrence in Invasive Lobular Carcinoma after Accelerated Partial Breast Irradiation Brachytherapy.

BACKGROUND: The suitability criteria for accelerated partial breast irradiation (APBI) from the American Brachytherapy Society (ABS), American Society for Radiation Oncology (ASTRO), and The Groupe Européende Curiethérapie European SocieTy for Radiotherapy & Oncology (GEC-ESTRO) have significant differences. MATERIALS AND METHODS: This is a single institution retrospective review of 946 consecutive patients with invasive breast cancer who underwent lumpectomy and APBI intracavitary brachytherapy from 2003 to 2018. Overall survival (OS), breast cancer-specific survival (BCSS), relapse-free survival (RFS), and ipsilateral breast tumor recurrence (IBTR) were estimated with Kaplan-Meier method. RESULTS: Median follow-up time was 60.2 months. Median age was 68 years (46-94 years). The majority of patients had estrogen receptor (ER)-positive disease (94%). There were 821 (87%) cases of invasive ductal carcinoma and 68 cases (7%) of invasive lobular carcinoma (ILC). The 5-year OS, BCSS, RFS, and IBTR were 93%, 99%, 90%, and 1.5%, respectively. Upon univariate analysis, ILC (hazard ratio [HR], 4.6; p = .008) and lack of nodal evaluation (HR, 6.9; p = .01) were risk factors for IBTR. The 10-year IBTR was 2.5% for IDC and 14% for ILC. While the ABS and ASTRO criteria could not predict IBTR, the GEC-ESTRO intermediate risk group was associated with inferior IBTR (p = .04) when compared to both low risk and high risk groups. None of the suitability criteria was able to predict RFS. CONCLUSION: These results show that APBI is an effective treatment for patients with invasive breast cancer. Expansion of the current eligibility criteria should be considered, although prospective validation is needed. Caution is required when considering APBI for patients with ILC. IMPLICATIONS FOR PRACTICE: In a large retrospective review of 946 patients with early breast cancer treated with partial mastectomy and accelerated partial breast irradiation (APBI) intracavitary brachytherapy, this study demonstrates durable local control. Patients deemed unsuitable or high risk by the American Brachytherapy Society, American Society for Radiation Oncology, and European Society for Radiotherapy and Oncology guidelines were not at increased risk for ipsilateral breast tumor recurrence (IBTR), suggesting that expansion of the current criteria should be considered. Importantly, however, these results demonstrate that caution should be taken when considering APBI for patients with invasive lobular carcinoma, as these patients had relatively high risk for IBTR (10-year IBTR, 14%).

Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial.

Importance: The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor-positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). Objective: To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. Design, Setting, and Participants: The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. Interventions: All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. Main Outcomes and Measures: The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. Results: Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI, 0-1.16]; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17]; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. Conclusions and Relevance: Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT00003855.

Use of hydrogel breast biopsy tissue markers reduces the need for wire localization.

BACKGROUND: The purpose of this study was to determine whether breast biopsy tissue markers composed of an ultrasound-visible hydrogel reduced the need for preoperative wire localization (WL) in patients undergoing a partial mastectomy. METHODS: A single-surgeon, single-institution, retrospective chart review was performed on 691 consecutive female patients, with mean age 67 years (range 36-98 years), from 2009 to 2012 undergoing partial mastectomies after percutaneous biopsies by stereotactic or ultrasound guidance. RESULTS: Overall, the use of WL was more frequent in patients who had standard (other) markers placed during biopsy as opposed to those with hydrogel markers (HydroMARK). For stereotactic biopsy, 75.8 % of patients with a standard marker required WL versus 17.1 % with HydroMARK and for ultrasound biopsy, 22.6 % standard versus 4.3 % HydroMARK (p < .0001, p < .0001). In some cases where hydrogel markers were used, WL was used for "bracketing" because of the presence of microcalcifications. In cases where standard markers were used, WL was not used because of either IOUS visibility of residual lesion or marker visibility. Specimen volume and re-excision rate were comparable between patients with hydrogel and standard markers, showing no significant differences (p = .1673, p = .1813 respectively). CONCLUSIONS: Hydrogel biopsy tissue markers optimize the surgeon's ability to perform a partial mastectomy without the use of WL. HydroMARK was as effective as a standard marker in terms of partial mastectomy specimen volume and re-excision rate. This yields potential for cost savings, increased efficacy in operating room and radiology scheduling, and patient comfort and convenience.

