Premastectomy Radiotherapy and Immediate Breast Reconstruction: A Randomized Clinical Trial.

Importance: Premastectomy radiotherapy (PreMRT) is a new treatment sequence to avoid the adverse effects of radiotherapy on the final breast reconstruction while achieving the benefits of immediate breast reconstruction (IMBR). Objective: To evaluate outcomes among patients who received PreMRT and regional nodal irradiation (RNI) followed by mastectomy and IMBR. Design, Setting, and Participants: This was a phase 2 single-center randomized clinical trial conducted between August 3, 2018, and August 2, 2022, evaluating the feasibility and safety of PreMRT and RNI (including internal mammary lymph nodes). Patients with cT0-T3, N0-N3b breast cancer and a recommendation for radiotherapy were eligible. Intervention: This trial evaluated outcomes after PreMRT followed by mastectomy and IMBR. Patients were randomized to receive either hypofractionated (40.05 Gy/15 fractions) or conventionally fractionated (50 Gy/25 fractions) RNI. Main Outcome and Measures: The primary outcome was reconstructive failure, defined as complete autologous flap loss. Demographic, treatment, and outcomes data were collected, and associations between multiple variables and outcomes were evaluated. Analysis was performed on an intent-to-treat basis. Results: Fifty patients were enrolled. Among 49 evaluable patients, the median age was 48 years (range, 31-72 years), and 46 patients (94%) received neoadjuvant systemic therapy. Twenty-five patients received 50 Gy in 25 fractions to the breast and 45 Gy in 25 fractions to regional nodes, and 24 patients received 40.05 Gy in 15 fractions to the breast and 37.5 Gy in 15 fractions to regional nodes, including internal mammary lymph nodes. Forty-eight patients underwent mastectomy with IMBR, at a median of 23 days (IQR, 20-28.5 days) after radiotherapy. Forty-one patients had microvascular autologous flap reconstruction, 5 underwent latissimus dorsi pedicled flap reconstruction, and 2 had tissue expander placement. There were no complete autologous flap losses, and 1 patient underwent tissue expander explantation. Eight of 48 patients (17%) had mastectomy skin flap necrosis of the treated breast, of whom 1 underwent reoperation. During follow-up (median, 29.7 months [range, 10.1-65.2 months]), there were no locoregional recurrences or distant metastasis. Conclusions and Relevance: This randomized clinical trial found PreMRT and RNI followed by mastectomy and microvascular autologous flap IMBR to be feasible and safe. Based on these results, a larger randomized clinical trial of hypofractionated vs conventionally fractionated PreMRT has been started (NCT05774678). Trial Registration: ClinicalTrials.gov Identifier: NCT02912312.

Prospective Feasibility Trial of Sentinel Lymph Node Biopsy in the Setting of Inflammatory Breast Cancer.

BACKGROUND: Most inflammatory breast cancer (IBC) patients have axillary disease at presentation. Current standard is axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NACT). Advances in NACT have improved pathologic complete response (pCR) rates increasing interest in performing sentinel lymph node (SLN) biopsy (SLNB). Previous studies on SLNB for IBC patients did not assess nodal response with imaging or use dual tracer mapping. We sought to prospectively determine false negative rates of SLNB in IBC patients using dual tracer mapping, and to correlate pathology with preoperative axillary imaging. PATIENTS AND METHODS: Patients with IBC were prospectively enrolled. Patients underwent axillary staging with physical examination and axillary ultrasound before and after NACT. All patients underwent SLNB using blue dye and radioisotope, followed by ALND. RESULTS: Sixteen patients were prospectively enrolled. Clinical N stage was N0 in 1 patient, N1 in 8, and N3 in 7. SLN mapping was successful in only 4 patients (25%) with 12 (75%) not draining either tracer to a SLN. Three of the 4 (75%) who mapped had an axillary pCR. The patient who mapped but did not have an axillary pCR had a positive SLNB with additional axillary nodal disease identified on ALND. All patients who successfully mapped had presumed residual nodal disease on preoperative axillary ultrasound. CONCLUSION: SLNB was unsuccessful in most IBC patients. A small subset who have pCR might undergo successful SLNB, but preoperative axillary imaging failed to identify these patients. ALND should remain standard practice for IBC patients.

Factors impacting the accuracy of intra-operative evaluation of sentinel lymph nodes in breast cancer.

