A multi-institutional prediction model to estimate the risk of recurrence and mortality after mastectomy for T1-2N1 breast cancer.

BACKGROUND: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial. METHODS: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM). RESULTS: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more adverse risk factors than those patients not receiving PMRT: younger age, larger tumors, more positive lymph nodes, lymphovascular invasion, extracapsular extension, and positive margins (p < .05 for all). On competing risk regression analysis, receipt of PMRT was significantly associated with a decreased risk of LRR (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.14-0.31; p < .001) and OR (HR, 0.76; 95% CI, 0.62-0.94; p = .011). Model performance metrics for each end point showed good discrimination and calibration. An online prediction model to estimate predicted risks for each outcome based on individual patient and tumor characteristics was created from the model. CONCLUSIONS: In a large multi-institutional cohort of patients, PMRT for T1-2N1 breast cancer was associated with a significant reduction in locoregional and overall recurrence after accounting for known prognostic factors. An online calculator was developed to aid in personalized decision-making regarding PMRT in this population.

Weight loss does not decrease risk of breast cancer-related arm lymphedema.

BACKGROUND: The goal of this study was to determine the relationship between postoperative weight change and breast cancer-related lymphedema (BCRL). METHODS: In this cohort study, 1161 women underwent unilateral breast surgery for breast cancer from 2005 to 2020 and were prospectively screened for BCRL. Arm volume measurements were obtained via an optoelectronic perometer preoperatively, postoperatively, and in the follow-up setting every 6 to 12 months. Mean follow-up from preoperative baseline was 49.1 months. The main outcome was BCRL, defined as a relative volume change of the ipsilateral arm of ≥10% at least 3 months after surgery. RESULTS: A total of 92 patients (7.9%) developed BCRL. Net weight loss versus net weight gain from baseline to last follow-up was not protective against developing BCRL (hazard ratio, 1.38; 95% confidence interval, 0.89-2.13; P = .152). CONCLUSIONS: Although weight loss may be recommended as part of an individualized lifestyle management program for overall health, weight loss alone may not decrease the risk of developing BCRL.

Subclinical Lymphedema After Treatment for Breast Cancer: Risk of Progression and Considerations for Early Intervention.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is a devastating complication of breast cancer (BC) treatment. The authors hypothesized that identifying subclinical lymphedema (SCL) presents an opportunity to prevent BCRL development. They aimed to assess rates of SCL progression (relative volume change [RVC], 5-10%) to BCRL (RVC, ≥10%) in women undergoing axillary surgery for BC via axillary lymph node dissection (ALND) or sentinel lymph node biopsy (SLNB). METHODS: Patients treated for BC were prospectively screened at preoperative baseline and throughout the follow-up period using the perometer. The cohort was stratified according to nodal surgery (ALND or SLNB) to analyze rates of progression to BCRL. RESULTS: The study cohort included 1790 patients. Of the 1359 patients who underwent SLNB, 331 (24.4%) experienced SCL, with 38 (11.5%) of these patients progressing to BCRL. Of the 431 patients who underwent ALND, 171 (39.7%) experienced SCL, with 67 (39.2%) of these patients progressing to BCRL. Relative to the patients without SCL, those more likely to experience BCRL were the ALND patients with early SCL (< 3 months postoperatively; hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.58-4.27; p = 0.0002) or late SCL (≥3 months postoperatively; HR, 3.14; 95% CI, 1.95-5.05; p < 0.0001) and the SLNB patients with early SCL (HR, 6.75; 95% CI, 3.8-11.98; p < 0.0001 or late SCL (HR, 3.02; 95% CI, 1.65-5.50; p = 0.0003). CONCLUSION: The study suggests that patients with SCL after axillary nodal surgery for BC are more likely to progress to BCRL than those who do not experience SCL. This presents a tremendous opportunity for early intervention to prevent BCRL and improve the quality of life for women treated for BC.

Optimal breast reconstruction type for patients treated with neoadjuvant chemotherapy, mastectomy followed by radiation therapy.

