Negative Sentinel Lymph Node Biopsy Research Articles

Abstract PO1-19-01: NRG-BR008: A Phase III Randomized Trial of Radiotherapy Optimization for Low-risk HER2-positive Breast Cancer (HERO)

Abstract Background: Breast radiotherapy (RT) is the standard of care for patients with early-stage breast cancer (BC) who undergo breast-conserving surgery (BCS). However, the magnitude of benefit of RT is less clear in BCS patients with low-risk disease who receive effective systemic therapy. Among patients with early-stage HER2-positive (HER2+) BC, 10-year locoregional recurrence has been reported as low as 1.5% following BCS, adjuvant chemotherapy and HER2-targeted therapy, and RT. Given these exceedingly favorable outcomes, with the addition of HER2-directed therapy, we seek to evaluate the feasibility of omitting RT among patients with early-stage HER2+ BC following BCS and appropriate systemic therapy. Methods: This is a phase III randomized trial for patients ≥40 years with early-stage, node-negative HER2+ (IHC/FISH) BC treated with BCS with negative margins and sentinel lymph node biopsy or axillary dissection. Patients undergoing primary surgery must have pathologic T1 (< 2 cm) N0 disease, while patients receiving neoadjuvant therapy must have clinical T1-2 (with radiographically T< 3.0 cm) N0 disease and exhibit a pathologic complete response (ypT0N0) at surgery. All patients must receive cytotoxic chemotherapy and HER2-targeted therapy, either in the adjuvant or neoadjuvant setting. Stratification is by age (< 60; ≥60), tumor size (≤1 cm; >1 cm), estrogen-receptor status (positive; negative), and systemic therapy sequencing (adjuvant vs neoadjuvant). Patients will be randomized to standard breast RT in addition to continuation of trastuzumab to complete a year of treatment (Arm 1), or trastuzumab alone (Arm 2). Endocrine therapy will be recommended for patients with hormone-receptor positive tumors. The primary endpoint is the recurrence-free interval (RFI). Secondary endpoints include the time to ipsilateral breast recurrence, locoregional recurrence, disease-free survival, and overall survival, in addition to the 7-year ipsilateral breast recurrence rate among those not receiving RT. A health-related quality of life sub-study will assess differences in patient-reported breast pain and worry. We estimate a 7-year RFI of 97.5% with RT and allow for a clinically acceptable decrement of 3.63% without RT (7-year RFI of 93.87%; HR 2.5) to establish omission of RT as non-inferior. NRG-BR008 aims to enroll 1,300 patients over 4.5 years, yielding 80% power to detect the non-inferiority of RT omission with a one-sided α=0.05. We expect to observe the required 38 RFI events within 6 years of additional follow-up. The NRG-BR008/HERO trial opened to accrual in March, 2023. NCT05705401. Support: U10CA180868, -180822, UG1CA189867, U24CA196067; Susan G. Komen Foundation (JR) Citation Format: Lior Braunstein, Melissa Mitchell, Hanna Bandos, William Sikov, Atif Khan, Peter Chen, Patricia Ganz, Reshma Jagsi, Julia White, Reena Cecchini, Hyejoo Kang, Shannon Puhalla, Kelly Bolton, Eileen Connolly, Erica Stringer-Reasor, Kimberly Gergelis, Thomas Julian, Eleftherios Mamounas, Norman Wolmark. NRG-BR008: A Phase III Randomized Trial of Radiotherapy Optimization for Low-risk HER2-positive Breast Cancer (HERO) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-01.

Sentinel Node Navigation Surgery for Early Gastric Cancer: A Narrative Review.

Early gastric cancer (EGC) refers to malignant tumor lesions that are limited to the mucosa and submucosa layers, regardless of the presence of lymph node metastasis. Typically, EGC has a low rate of perigastric lymph node metastasis, and long-term survival outcomes are good after radical surgical treatment. The primary objective of surgical treatment for EGC is to achieve functional preservation while ensuring a radical cure. Sentinel node navigation surgery (SNNS) is a surgical technique used in the treatment of EGC. This approach achieves functional preservation by limiting lymph node dissection and performing restrictive gastrectomy guided by intraoperative negative sentinel node (SN) biopsy. Despite the apparent improvement in the detection rate of SN with the emergence of various tracing dyes and laparoscopic fluorescence systems, the oncological safety of SNNS remains a controversial research topic. SNNS, as a true form of stomach preservation surgery that enhances the quality of life, has become a topic of interest in the EGC field. In recent years, scholars from Japan and South Korea have conducted extensive research on the feasibility and safety of SNNS in the treatment of EGC. This article aims to provide reference choices for surgeons treating EGC by reviewing relevant research on SNNS for EGC in recent years.

Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy in cN0 Breast Cancer: Impact of HER2-Positive Status on Survival.

High rates of negative sentinel lymph node biopsy (SLNB) in clinically node-negative (cN0) breast cancer (BC) after neoadjuvant chemotherapy (NAC) have been described. These results are associated with triple-negative (TNBC) and human epidermal growth factor receptor 2 (HER2+) subtypes achieving pathologic complete response (pCR). This study evaluates predictive variables and survival in order to assess the possible omission of SLNB after NAC. Prospective study of women with cN0 BC treated with NAC and subsequent surgery, between April 2010 and May 2021. SLNB technique included, performing axillary lymphadenectomy in the absence of detection or SLNB-positivity. Multivariable logistic regression was used for analysis of NAC-response and SLNB-results in molecular subtypes: HR-/HER2+, TNBC, HR+/HER2- and HR+/HER2+. Kaplan-Meyer and log-rank were used for survival analysis. A total of 179 patients (50.5±10.1 years) were included. Of these, 39.7% achieved pCR (ypT0/Tis). HR-negative subtypes had higher pCR rates (HR-/HER2+: 59.4%; TNBC: 53.4%), with no cases of SLNB-positive. With residual disease, HR-/HER2+ and TNBC showed low rates of SLNB-positivity (6.7% and 10.3%) versus HR+ (HR+/HER2+: 20%; HR+/HER2-: 44%; p<0.001). Multivariable analysis identified independent predictors of SLNB-negativity (p<0.0001) to be: HR- [odds ratio (OR)=0.15; 95% confidence interval (CI): 0.06-0.37; p = 0.0001], HER2+ (OR=0.34; 95% CI: 0.14-0.81; p = 0.015) and high-grade Nottingham (OR=0.42; 95% CI: 0.18-0.99; p = 0.048). Disease-free survival showed worse outcomes with SLNB-positivity (p<0.0001), HR+/HER2- (p = 0.0277), larger tumor size (p = 0.002) and residual disease after NAC (p<0.0001). Patient selection based on NAC response, molecular subtype, and survival outcomes is a priority for establishing individualized therapeutic strategies after NAC. Molecular subtypes with higher pCR rates and lower rates of SLNB-positivity could benefit from non-invasive strategies that include omission of SLNB.

The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma.

Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in patients with clinically occult disease. Since the advent of new systemic therapies, its role in melanoma has been extensively debated over the last years. In this article, three possible scenarios are discussed, considering the SLNB impact on the management of melanoma patients. First, pT1b and pT2a patients with negative SLNB (stages IA and IB) and those with positive SLNB (stage IIIA) would all not benefit from adjuvant treatment. Therefore, SLNB might be avoided in these categories of patients. Second, in IIB and IIC, melanoma patients are already candidates for adjuvant treatment; therefore, SLNB in patients with T3b, T4a, or T4b melanoma would not change treatment decisions. On the other end of the spectrum, patients with pT2b and pT3a melanomas (clinical stage IIA) represent the only two groups whose management would be significantly affected by the SLNB status, being adjuvant therapy only indicated for SLN-positive patients. Further studies are needed to investigate which melanoma patient deserves SLNB.