Sentinel lymph node dissection (SLND) is a standard axillary staging technique in breast cancer and intraoperative sentinel lymph node (SLN) assessment is important for decision-making regarding additional treatment and reconstruction. This study was undertaken to investigate clinicopathologic factors impacting the accuracy of intraoperative SLN evaluation. Records of patients with clinically node-negative, invasive breast cancer who underwent SLND with frozen section intraoperative pathologic evaluation from 2004 to 2007 were reviewed. Intraoperative SLN assessment results were compared to final pathology. Patients with positive SLNs that were initially reported as negative during intraoperative assessment were considered false negative (FN) events. Primary tumor histology, grade, receptor status, size, lymphovascular invasion (LVI), multifocality, neoadjuvant chemotherapy or hormonal therapy, number of SLNs retrieved, and SLN metastasis size were evaluated. The study included 681 patients, of whom 262 (38%) received neoadjuvant therapy. There were 183 (27%) patients who had a positive SLN on final pathology, of whom 60 (33%) had FN events. On univariate analysis, lobular histology, favorable histology, absence of LVI and micrometastasis were associated with a higher FN rate. On multivariate analysis, favorable and lobular histology and micrometastasis were independent predictors of FN events whereas LVI and receipt of neoadjuvant therapy were not statistically significant predictors. The accuracy of intraoperative SLN evaluation for breast cancer is affected by primary tumor histology and size of the SLN metastasis. There was no significant association between neoadjuvant therapy and the FN rate by intraoperative assessment. This information may be helpful in counseling patients about their risk for a FN intraoperative SLN assessment and for planning for immediate breast reconstruction in patients undergoing mastectomy.

Molecular cytogenetic characterization of mammary neuroendocrine carcinoma.

Primary mammary neuroendocrine carcinoma (NEC) is an uncommon entity that accounts for 2% to 5% of breast carcinomas. Recent reports have shown that NEC of the breast is an aggressive subtype of mammary carcinoma that is distinct from invasive ductal carcinoma, not otherwise specified, and have suggested that these tumors have a poorer prognosis than invasive ductal carcinoma, not otherwise specified. In this study, we provide the first cytogenetic characterization of mammary NEC using both conventional G-banding and spectral karyotype on a group of 7 tumors. We identified clonal chromosomal aberrations in 5 (71.4%) cases, with 4 of them showing complex karyotypes. Of these, recurrent numerical aberrations included gain of chromosome 7 (n = 2) and loss of chromosome 15 (n = 2). Recurrent clonal structural chromosomal aberrations involved chromosomes 1 (n = 3), 3 (n = 2), 6q (n = 3), and 17q (n = 3). Of the 4 (57.1%) cases with complex karyotypes, 2 showed evidence of chromothripsis, a phenomenon in which tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. One of these had evidence of chromothripsis involving chromosomes 1, 6, 8, and 15. The other also had evidence of chromosome 8 chromothripsis, making this a recurrent finding shared by both cases. We also found that mammary NEC shared some cytogenetic abnormalities--such as trisomy 7 and 12--with other neuroendocrine tumors in the lung and gastrointestinal tract, suggesting trisomy 7 and 12 as potential common molecular aberrations in neuroendocrine tumors. To our knowledge, this is the first report on molecular cytogenetic characterization of mammary NEC.

Predictors of durable no evidence of disease status in de novo metastatic inflammatory breast cancer patients treated with neoadjuvant chemotherapy and post-mastectomy radiation.

INTRODUCTION: Definitive locoregional therapy including surgery and post-mastectomy radiation therapy (PMRT) has been offered to select IBC patients with de novo metastatic disease. Herein we examined predictive factors for progression-free survival after comprehensive PMRT radiation +/- locoregional treatment of metastatic sites. METHODS: Charts of T4d, any N, M1 (de novo) patients who completed PMRT to ≥ 50 Gy from 2006-2011 were reviewed. Patients who received doses <50Gy to the primary site, received radiation at another facility or were treated pre-operatively were excluded. The remaining 36 patients formed the study cohort. Progression-free survival post-PMRT (PFSx) was assessed from the last day of radiation. Median dose to primary fields was 51 Gy. Boost doses ranged from 6-16 Gy. RESULTS: Median age at diagnosis was 54 (range 33-70). Median follow up from primary irradiation completion was 31 months. Sixteen patients were Stage IV NED at last follow-up (IR 37-60 mo). Fifteen patients died of disease. Five patients experienced an in-field recurrence, three of which resulted from local recurrence at the medial edge of the field. Actuarial 5 year locoregional control (LRC) was 86%. Median PFSx was 20 months. All sites of gross disease were treated with radiation in 21/36 patients. Location of metastatic disease had no correlation with PFSx. Estrogen receptor (ER)- patients had shorter 5-yr actuarial PFSx (28% vs. 66%, P = 0.03) and 5 year actuarial OSx (37% vs 71%, P = 0.02). Nine patients (25%) developed a pathological complete response (pCR) after chemotherapy and with a median follow-up of 59 months, 7 remained without evidence of disease. CONCLUSIONS: Despite the poor prognosis associated with metastatic IBC, our data suggest that select patients may be appropriate candidates for locoregional therapy. Patients who achieve a pCR or those with ER + disease have a favorable PFSx. It remains unclear whether all gross disease needs to be addressed with locoregional therapy to provide benefit.

Primary tumor resection as a component of multimodality treatment may improve local control and survival in patients with stage IV inflammatory breast cancer.