PURPOSE: To explore the optimal type of breast reconstruction and the time interval to postmastectomy radiotherapy (PMRT) associated with lower complications in breast cancer patients receiving neoadjuvant chemotherapy. METHODS: We reviewed the medical records of 300 patients who received neoadjuvant chemotherapy, mastectomy with breast reconstruction and PMRT at our institution from 2000 to 2017. Reconstruction types included autologous flaps (AR), single-stage-direct-to-implant and two-stages expander/implant (TE/I). The primary endpoint was the rate of reconstruction complications including infection, skin and fat necrosis. Subgroup analysis compared rates of capsular contracture, implant rupture, implant exposure and overall implant failure in single-stage-direct-to-implant to TE/I. The secondary endpoint was identifying the time interval between surgery with immediate implant-based reconstruction and PMRT associated with lower probability of implant failure. Logistic regression models, Kaplan-Meier estimates and Polynomial regression were used to assess endpoints. RESULTS: The median follow-up was 43.5 months. 29.3%, 28.3% and 42.4% of the cohort had AR, TE/I and single-stage-direct-to-implant D, respectively. The 5-year cumulative incidence rate of complications was 14.0%, 29.7% and 19.4% for AR, TE/I and single-stage-direct-to-implant, respectively (Log rank p = 0.02). Multivariate analysis showed significant association between TE/I and higher risk of infection (OR 8.1, p = 0.009) compared to AR, while single-stage-direct-to-implant and AR were comparable (OR 3.2, p = 0.2). On subgroup analysis, TE/I was significantly associated with higher rates of implant failure. The mean wait time to deliver PMRT after immediate reconstruction with no adjuvant chemotherapy was 8.4 and 10.7 weeks in single-stage-direct-to-implant and TE/I, respectively (p < 0.005). Delivering PMRT after 8 weeks of surgery yielded 10% probability of reconstruction failure in single-stage-direct-to-implant versus 40% in TE/I. CONCLUSION: In comparison to two stages reconstruction, single-stage-direct-to-implant following neoadjuvant chemotherapy has lower complications and offers timely delivery of PMRT.

Patients who report cording after breast cancer surgery are at higher risk of lymphedema: Results from a large prospective screening cohort.

OBJECTIVES: To identify the association between cording and breast cancer-related lymphedema (BCRL); describe time course, location, symptoms and functional impairments. METHODS: A total of 1181 patients were prospectively screened for BCRL after breast cancer (BC) surgery, including patient-reported outcome measures (4193) and perometric arm volume measurements (BCRL defined as relative or weight-adjusted volume change [RVC or WAC] ≥10% ≥3 months postoperatively). RESULTS: A total of 374/1181 patients (31.7%) reported cording first a median of 4.5 months postoperatively, and were more likely to: have body mass index less than 30 kg/m2 ; be less than 55 years of age; have had mastectomy, axillary lymph node dissection, regional lymph node radiation, neoadjuvant chemotherapy (all P < .001), or RVC/WAC ≥10% (P = .002). Patients who reported cording had 2.4 times the odds of developing BCRL compared to those who did not (odds ratio = 2.40; 95% confidence interval = 1.40-4.11; P = .002), and most frequently reported these symptoms: tenderness (61.2%), aching (60.7%), and firmness/tightness (59.8%). On multivariable analysis, cording was significantly correlated with functional difficulty for 17 actions. CONCLUSIONS: Patients frequently present with cording, potentially months after BC surgery. Risk factors for and symptoms of cording are identified, and treatment is recommended. Patients reporting cording are at higher risk of BCRL, therefore, cording should be incorporated into BCRL risk stratification.

Incidence of peripheral edema in patients receiving PI3K/mTOR/CDK4/6 inhibitors for metastatic breast cancer.