Intraoperative Fluorescence Guidance for Breast Cancer Lumpectomy Surgery.

BACKGROUND: Although lumpectomy and mastectomy provide equivalent survival for patients with breast cancer, local recurrence after lumpectomy increases breast cancer mortality. Positive lumpectomy margins, which imply incomplete tumor removal, are the strongest predictor of local recurrence and are identified days after surgery, necessitating a second surgery. METHODS: In this prospective trial, we assessed margin status with or without pegulicianine fluorescence-guided surgery (pFGS) for stages 0 to 3 breast cancers. To prevent surgeons from performing smaller than standard lumpectomies in anticipation of pFGS assistance, patients were randomly assigned 10:1 to pFGS or control groups, thus randomization was not designed to provide a control group for evaluating device performance. In patients undergoing pFGS, additional pFGS-guided cavity margins were excised at sites of pegulicianine signal. We evaluated three coprimary end points: the percentage of patients for whom pFGS-guided margins contained cancer, sensitivity, and specificity. RESULTS: Overall, 406 patients received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Among 392 patients randomly assigned, 316 had invasive cancers, and 76 had in situ cancers. In 27 of 357 patients undergoing pFGS, pFGS-guided margins removed tumor left behind after standard lumpectomy, 22 from cavity orientations deemed negative on standard margin evaluation. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins. On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. Pegulicianine administration was stopped for adverse events in six patients. Two patients had grade 3 serious adverse events related to pegulicianine. CONCLUSIONS: The use of pFGS in breast cancer surgery met prespecified thresholds for removal of residual tumor and specificity but did not meet the prespecified threshold for sensitivity. (Funded by Lumicell, Inc. and the National Institutes of Health; Clinicaltrials.gov number, NCT03686215.)

Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.

CONTEXT: Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection affects survival. OBJECTIVE: To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer. DESIGN, SETTING, AND PATIENTS: The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected. INTERVENTIONS: All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic therapy was at the discretion of the treating physician. MAIN OUTCOME MEASURES: Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a secondary end point. RESULTS: Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy. CONCLUSION: Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003855.

Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer.

CONTEXT: Immunochemical staining of sentinel lymph nodes (SLNs) and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination. OBJECTIVE: To determine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer. DESIGN, SETTING, AND PATIENTS: From May 1999 to May 2003, 126 sites in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study. INTERVENTIONS: All 5210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens (hematoxylin-eosin negative) and bone marrow specimens were sent to a central laboratory for immunochemical staining; treating clinicians were blinded to results. MAIN OUTCOME MEASURES: Overall survival (primary end point) and disease-free survival (a secondary end point). RESULTS: Of 5119 SLN specimens (98.3%), 3904 (76.3%) were tumor-negative by hematoxylin-eosin staining. Of 3326 SLN specimens examined by immunohistochemistry, 349 (10.5%) were positive for tumor. Of 3413 bone marrow specimens examined by immunocytochemistry, 104 (3.0%) were positive for tumors. At a median follow-up of 6.3 years (through April 2010), 435 patients had died and 376 had disease recurrence. Immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7%; 95% confidence interval [CI], 95.0%-96.5% for immunohistochemical negative and 95.1%; 95% CI, 92.7%-97.5% for immunohistochemical positive disease; P = .64; unadjusted hazard ratio [HR], 0.90; 95% CI, 0.59-1.39; P = .64). Bone marrow metastases were associated with decreased overall survival (unadjusted HR for mortality, 1.94; 95% CI, 1.02-3.67; P = .04), but neither immunohistochemical evidence of tumor in SLNs (adjusted HR, 0.88; 95% CI, 0.45-1.71; P = .70) nor immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% CI, 0.79-4.26; P = .15) was statistically significant on multivariable analysis. CONCLUSION: Among women receiving breast-conserving therapy and SLN dissection, immunohistochemical evidence of SLN metastasis was not associated with overall survival over a median of 6.3 years, whereas occult bone marrow metastasis, although rare, was associated with decreased survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003854.

Management of ductal carcinoma in situ with accelerated partial breast irradiation brachytherapy: Implications for guideline expansion.