Concordance between Axillary Ultrasound and Sentinel Biopsy in Clinically Node-Negative Early Breast Cancer

Objective: To determine the sensitivity of axillary ultrasound in detecting axillary nodal metastasis in clinically and radiologically uninvolved axillary nodes in early carcinoma breast by comparing with sentinel node biopsy histopathology on frozen section. Study Design: Comparative cross-sectional study Place and Duration of Study: Breast Clinic, CMH, Rawalpindi Pakistan, from Aug 2020 to May 2021. Methodology: Patients included in the study presented with breast cancer lesions with clinically impalpable axillary lymph nodes aged 18-75. Patients with clinically impalpable nodes underwent an ultrasound of the axilla; if suspicious nodes were found, the patient had subsequent axillary node dissection. Sentinel node biopsy (SLNB) was performed on axillary ultrasound in all patients with no suspicious or benign-looking nodes. Histopathological reporting was taken as standard. Lymph nodal status on axillary ultrasound, SLN biopsy and axillary lymph node clearance were documented and analyzed. Results: Twenty-nine patients were included who had benign-looking lymph nodes on axillary ultrasound and underwent sentinel lymph node biopsy. The mean age of the patients was 54.03 ± 7.94. Out of 29 patients, 24(82.8%) patients had negative Sentinel lymph node biopsy, and 5(17.2%) had positive Sentinel lymph node biopsy, who then underwent axillary lymph node dissection. Conclusion: Sentinel lymph node biopsy is the gold standard to determine axillary lymph nodes involved in early carcinoma breast, which seem benign on pre-operative axillary ultrasound.

Early Results of the French Multicenter, Randomized SHARE Trial Comparing Whole Breast Irradiation vs. Accelerated Partial Breast Irradiation in Postmenopausal Women with Early-Stage Breast Cancer

The aim is to report toxicity and cosmetic outcomes at 3 and up to 9 years of follow-up of post-menopausal patients randomized to receive either standard whole breast irradiation (WBI), including hypofractionated options, versus accelerated partial breast irradiation (APBI). From December 2010 to July 2015, 1006 patients were enrolled in 34 French centers. Among the whole population, 28 patients who did not meet the final selection criteria or withdrew consent were excluded leading to a modified intention to treat analysis dataset of 978 patients (WBI: n = 488; APBI: n = 490). Median age (65y) and tumor stage pT1 (99%) rates were similar in both arms. Patients had conservative surgery with clip placement in the tumor bed. Clear margins (> 2mm) were observed in 99% of the patients. In both arms, 96-97% of the patients had negative sentinel lymph node biopsy. The median time interval between surgery and radiotherapy was 57d in WBI vs 62d in APBI. WBI schedules consisted of 50 Gy in 25 fr+16 Gy (n = 212) or 40 Gy in 15 fr (n = 156) or 42.5 Gy in 16 fr (n = 120). APBI arm consisted of 38.5 Gy or 40 Gy in 10 fr, 2 fr/day. Overall, 94 patients from the APBI arm finally received standard WBI. For statistical considerations, SHARE trial, sponsored by UNICANCER (NCT01247233) is a non-inferiority randomized controlled trial comparing APBI versus WBI in terms of local control as primary objective. Secondary endpoints were severe toxicity (NCI-CTCAE v4 grade ≥ 2), and cosmetic results. For both outcomes, we estimated the cumulative incidences (CI) using Kalbfleish and Prentice method, considering disease relapse, secondary cancer or death as competing events. Treatment effect (APBI vs WBI) was estimated by cause-specific Hazard Ratios (cs-HR) from Cox models. Median follow-up was 5.8y (range, 0.13-9.5). The number of deaths was 27, and the number of local relapses was 8. Among the 978 patients, 582 and 396 had finally WBI and APBI, respectively. The rates of post-operative hematoma, edema and infection were low: 8-9%, 2%, 3-2%, respectively. When considering any type of severe toxicity, we observed a significant reduction rate in APBI compared to WBI: cs-HR = 0.73 (95% confidence interval: 0.61-0.88); p = 0.001, and 3-year CI of severe toxicity at 45% in WBI vs 36% in APBI arm. The difference was also in favor of APBI when considering breast skin toxicity alone: cs-HR = 0.55 (0.44-0.70), p<0.001 and 3-year CI at 36% in WBI vs 21% in APBI arm. Conversely, for breast other toxicities, WBI was found less toxic than APBI with a 3-year CI of 8% vs 15%, respectively. When considering cosmetic results, we observed no significant difference between the two arms in both evaluations by physicians and patients. Historically SHARE is the first APBI trial that included hypofractionated schedules in the standard arm. We report increased risk of severe toxicity and skin breast toxicity in standard arm as compared with APBI arm without any difference in terms of cosmetic results. Longer follow-up is needed.