PURPOSE: This study evaluated development of edema in patients receiving PI3K/mTOR/CDK4/6 targeted therapy for metastatic breast cancer (MBC). METHODS: We reviewed medical records of 160 patients receiving targeted therapy with PI3K/mTOR/CDK4/6 inhibitors to treat MBC (n = 160; 185 treatment occurrences). Clinicopathologic data, treatment details, and edema incidence were recorded. RESULTS: Edema incidence was 43.1% (69/160) overall and 25.6% (41/160) in the upper extremity ipsilateral to the treated breast. In 185 therapy regimens administered, 6.8% of patients on a PI3K inhibitor, 8.8% of patients on an mTOR inhibitor, and 9.2% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting upper extremity edema. Further, 9.1% of patients on a PI3K inhibitor, 18.8% of patients on an mTOR inhibitor, and 10.5% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting edema elsewhere in the body. Multivariate logistic regression showed that, beyond the established breast cancer-related lymphedema (BCRL) risk factors [axillary lymph node dissection (Odds Ratio (OR) 2.69, p = 0.020), regional lymph node irradiation (OR 6.47, p < 0.001), and body-mass index ≥ 30 kg/m2 (OR 3.46, p = 0.006)], a relative decrease in serum albumin after 3 months of treatment increased risk of developing edema (OR 2.07, p = 0.062). Neither duration nor type of therapy were significant risk factors for edema. CONCLUSION: PI3K/mTOR/CDK4/6 inhibitors may influence the development of edema, which may cause or exacerbate progression of BCRL in patients with MBC. The varied incidence of edema between therapeutic regimens warrants vigilant monitoring of patients treated with these therapies, especially those at high risk of developing BCRL.

Evaluation of radiation-induced cardiac toxicity in breast cancer patients treated with Trastuzumab-based chemotherapy.

PURPOSE: Patients with Her2-positive breast cancer treated with trastuzumab have higher rates of cardiotoxicity (CT). Left-breast radiation might increase the risk for CT from cardiac exposure to radiation. The goal of our study is to evaluate the contribution of radiotherapy (RT) in the development of CT in breast cancer patients receiving trastuzumab. METHODS: Two hundred and two patients were treated with RT and trastuzumab from 2000 to 2014. The RT plans for left-side disease were recalled from archives. The heart, each chamber, and left anterior descending artery (LAD) were independently contoured. New dose-volume histograms (DVH) were generated. Their serial left-ventricular ejection fractions (LVEF) were studied. CT for left and right side were compared using Fisher's exact test. The DVH data were correlated with the predefined cardiac events using actuarial Cox regression analysis. RESULTS: Compared to the right sided, the left-side cases showed statistically significant development of arrhythmia (14.2%) versus (< 1%) (p < 0.001). Cardiac ischemia was found in 10 patients in left and one patient in right side (p = 0.011). The equivalent uniform dose (EUD) to the left ventricle (LV), right ventricle (RV), and LAD was significantly associated with decrease in LVEF by > 10% (p = 0.037, p = 0.023 and p = 0.049, respectively). CONCLUSIONS: Among patients treated for left-sided lesions, there were no significant differences in EF decline. However, there was a higher rate of ischemia and arrhythmia compared to those with right-sided disease. The EUD index of LV, RV, and LAD could be considered as a parameter to describe the risk of radiation-induced CT.

Signaling cascades in thyroid cancer: Increasing the armory of archers to hit bullseye.

Thyroid cancer is a multifaceted and therapeutically challenging disease and rapidly accumulating experimentally verified findings have considerably improve our understanding of the molecular mechanisms which underlie its development. Substantial fraction of information has been added into existing landscape of molecular oncology and we have started to develop a sharper understanding of the underlying mechanisms of thyroid cancer. Wealth of information demystified different intracellular signaling cascades which are frequently deregulated in thyroid cancer. In vitro assays and xenografted mice based studies have helped us to identify drug targets and different synthetic and natural products are currently being tested to effectively treat thyroid cancer. Cabozantinib and vandetanib have been approved to treat medullary thyroid cancer (MTC) and two agents (lenvatinib and sorafenib) are also being used to treat radioactive-iodine refractory differentiated thyroid cancer. This review comprehensively summarizes most recent advancements in our knowledge related to dysregulated intracellular signaling cascades in thyroid cancer and how different proteins can be therapeutically exploited. (1) We discuss how loss of TRAIL mediated apoptosis occurred in thyroid cancer cells and how different strategies can be used to restore apoptosis in resistant cancer cells; (2) We provide detailed account of seemingly opposite roles of NOTCH signaling in thyroid cancers; (3) TGF/SMAD mediated signaling also needs detailed research because of context dependent role in thyroid cancer. Researchers have only begun to scratch the surface of how TGF signaling works in thyroid cancer and metastasis; and (4) Role of SHH signaling in thyroid cancer stem cells is also well appreciated and targeting of SHH pathway will be an important aspect in treatment of thyroid cancer. Better concepts and improved knowledge will be helpful for clinicians in getting a step closer to individualized medicine.