PURPOSE: Accelerated partial breast irradiation (APBI) for patients with ductal carcinoma in situ (DCIS) is controversial, and the suitability criteria from the American Brachytherapy Society (ABS), American Society of Therapeutic Radiology and Oncology (ASTRO), and the European Society for Radiotherapy and Oncology (GEC-ESTRO) have important differences. METHODS AND MATERIALS: This is a single-institution retrospective review of 169 consecutive patients with DCIS who underwent lumpectomy followed by APBI intracavitary brachytherapy from 2003 to 2018. Outcomes, including overall survival, recurrence-free survival (RFS), ipsilateral breast tumor recurrence, and distant metastasis, were estimated with the Kaplan-Meier method. RESULTS: The median followup time was 62.5 months. Median age was 66 years (47-89 years). The majority of patients had estrogen receptor-positive disease (89%). Fifty patients (30%) had Grade 3 disease. Of the 142 patients with adequate pathology interpretation, 91 and 108 cases had margins ≥ 3 mm and ≥2 mm, respectively. Most patients (72%) were prescribed and started endocrine therapy. Of the patients evaluable for ABS criteria (N = 130), 97 met the suitability criteria. Of the patients evaluable for ASTRO criteria (N = 129), 42 were deemed cautionary and 33 were deemed unsuitable. Of the patients evaluable for GEC-ESTRO criteria (N = 143), 141 cases were at intermediate risk and two were at high risk. Five-year ipsilateral breast tumor recurrence, RFS, and overall survival were 0.6%, 97.7%, and 97.2%, respectively. The ABS, ASTRO, and GEC-ESTRO criteria failed to significantly predict for RFS. CONCLUSIONS: These results, although limited by short-term followup, indicate that expansion of the eligibility criteria of APBI for patients with DCIS should be considered.

Adherence to the National Quality Forum (NQF) breast cancer measures within cancer clinical trials: a review from ACOSOG Z0010.

BACKGROUND: In 2007, the National Quality Forum (NQF) released four performance measures for the treatment of breast cancer. We proposed to study the degree of adherence with these measures among participating institutions in a multi-institutional trial. METHODS: American College of Surgeons Oncology Group (ACOSOG) Z0010 enrolled breast cancer patients onto a phase II trial studying the prognostic significance of bone marrow and sentinel node micrometastases. The current study used chi(2) analyses to determine the degree of adherence with four NQF measures among three institution types: academic, community, and teaching affiliate. RESULTS: The study revealed small but important differences in two measures. Ninety-five percent of patients from teaching affiliated institutions received whole-breast radiation compared to 92% at academic and 91% at community hospitals. Among patients who were underinsured or uninsured, a marked decrease in radiation use was noted in comparison to patients with insurance-85 versus 93%, respectively. The study also revealed a difference among institutional types in patients undergoing excisional biopsy for diagnosis. In teaching-affiliated hospitals, 28.6% underwent excisional biopsy as compared to 36.8 and 37.4% in academic and community hospitals, respectively. There was no statistically significant difference between adherence rates with the remaining two measures. Adjuvant chemotherapy was administered to patients with hormone receptor negative tumors > or =1 cm in size in 79-85% of institutions. Tamoxifen was administered to 79-82% of those patients with hormone receptor-positive cancers. CONCLUSIONS: Among breast cancer patients enrolled onto a multi-institutional clinical trial, we found a high degree of adherence with current consensus standards for adjuvant treatment, despite varied practice environments.

Utilizing the genomically adjusted radiation dose (GARD) to personalize adjuvant radiotherapy in triple negative breast cancer management.

BACKGROUND: Utilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose. METHODS: TN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy. FINDINGS: In cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1-7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1-29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy. INTERPRETATION: GARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC.

Molecular analysis of breast sentinel lymph nodes.

Lymphatic mapping and sentinel lymph node (SLN) biopsy have become the standard of care for staging the axilla in patients with invasive breast cancer. Current histologic methods for SLN evaluation have limitations, including subjectivity, limited sensitivity, and lack of standardization. The discovery of molecular markers to detect metastases has been reported over the last 2 decades. The authors review the historical development of these markers and the clinical use of one of the molecular platforms in 478 patients at their institution. Controversies and future directions are discussed.

Impact of immediate versus delayed axillary node dissection on surgical outcomes in breast cancer patients with positive sentinel nodes: results from American College of Surgeons Oncology Group Trials Z0010 and Z0011.