Prospective Cohort Study to Evaluate Toxicity and Cosmesis between Interstitial APBI and Ultra-Hypo-Fractionated Whole Breast Irradiation in Patients with Early Breast Cancer

Both interstitial multi-catheter brachytherapy based accelerated partial breast irradiation (APBI) and ultra-hypo-fractionated whole breast irradiation (WBI) with 5 fractions can complete treatment in a short time and result in lower treatment-related costs. Although data are available on their toxicity compared with conventional and hypo-fractionated regimens, there are few data directly comparing these two techniques. This prospective cohort study enrolled early breast cancer patients with negative ink margin, T1 or T2 stage, and tumor size of 3 cm or less, with 0 to 3 positive lymph nodes after adequate axillary dissection or negative sentinel lymph node biopsy (N0-1), regardless of receptor status (ER, PR, HER2neu). Of the total 31 patients, 15 received APBI with multi-catheter interstitial brachytherapy (35 Gy in10 fractions over 5 days with a minimum interval of 6 hours between fractions) and 16 patients received WBI (27 Gy in 5 fractions over 5 days) with either 3DCRT or VMAT technique. Acute toxicity was assessed using the RTOG toxicity grading and breast cosmesis was assessed using the Harvard breast cosmesis score. Toxicity and cosmesis were assessed immediately after treatment, after one month, and after three months of treatment. Results were compared between groups using the Mann Whitney U test. All patients completed a 3-month follow-up after completion of treatment. There was no statistically significant difference between the 2 groups in terms of highest grade toxicity (p = 0.97) and acute toxicity immediately after RT (p = 1.0) and after 1 month of RT (p = 0.91). However, at 3 months, more patients in the WBI group had a residual skin reaction than in the APBI group (p = 0.03). There was no statistically significant difference in breast cosmesis scores at any time point. 53.3%, 6.6% had grade 1 and 2 skin toxicities respectively immediately after RT in the APBI group and 62.5% of patients had grade 1 skin toxicity in WBI group. After 1 month 26.6%, 26.6% & 13.3% patients had grade 2, grade 1 and grade 3 toxicities respectively. In the WBI group, at 1 month, 50%, 18.7% and 12.5% patients had grade 1, 3 and 2 skin toxicities respectively. At 3 months, 42.8% and 7.1% of patients in the APBI group had grade 1 and grade 2 toxicities, respectively. In the WBI group, 78.5% and 7.1% of patients had grade 1 and 2 skin toxicities respectively. In this study, no difference in acute toxicity or breast cosmesis was demonstrated between APBI-based interstitial brachytherapy and ultra-hypo-fractionated WBI. Since both regimens can be administered within 5 days, the decision between them is challenging for both physicians and patients. This study can be considered hypothesis-generating and used for further planning of equivalence or noninferiority studies.

Survival after sentinel lymph node biopsy for early cervical cancers: a systematic review and meta-analysis

BackgroundSentinel lymph node biopsy represents an alternative to pelvic lymphadenectomy for lymph node staging of early-stage cervical carcinoma, but prospective evidence on long-term oncological safety of sentinel lymph node biopsy...

Refractory Axillary Web Syndrome Successfully Treated with Steroid Injections: A Case Report

Background: Axillary Web Syndrome (AWS) manifests after breast cancer surgery as 1mm wide, singular, or multiple cords that can extend from the ipsilateral axilla to the antecubital fossa and further into the forearm and wrist. These cords can be painful and cause diminished range of motion. Even though there is no current standard treatment for AWS, physical therapy is recommended as the first approach in management. In refractory cases, no management has been proposed. Case Presentation: We present a case of a 59-year-old female with right-sided breast pain and a palpable cord, refractory to one year of physical therapy, which began at the inframammary fold up towards the lumpectomy scar and further towards the axilla. Cord developed post-lumpectomy and post-radiation for a right-sided stage I invasive ductal carcinoma with negative sentinel lymph node biopsy. Based on the refractory nature of the cord, the patient underwent three treatments of steroid injections which made the cord less palpable and improved the pain. Due to persistent diminished range of motion and tenderness, the patient underwent a percutaneous needle cord disruption procedure with a last round of corticosteroid injection to prevent adherence of the cord pieces. At a 7-month follow up post-procedure, the breast cord was no longer present, and range of motion had been restored. Conclusion: We found that percutaneous cord disruption with concurrent steroid injections can be an effective treatment for AWS refractory to physical therapy.