Novel targeted therapies and immunotherapy for advanced thyroid cancers.

Thyroid cancer is a frequently encountered endocrine malignancy. Despite the favorable prognosis of this disease, 15-20% of differentiated thyroid cancer (DTC) cases and most anaplastic types, remain resistant to standard treatment options, including radioactive iodine (RAI). In addition, around 30% of medullary thyroid cancer (MTC) cases show resistance after surgery. The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of two targeted therapies (Sorafenib and Lenvatinib) for RAI refractory DTC and another two drugs (Vandetanib and Cabozantinib) for MTC. These advanced therapies exert their effects by blocking the MAPK pathway, which has been widely correlated to different types of thyroid cancers. While these drugs remain reserved for thyroid cancer patients who failed all treatment options, their ability to improve patients' overall survival remain hindered by their low efficacy and other molecular factors. Among these factors is the tumor's ability to activate parallel proliferative signaling pathways other than the cascades blocked by these drugs, along with overexpression of some tyrosine kinase receptors (TKR). These facts urge the search for novel different treatment strategies for advanced thyroid cases beyond these drugs. Furthermore, the growing knowledge of the dynamic immune system interaction with tumor microenvironment has revolutionized the cancer immune therapy field. In this review, we aim to discuss the molecular escape mechanisms of thyroid tumors from these drugs. We also highlight novel therapeutic options targeting other pathways than MAPK, including PI3K pathway, ALK translocations and HER2/3 receptors and their clinical impact. We also aim to discuss the usage of targeted therapy in restoring thyroid tumor sensitivity to RAI, and finally turn to extensively discuss the role of immunotherapy as a potential alternative treatment option for advanced thyroid diseases.

Pathologic Exploration of the Axillary Soft Tissue Microenvironment and Its Impact on Axillary Management and Breast Cancer Outcomes.

PURPOSE: Axillary soft tissue (AXT) involvement with tumor cells extending beyond the positive lymph node (LN+) and extracapsular extension (ECE) has been overlooked in breast pathology specimen analysis. MATERIALS AND METHODS: We analyzed 2,162 LN+ patients, dividing them into four groups on the basis of axillary pathology: (1) LN+ only, (2) LN+ and ECE only, (3) LN+ and AXT without ECE, and (4) LN+ with both AXT and ECE. The primary end points were 10-year locoregional failure (LRF), the 10-year axillary failure, and 10-year distant metastasis rates. Multivariable Cox models, accounting for clinical factors, were fitted using the entire cohort, and subgroups analyses were conducted. RESULTS: The median follow-up was 9.4 years. The 10-year distant metastasis incidence was 42% for LN + AXT + ECE, 23% for both LN + AXT and LN + ECE only, and 13% for LN+ only. The 10-year axillary failure rates were 4.5% for LN + AXT + ECE, 4.6% for LN + AXT, 0.8% for LN + ECE only, and 1.6% for LN+ only. The 10-year LRF rates were 14% for LN + AXT + ECE, 10% for LN + AXT, 5.7% for LN + ECE only, and 6.2% for LN+ only. Multivariable analysis revealed that AXT was significantly associated with distant metastasis (hazard ratio [HR], 1.6; P < .001), locoregional failure (HR, 2.3; P < .001), and axillary failure (HR, 3.3; P = .003). Subgroup analyses showed that regional LN radiation (RLNR) improved locoregional tumor outcomes with AXT, ECE, or both (HR, 0.5; P = .03). Delivering ≤50 Gy to the axilla in the presence of AXT/ECE increased axillary failure (HR, 3.0; P = .04). Moreover, when delivering RLNR, axillary LN dissection could be de-escalated to sentinel node biopsy even in the presence of features such as AXT or ECE without significantly increasing any failure outcome: (HR, 1.0; P = .92) for LRF, (HR, 1.1; P = .94) axillary failure, and (HR, 0.4; P = .01) distant metastasis. CONCLUSION: Routine reporting of axillary tissue involvement, beyond LNs and ECE, is crucial in predicting breast cancer outcomes. Ruling out the presence of AXT is imperative before any form of axillary de-escalation, especially RLNR omission.