PURPOSE: Patients with breast cancer metastasis to the sentinel lymph nodes (SLNs) generally undergo completion axillary lymph node dissection (cALND), either concurrently with SLN biopsy or at a second procedure. The impact of the timing of cALND on pathologic results and complications in these patients has not been examined. PATIENTS AND METHODS: We examined outcomes from SLN-positive patients in American College of Surgeons Oncology Group (ACOSOG) trials Z0010 and Z0011. Pathologic data examined included primary tumor characteristics, total number of SLNs recovered, positive SLN(s) and non-SLN(s) identified. Complications assessed included axillary seroma, paresthesia, arm morbidity and range of motion, and lymphedema. RESULTS: A total of 1,003 assessable patients with SLN metastasis had immediate (n = 425) or delayed (n = 578) cALND. The median number of SLNs and axillary LNs removed were the same between groups. Patients who had immediate cALND more often had larger tumors, SLN metastasis identified intraoperatively, two or more positive SLNs, and higher pathologic N stage. Axillary paresthesia, seroma, and impaired extremity range of motion were more common in the immediate group during the early postoperative period, but not at later time points. There was no difference in lymphedema at any time point. CONCLUSION: In ACOSOG trials Z0010 and Z0011, LN recovery and long-term complications were similar after either delayed or immediate cALND for patients with metastasis to SLNs. Patients who undergo immediate cALND experience more short-term morbidity. With respect to staging and complications, there is no clear detriment for patients with a positive SLN who undergo a second procedure for cALND.

Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011.

PURPOSE: The American College of Surgeons Oncology Group trial Z0011 was a prospective, randomized, multicenter trial comparing overall survival between patients with positive sentinel lymph nodes (SLNs) who did and did not undergo axillary lymph node dissection (ALND). The current study compares complications associated with SLN dissection (SLND) plus ALND, versus SLND alone. PATIENTS AND METHODS: From May 1999 to December 2004, 891 patients were randomly assigned to SLND + ALND (n = 445) or SLND alone (n = 446). Information on wound infection, axillary seroma, paresthesia, brachial plexus injury (BPI), and lymphedema was available for 821 patients. RESULTS: Adverse surgical effects were reported in 70% (278 of 399) of patients after SLND + ALND and 25% (103 of 411) after SLND alone (P

Sentinel node skills verification and surgeon performance: data from a multicenter clinical trial for early-stage breast cancer.

OBJECTIVE: Marked variations in sentinel lymph node dissection (SLND) technique have been identified, and definitive qualifications for SLND performance remain controversial. Based on previous reports and expert opinion, we predicted that 20 to 30 cases of SLND with axillary lymph node dissection (ALND) would enable surgeons to identify sentinel lymph nodes (SLN). SUMMARY BACKGROUND DATA: In 1999, the American College of Surgeons Oncology Group initiated a prospective trial, Z0010, to evaluate micrometastatic disease in the SLN and bone marrow of women with early-stage breast cancer. Eligible patients included women with biopsy-proven T1/T2 breast cancer and clinically negative lymph nodes who were candidates for lumpectomy and SLND. METHODS: Participating surgeons were required to document 20 to 30 SLNDs followed by immediate ALND with failure rates less than 15%. Prior fellowship or residency training in SLND provided exemption from skill requirements. Data for 5237 subjects and 198 surgeons were available for analysis. RESULTS: Surgeons from academic (48.4%), community (28.6%), or teaching-affiliated (19.8%) institutions qualified with 30 SLND + ALND cases (64.6%), 20 cases (22.2%), or exemption (13.1%). Participants used blue dye + radiocolloid in 79.4%, blue dye alone in 14.8%, and radiocolloid alone in 5.7% of cases, achieving a 98.7% SLN identification rate. Patient factors associated with increased SLND failure included increased body mass index and age, whereas tumor location, stage, and histology, presence of nodal metastases, and number of positive nodes were not. Surgeon accrual of fewer than 50 patients was associated with increased SLND failure; however, SLND technique, specific skill qualification, and institution type were not. CONCLUSIONS: Using a standard skill requirement, surgeons from a variety of institutions achieved an acceptably low SLND failure rate in the setting of a large multicenter trial, validating the incorporation of SLND into clinical practice.