820 Atypical Presentation of Muscular Metastasis of Melanoma in the Contralateral Limb

Abstract Case Presentation A gentleman in his 50s presented to his GP with an asymptomatic, soft, enlarging mass on his left upper arm. He had previously been diagnosed with a 4.5mm cutaneous malignant melanoma (MM) on his right arm, which was treated with an excision biopsy and a further 2cm wide local excision. He further had a sentinel lymph node biopsy (SLNB), which confirmed no residual melanoma. He was subsequently followed up routinely by the skin cancer multidisciplinary team (MDT) for five years with no concern. The patient subsequently underwent an ultrasound scan, a Magnetic Resonance Imaging (MRI) scan, and a final staging Computed Tomography (CT). Imaging was suspicious for an intramuscular soft tissue malignancy. Core biopsy of this mass suggested a diagnosis of metastatic MM. Excision was performed within three weeks of his core biopsy. The lesion was completely excised, and formal pathology confirmed the diagnosis of metastatic MM. He has been referred to the oncology services for the commencement of Nivolumab (anti PD-1 antibody) immunotherapy according to the genetic analysis. Summary This case highlights a rare example of muscular metastasis of MM, presenting in a distant site, despite a negative SLNB, over five years from the original diagnosis. Such cases highlight the unpredictable nature of MM, reminding clinicians of the need for a low threshold for investigation of soft tissue masses in patients with a history of cutaneous malignancy.

Cost-Effectiveness of [99mTc]Tilmanocept Relative to [99mTc]Sulfur Colloid for Sentinel Lymph Node Biopsy in Early Stage Oral Cavity Cancer

BackgroundSeveral studies have demonstrated varying rates of efficacy, reliability, and sensitivity of sentinel lymph node biopsy (SLNB) in identifying occult nodal disease for early stage oral cavity squamous cell carcinoma (OCSCC) depending on the radionuclide agent utilized. No head-to-head comparison of cost or clinical outcomes of SLNB when utilizing [99mTc]tilmanocept versus [99mTc]sulfur colloid has been performed. The goal of this study was to develop a decision model to compare the cost-effectiveness of [99mTc]tilmanocept versus [99mTc]sulfur colloid in early stage OCSCC.Patients and MethodsA decision model of disease and treatment as a function of SLNB was created. Patients with a negative SLNB entered a Markov model of the natural history of OCSCC parameterized with published data to simulate five states of health and iterated over a 30-year time horizon. Treatment costs and quality-adjusted life-years (QALYs) for each health state were included. The incremental cost-effectiveness ratio (ICER) was then estimated using $100,000 per additional QALY as the threshold for determining cost-effectiveness.ResultsThe base case cost-effectiveness analysis suggested [99mTc]tilmanocept was more effective than [99mTc]sulfur colloid by 0.12 QALYs (7.06 versus 6.94 QALYs). [99mTc]Tilmanocept was more costly, with a lifetime cost of $84,961 in comparison with $84,264 for sulfur colloid, however, the overall base case ICER was $5859 per additional QALY, well under the threshold for cost-effectiveness. Multiple one-way sensitivity analyses were performed, and demonstrated the model was robust to alternative parameter values.ConclusionOur analysis showed that while [99mTc]tilmanocept is more costly upfront, these costs are worth the additional QALYs gained by the use of [99mTc]tilmanocept.

External validation of the Melanoma Institute Australia Sentinel Node Metastasis Risk Prediction Tool using the National Cancer Database

To improve patient selection for sentinel node biopsy, the Melanoma Institute of Australia (MIA) created a predictive model based on readily available clinicopathologic factors. Validation of the MIA nomogram using the National Cancer Database (NCDB), a nationwide oncology outcomes database for more than 1,500 Commission-accredited cancer programs in the United States. A total of 60,165 patients were included in the validation. The probability of sentinel node (SN) positivity was calculated for each patient. Using calculated probabilities, a receiver operating characteristic (ROC) curve was generated to assess the model's discrimination ability. At baseline, the NCDB cohort had different clinicopathologic characteristics compared to the original MIA dataset. Despite these differences, the MIA nomogram retained high predictive accuracy within the NCDB dataset (C-statistic: 0.733 [95% CI: 0.726 to 0.739]), though calibration weakened for the highest-risk decile. The NCDB collects data from hospital registries accredited by the Commission on Cancer (CoC). In conclusion, this study validated the use of the MIA nomogram in a nationwide oncology outcomes database collected from more than 1,500 Commission-accredited cancer programs in the United States, demonstrating the potential for this nomogram to predict SN positivity and reduce the number of negative SN biopsies.