Side effects of COVID-19 vaccinations in patients treated for breast cancer.

Lymph node swelling is a side effect of the mRNA COVID-19 vaccines, a distressing side effect for women treated for breast cancer. The purpose of this study is to present side effects reported by a cohort of patients treated for breast cancer. A survey link was sent to 4945 women who received breast cancer treatment and were prospectively screened for breast cancer-related lymphedema. In total, 621 patients who received an mRNA vaccine and responded to the survey were included in analysis. We assessed the frequency and predictors of side effects. The most frequent side effects reported were injection site soreness, fatigue, generalized muscle soreness, headache, and chills, with median duration ≤ 48 h. Lymph node swelling occurred most often in the axilla ipsilateral to the vaccine. The median duration was 1 week or less after all doses. These data will inform patient education regarding future vaccine doses, including reassurances about which side effects to expect, particularly lymph node swelling which may impact mammograms after vaccination. Type and duration of side effects were similar to that reported by the general population in Phase 3 testing trials of the mRNA vaccines. Clinical Trial Registration NCT04872738 posted May 4, 2021.

Radiation Modality (Proton/Photon), Timing, and Complication Rates in Patients With Breast Cancer Receiving 2-Stages Expander/Implant Reconstruction.

PURPOSE: Our purpose is to explore the effect of postmastectomy radiation therapy (PMRT) modality and timing on complication rates in breast cancer patients receiving immediate 2-stages expander/implant. METHODS AND MATERIALS: We reviewed the charts of 661 patients who underwent immediate 2-stages expander/implant with/without PMRT at our institution from 2000 to 2019. Patients were divided into 3 cohorts: no radiation, PMRT to expanders (RTE), and PMRT to implants after expander exchange (RTI). PMRT was delivered either with 3-dimensional conformal photon with or without chest wall boost (CWB) or proton therapy. Reconstruction complications were defined as infection/necrosis requiring debridement, capsular-contracture requiring capsulotomy, and reconstruction failure requiring prothesis removal. Logistic regression and Cox models were used to assess the effect of different radiation therapy modalities on complication rates and local control. RESULTS: Among 661 patients, 309 (46.7%) received PMRT, 220 of the 309 (71.2%) received RTE before exchange, and 89 (28.8%) received RTI after exchange. Seventeen out of 309 (5.5%) patients received proton therapy. The complications among RTE versus RTI cohorts were 22.7% versus 15.7% for infection/necrosis, 13.6% versus 19.1% for capsular-contracture, and 39.5% versus 31.5% for overall reconstruction failure, respectively. Among proton patients, 8/17 (47%) developed capsular contracture compared with 16.4% (24/146) and 10.3% (15/146) in CWB and non-CWB groups, respectively. Adjusted multivariable analysis showed no significant difference between RTI and RTE in terms of infection/necrosis and capsular contracture. Yet, RTE significantly increased overall reconstruction failure compared with RTI (39.5% vs 31.5%; odds ratio [OR], 2.11; P = .02). Protons significantly increased capsular contracture compared with both CWB and non-CWB groups (OR, 5.4; P = .01 and OR, 10.9; P < .001, respectively). Moreover, proton significantly increased overall reconstruction failure. The 5-year local control rates were 95.3% and 97.7% for RTE and RTI, respectively (hazard ratio, 1.2; P = .7). CONCLUSIONS: Early radiation to the expander before the exchange to implant significantly increased overall reconstruction failure without improving local control. Protons significantly increased capsular contracture rates and overall reconstruction failure leading to more revision surgeries.

Risk of Developing Breast Reconstruction Complications: A Machine-Learning Nomogram for Individualized Risk Estimation with and without Postmastectomy Radiation Therapy.