BACKGROUND: To the authors' knowledge, the benefit of primary tumor resection among patients with metastatic inflammatory breast cancer (IBC) is unknown. METHODS: The authors reviewed 172 cases of metastatic IBC. All patients received chemotherapy with or without radiotherapy and/or surgery. Patients were classified as responders or nonresponders to chemotherapy. The 5-year overall survival (OS) and distant progression-free survival (DPFS) and local control at the time of last follow-up were evaluated. RESULTS: A total of 79 patients (46%) underwent surgery. OS and DPFS were better among patients treated with surgery versus no surgery (47% vs 10%, respectively [P<.0001] and 30% vs 3%, respectively [P<.0001]). Surgery plus radiotherapy was associated with better survival compared with treatment with surgery or radiotherapy alone (OS rate: 50% vs 25% vs 14%, respectively; DPFS rate: 32% vs 18% vs 15%, respectively [P<.0001 for both]). Surgery was associated with better survival for both responders (OS rate for surgery vs no surgery: 49% vs 23% [P<.0001] and DPFS rate for surgery vs no surgery: 31% vs 8% [P<.0001]) and nonresponders (OS rate for surgery vs no surgery: 40% vs 6% [P<.0001] and DPFS rate for surgery vs no surgery: 30% vs 0% [P<.0001]). On multivariate analysis, treatment with surgery plus radiotherapy and response to chemotherapy were found to be significant predictors of better OS and DPFS. Local control at the time of last follow-up was 4-fold more likely in patients who underwent surgery with or without radiotherapy compared with patients who received chemotherapy alone (81% vs 18%; P<.0001). Surgery and response to chemotherapy independently predicted local control on multivariate analysis. CONCLUSIONS: The results of the current study demonstrate that for select patients with metastatic IBC, multimodality treatment including primary tumor resection may result in better local control and survival. However, a randomized trial is needed to validate these findings.

Evaluation of the MD Anderson Prognostic Index for local-regional recurrence after breast conserving therapy in patients receiving neoadjuvant chemotherapy.

BACKGROUND: We previously developed a prognostic index for assessing local-regional recurrence (LRR) risk in patients undergoing breast conservation therapy (BCT) after neoadjuvant chemotherapy. The prognostic index assigns a point for each of the following variables: clinical N2/N3 disease, lymphovascular invasion, residual pathologic tumor size >2 cm, and multifocal residual disease on pathology. The current study was undertaken to evaluate this prognostic index in an independent cohort. METHODS: We identified 551 patients treated from 2001 to 2005 with neoadjuvant chemotherapy, mastectomy or BCT, and radiation. These patients were not used in the original development of the prognostic index. Outcomes were stratified by prognostic index. The 5-year LRR-free survival was calculated using the Kaplan-Meier method, and differences were compared using the log-rank test. RESULTS: For patients undergoing BCT, the 5-year LRR-free survival rates were 92, 92, 84, and 69% when the prognostic index was 0 (n = 91), 1 (n = 82), 2 (n = 38), or 3-4 (n = 13) (P = 0.01). The 5-year LRR-free survival rates were similar between patients undergoing mastectomy or BCT when the prognostic index score was 0, 1, or 2. When the prognostic index score was 3-4, the 5-year LRR-free survival was significantly lower for patients treated with BCT compared with mastectomy (69 vs. 93%, P = 0.007). CONCLUSION: The previously developed prognostic index was successful in stratifying patients with respect to LRR in an independent cohort undergoing BCT after neoadjuvant chemotherapy. The prognostic index can be used to identify patients at high risk for LRR who may be considered for more extensive surgery or enrollment into clinical trials evaluating novel strategies for local-regional control.

Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes.

BACKGROUND: Colorectal cancer staging criteria do not rely on examination of neuronal tissue. The authors previously demonstrated that perineural invasion is an independent prognostic factor of outcomes in colorectal cancer. For the current study, they hypothesized that neurogenesis occurs in colorectal cancer and portends an aggressive tumor phenotype. METHODS: In total, samples from 236 patients with colorectal cancer were used to create a tissue array and database. Tissue array slides were immunostained for protein gene product 9.5 (PGP9.5) to identify nerve tissue. The correlation between markers of neurogenesis and oncologic outcomes was determined. The effect of colorectal cancer cells on stimulating neurogenesis in vitro was evaluated using a dorsal root ganglia coculture model. RESULTS: Patients whose tumors exhibited high degrees of neurogenesis had 50% reductions in 5-year overall survival and disease-free survival compared with patients whose tumors contained no detectable neurogenesis (P = .002 and P = .006, respectively). Patients with stage II disease and high degrees of neurogenesis had greater reductions in 5-year overall survival and disease-free survival compared with lymph node-negative patients with no neurogenesis (P = .002 and P = .008, respectively). Patients with stage II disease and high degrees of neurogenesis had lower 5-year overall survival and disease-free survival compared with patients who had stage III disease with no neurogenesis (P = .01 and P = .008, respectively). Colorectal cancer cells stimulated neurogenesis and exhibited evidence of neuroepithelial interactions between nerves and tumor cells in vitro. CONCLUSIONS: Neurogenesis in colorectal cancer appeared to play a critical role in colorectal cancer progression. Furthermore, the current results indicated that neurogenesis functions as an independent predictor of outcomes and may play a role in therapy stratification for patients with lymph node-negative disease.