Sentinel lymph node biopsy after nipple-sparing mastectomy in early postoperative period: Is it feasible?

Axillary lymph node status is one of the most important prognostic factors for breast cancer. Sentinel lymph node biopsy (SLNB) after mastectomy is highly controversial. There is not enough data about SLNB in the early period after nipple-sparing mastectomy (NSM). This study investigated the feasibility of SLNB in the early postoperative period of NSM. Patients who were operated on for breast cancer in Acibadem Maslak Hospital between 2009 and 2018 were searched retrospectively. Results of SLNB as the second session in patients whose final pathology report revealed breast carcinoma after contralateral/bilateral prophylactic mastectomy and mastectomy for benign lesions were evaluated. In the early period (median 14 days) after NSM, SLNB was performed by intradermal radioisotope injection in five patients with occult breast cancer in contralateral/bilateral prophylactic mastectomy and in one patient with preoperatively suspicious mass which yielded breast cancer at final pathology. In five (80%) patients, SLNB was performed, whereas in one patient axillary lymph node dissection (ALND) was performed due to the undetectability of SLN. In one patient, micrometastasis was observed, whereas no metastasis was observed in other patients including the one who underwent ALND. No complication due to SLNB was detected. No recurrence and distant metastasis were detected in a mean follow-up of 42.82 (19-70) months. While SLNB did not change the treatment of patients with contralateral occult carcinoma, other patients had hormonal therapy due to negative SLNB. SLNB in the early postoperative period of NSM can be performed by intradermal radioisotope injection. However, further studies are needed to determine the feasibility of SLNB in the early postoperative period of NSM.

Pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: Final analysis of distant metastasis-free survival in the phase 3 KEYNOTE-716 study.

LBA9505 Background: Adjuvant pembrolizumab significantly improved distant metastasis-free survival (DMFS) and recurrence-free survival (RFS) in patients with resected stage IIB or IIC melanoma versus placebo. We present the protocol-specified final DMFS analysis from KEYNOTE-716 (NCT03553836). Methods: Eligible patients were ≥12 years old with resected stage IIB or IIC cutaneous melanoma per American Joint Committee on Cancer, 8th edition, guidelines and a negative sentinel lymph node biopsy. In part 1 of the study, patients were randomly assigned (1:1) to pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for up to 17 cycles (~1 year) or until disease recurrence, unacceptable toxicity, or withdrawal. Randomization was stratified by T category for adults (T3b vs T4a vs T4b), with a separate stratum for pediatric patients. The primary end point was RFS per investigator review. DMFS per investigator review was a secondary end point. The protocol-specified final DMFS analysis was based on a target of 195 DMFS events. No formal hypothesis testing was performed because DMFS and RFS end points were met at previous interim analyses. The data cutoff date for this analysis was January 4, 2023. Results: Overall, 976 patients were randomly assigned to receive pembrolizumab (n = 487) or placebo (n = 489). Median duration of follow-up (time from randomization to the data cutoff date) was 39.4 months (range, 26.0-51.4). Compared with placebo, adjuvant pembrolizumab improved DMFS (medians: not reached; hazard ratio [HR], 0.59 [95% CI, 0.44-0.79]) and RFS (medians: not reached; HR, 0.62 [95% CI, 0.49-0.79]). The 36-month DMFS rate was 84.4% with adjuvant pembrolizumab versus 74.7% with placebo; the 36-month RFS rate was 76.2% with adjuvant pembrolizumab versus 63.4% with placebo. DMFS benefit with adjuvant pembrolizumab over placebo was observed regardless of cancer stage at baseline (stage IIB HR, 0.62 [95% CI, 0.42-0.92]; stage IIC HR, 0.57 [0.36-0.88]). Similar results were observed with RFS (stage IIB HR, 0.58 [95% CI, 0.43-0.79]; stage IIC HR, 0.65 [95% CI, 0.45-0.94]). No new safety signals were observed. Conclusions: With a median follow-up of 39.4 months, adjuvant pembrolizumab for resected stage IIB and IIC melanoma continued to show DMFS and RFS benefit over placebo, with no new safety signals. Clinical trial information: NCT03553836 .