BACKGROUND: The purpose of this study was to create a nomogram using machine learning models predicting risk of breast reconstruction complications with or without postmastectomy radiation therapy. METHODS: Between 1997 and 2017, 1617 breast cancer patients undergoing mastectomy and breast reconstruction were analyzed. Those with autologous, tissue expander/implant, and single-stage direct-to-implant reconstruction were included. Postmastectomy radiation therapy was delivered either with three-dimensional conformal photon or proton therapy. Complication endpoints were defined based on surgical reintervention operative notes as infection/necrosis requiring débridement. For implant-based patients, complications were defined as capsular contracture requiring capsulotomy and implant failure. For each complication endpoint, least absolute shrinkage and selection operator-penalized regression was used to select the subset of predictors associated with the smallest prediction error from 10-fold cross-validation. Nomograms were built using the least absolute shrinkage and selection operator-selected predictors, and internal validation using cross-validation was performed. RESULTS: Median follow-up was 6.6 years. Among 1617 patients, 23 percent underwent autologous reconstruction, 39 percent underwent direct-to-implant reconstruction, and 37 percent underwent tissue expander/implant reconstruction. Among 759 patients who received postmastectomy radiation therapy, 8.3 percent received proton-therapy to the chest wall and nodes and 43 percent received chest wall boost. Internal validation for each model showed an area under the receiver operating characteristic curve of 73 percent for infection, 75 percent for capsular contracture, 76 percent for absolute implant failure, and 68 percent for overall implant failure. Periareolar incisions and complete implant muscle coverage were found to be important predictors for infection and capsular contracture, respectively. In a multivariable analysis, we found that protons compared to no postmastectomy radiation therapy significantly increased capsular contracture risk (OR, 15.3; p < 0.001). This was higher than the effect of photons with electron boost versus no postmastectomy radiation therapy (OR, 2.5; p = 0.01). CONCLUSION: Using machine learning, these nomograms provided prediction of postmastectomy breast reconstruction complications with and without radiation therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Integrating Symptoms Into the Diagnostic Criteria for Breast Cancer-Related Lymphedema: Applying Results From a Prospective Surveillance Program.

OBJECTIVE: The objectives of this study were to determine whether patients reporting symptoms are more likely to develop lymphedema and to describe the temporal relationship between symptom onset and lymphedema. METHODS: This was a prospective longitudinal cohort study of 647 women treated for breast cancer and screened for lymphedema using arm volume measurements and subjective questionnaires (n = 647; 2284 questionnaires [median 3.5 per patient, range = 1-24]). Primary study outcome was lymphedema (relative volume change ≥10%). The Kaplan-Meier method was used to estimate cumulative lymphedema incidence. Cox proportional hazards models were used to assess the relationship between symptoms, other risk factors, and lymphedema. RESULTS: A total of 64 patients (9.9%) developed lymphedema. On multivariable analysis, patients reporting increased arm size (hazard ratio = 3.09, 95% CI = 1.62-5.89) were more likely to progress to lymphedema than those who did not report this symptom. Of those who developed lymphedema, 37 (58%) reported an increased arm size a median of 6.1 months before lymphedema onset (range = 68.6 months before to 50.2 months after lymphedema onset). CONCLUSION: Patients at risk of lymphedema who report increased arm size might do so prior to lymphedema onset and are at 3 times the risk of lymphedema as patients not reporting this symptom. Even without objective or observable edema, these patients should be followed vigilantly and considered for early intervention. Symptoms should be incorporated into screening and diagnostic criteria for lymphedema. IMPACT: This study shows that patients at risk for breast cancer-related lymphedema who report increased arm size should be considered at high risk for progression to lymphedema-even without edema on measurement or clinical examination-and should be followed vigilantly, with consideration of early intervention. LAY SUMMARY: If you are at risk of lymphedema and you feel as though your arm size has increased, you might develop lymphedema, and you are at 3 times the risk of lymphedema as patients not reporting this symptom. Even without measurable or observable edema, you should be followed vigilantly and consider early intervention.

Quantifying the Impact of Axillary Surgery and Nodal Irradiation on Breast Cancer-Related Lymphedema and Local Tumor Control: Long-Term Results From a Prospective Screening Trial.

PURPOSE: To independently evaluate the impact of axillary surgery type and regional lymph node radiation (RLNR) on breast cancer-related lymphedema (BCRL) rates in patients with breast cancer. PATIENTS AND METHODS: From 2005 to 2018, 1,815 patients with invasive breast cancer were enrolled in a lymphedema screening trial. Patients were divided into the following 4 groups according to axillary surgery approach: sentinel lymph node biopsy (SLNB) alone, SLNB+RLNR, axillary lymph node dissection (ALND) alone, and ALND+RLNR. A perometer was used to objectively assess limb volume. All patients received baseline preoperative and follow-up measurements after treatment. Lymphedema was defined as a ≥ 10% relative increase in arm volume arising > 3 months postoperatively. The primary end point was the BCRL rate across the groups. Secondary end points were 5-year locoregional control and disease-free-survival. RESULTS: The cohort included 1,340 patients with SLNB alone, 121 with SLNB+RLNR, 91 with ALND alone, and 263 with ALND+RLNR. The overall median follow-up time after diagnosis was 52.7 months for the entire cohort. The 5-year cumulative incidence rates of BCRL were 30.1%, 24.9%, 10.7%, and 8.0% for ALND+RLNR, ALND alone, SLNB+RLNR, and SLNB alone, respectively. Multivariable Cox models adjusted for age, body mass index, surgery, and reconstruction type showed that the ALND-alone group had a significantly higher BCRL risk (hazard ratio [HR], 2.66; P = .02) compared with the SLNB+RLNR group. There was no significant difference in BCRL risk between the ALND+RLNR and ALND-alone groups (HR, 1.20; P = .49) and between the SLNB-alone and SLNB+RLNR groups (HR, 1.33; P = .44). The 5-year locoregional control rates were similar for the ALND+RLNR, ALND-alone, SLNB+RLNR, and SLNB-alone groups (2.8%, 3.8%, 0%, and 2.3%, respectively). CONCLUSION: Although RLNR adds to the risk of lymphedema, the main risk factor is the type of axillary surgery used.

Single Stage Direct-to-Implant Breast Reconstruction Has Lower Complication Rates Than Tissue Expander and Implant and Comparable Rates to Autologous Reconstruction in Patients Receiving Postmastectomy Radiation.

PURPOSE: To compare single-stage direct-to-implant (DTI) immediate reconstruction to the commonly used 2-stages expander and implant (TE/I) or autologous reconstruction with focus on postmastectomy radiation therapy (PMRT) setting. METHODS AND MATERIALS: We reviewed the charts of 1,286 patients who underwent 1,814 breast reconstructions at our institution with and without PMRT from 1997 to 2017. Patients were divided into 6 groups according to type of reconstruction and PMRT status. Primary objective was reconstruction complications defined solely on surgical reintervention operative notes such as infection, skin necrosis, and fat necrosis across all groups. Implant-related complications such as capsular contracture, implant rupture or exposure, or implant failure were compared between TE/I and DTI. Kaplan-Meier estimates were used to calculate 5-year cumulative incidence of complications. The secondary objective was to compare the 3 reconstruction types in settings of immediate reconstruction followed by PMRT on multivariable analysis. RESULTS: Median follow-up was 5.8 years. Among 1286 patients, 41.1% (N = 529/1286) received PMRT. Among 1814 reconstructed breasts, autologous, single-stage, and TE/I represented 18.7%, 34.8%, and 46.2%, respectively. With no PMRT, the 5-year cumulative incidence of any reconstruction complication was 11.1%, 12.6%, and 19.5% for autologous, DTI, and TE/I reconstructions, respectively. The addition of PMRT resulted in 5-year cumulative incidence of 15.1%, 18.2%, and 36.8%, respectively. The multivariable analysis showed that DTI was associated with lesser complications compared with TE/I, whereas no significant difference was noted between DTI and autologous. CONCLUSIONS: Single-stage DTI reconstruction had significantly lower complication rates than TE/I with and without PMRT. Single-stage complication rates were not significantly different from autologous complication rates in PMRT settings. Single-stage reconstruction may offer a valuable option for patients receiving PMRT.

The Impact of Chest Wall Boost on Reconstruction Complications and Local Control in Patients Treated for Breast Cancer.

PURPOSE: Giving an additional radiation dose to the incision or chest wall has been a practice, but it has never been studied in a randomized setting, and it might lead to inferior cosmetic outcomes. This study aims to evaluate whether delivery of a chest wall boost (CWB) to the mastectomy scar or chest wall is independently associated with reconstruction complications and to assess its disease control efficacy in the setting of breast reconstruction. METHODS AND MATERIALS: We conducted a retrospective chart review of 746 patients with breast cancer who underwent mastectomy, breast reconstruction, and PMRT; all underwent treatment at our institution during 1997 to 2016. Various reconstruction techniques were used among this cohort including autologous reconstruction, single-stage direct-to-implant reconstruction, and 2-stage tissue expander implant. Cohorts were divided by administration of CWB. The primary objective was comparing the rate of reconstruction complications including skin necrosis, fat necrosis and infection between groups. Subgroup analysis for patients with implant-based reconstruction was performed to evaluate the effect of CWB on implant-related complications such as capsular contracture, implant exposure, and implant failure. The secondary objective was comparison of the cumulative incidence of local failure between groups overall and within clinically high-risk subgroups. RESULTS: The median follow-up was 5.2 years. Most clinicopathologic features were well balanced between the 379 (51%) patients who received CWB and the 367 (49%) who did not. On multivariate analysis, CWB was significantly associated with infection, skin necrosis, and implant exposure. For implant reconstruction patients, CWB independently increased risks of implant failure. CWB administration was not associated with local tumor control benefits, even in high-risk subgroups. CONCLUSIONS: Our findings suggest that omission of chest wall boost in postmastectomy radiation improves breast reconstruction outcomes without compromising local tumor control.

Timing of Lymphedema After Treatment for Breast Cancer: When Are Patients Most At Risk?

PURPOSE: The purpose of the study was to determine when the risk of lymphedema is highest after treatment of breast cancer and which factors influence the time course of lymphedema development. METHODS AND MATERIALS: Between 2005 and 2017, 2171 women (with 2266 at-risk arms) who received surgery for unilateral or bilateral breast cancer at our institution were enrolled. Perometry was used to objectively assess limb volume preoperatively, and lymphedema was defined as a ≥10% relative arm-volume increase arising >3 months postoperatively. Multivariable regression was used to uncover risk factors associated with lymphedema, the Cox proportional hazards model was used to calculate lymphedema incidence, and the semiannual hazard rate of lymphedema was calculated. RESULTS: With a median follow-up of 4 years, the overall estimated 5-year cumulative incidence of lymphedema was 13.7%. Significant factors associated with lymphedema on multivariable analysis were high preoperative body mass index, axillary lymph node dissection (ALND), and regional lymph node radiation (RLNR). Patients receiving ALND with RLNR experienced the highest 5-year rate of lymphedema (31.2%), followed by those receiving ALND without RLNR (24.6%) and sentinel lymph node biopsy with RLNR (12.2%). Overall, the risk of lymphedema peaked between 12 and 30 months postoperatively; however, the time course varied as a function of therapy received. Early-onset lymphedema (<12 months postoperatively) was associated with ALND (HR [hazard ratio], 4.75; P < .0001) but not with RLNR (HR, 1.21; P = .55). In contrast, late-onset lymphedema (>12 months postoperatively) was associated with RLNR (HR, 3.86; P = .0001) and, to a lesser extent, ALND (HR, 1.86; P = .029). The lymphedema risk peaked between 6 and 12 months in the ALND-without-RLNR group, between 18 and 24 months in the ALND-with-RLNR group, and between 36 and 48 months in the group receiving sentinel lymph node biopsy with RLNR. CONCLUSIONS: The time course for lymphedema development depends on the breast cancer treatment received. ALND is associated with early-onset lymphedema, and RLNR is associated with late-onset lymphedema. These results can influence clinical practice to guide lymphedema surveillance strategies and patient education.