Melanoma Prognosis and Associated Risk Factors: A Retrospective Cohort Study Using Semantic Map Analysis.

The overall patterns of correlations among various melanoma risk factors have not yet been examined. The aim of this study was to assess the impact of different parameters on disease-free and melanoma-related overall survival. A retrospective cohort study was conducted encompassing all patients with a primary cutaneous melanoma diagnosed in a university referral centre. Associations were explored using semantic map analysis, which uses graph theory to find the strongest path of connections between variables. A total of 1,110 melanoma patients (median follow-up 10.6 years) were included. The analysis revealed a clustering of variables around 2 main hubs: Breslow thickness < 1 mm and ≥ 4 mm. Factors connected with high melanoma thickness were: older age, positive sentinel lymph node biopsy findings, presence of ulceration, nodular melanoma type, and light skin phototype. Both disease-free and melanoma-related overall survival were in this cluster and connected with positive sentinel lymph node biopsy and Breslow ≥ 4 mm. Patients with Breslow between 1 and 3.9 mm were also in this cluster and linked with negative sentinel lymph node biopsy, nodular melanoma and safety distance > 10 mm. This semantic analysis confirmed the close link between Breslow thickness, age, sentinel lymph node biopsy findings, skin type, melanoma subtype and prognosis, and provides prognostic information useful for the further stratification and management of patients with melanoma.

D62. Sentinel Lymph Node Biopsy in Melanoma: A Single-surgeon, 1,000 Patient Experience

PURPOSE: With widespread use of sentinel lymph node biopsy (SLNB) in melanoma, the accuracy of this procedure has been examined, quantified, and improved. However, the reported sensitivity and specificity of the procedure have ranged from 64 to 100%, with false-negative rates (FNR) ranging from 5.6 to 21%. Herein, we review a single-surgeon’s experience in a large patient cohort with the purpose of evaluating the accuracy of gamma and Indocyanine green (ICG) combination technique in SLNB. METHODS: All melanoma patients who underwent SLNB surgery by the senior author at Cleveland Clinic in February 2011 to December 2021 were included. All patients underwent SLNB using a combination of gamma and ICG for SLN identification. RESULTS: 1,000 patients with mean age of 61 years met the inclusion criteria. 220 patients had a positive SLNB with a mean number of 1.25 positive nodes of from an average of 2.86 nodes removed. From the 277 positive nodes, 247 (90%) were identified using combination of gamma and ICG (n=180/220), 21 (7%) using gamma only (n= 26/ 220) and 8 (2%) using ICG only (n=14/220). 470 had a negative SLNB with an average of 2.9 nodes removed and a FNR of 2.3%. Mean follow-up was 2.3 years. CONCLUSION: We report one of the lowest false negative rates using a combination technique of gamma and ICG in SLNB, proving it a reliable technique in detecting melanoma nodal involvement.

Routine imaging guided by a 31-gene expression profile assay results in earlier detection of melanoma with decreased metastatic tumor burden compared to patients without surveillance imaging studies

Patients with early-stage disease typically have a good prognosis, but still have a risk of recurrence, even with negative sentinel lymph node biopsy (SLNB). This study explores the utility of routine imaging to detect metastases in patients with negative SLNB but high-risk 31 gene expression profile (31-GEP) scores. We retrospectively identified melanoma patients with negative SLNBs. Patients with high-risk GEP results were placed in the experimental group and patients without GEP testing were placed in the control group. Among both cohorts, recurrent melanoma groups were identified. The tumor burden at the time of recurrence and the time to recurrence were compared between experimental group patients with routine imaging and control group patients without imaging schedules. We identified 327 control patients and 307 experimental patients, of which 14.1% versus 20.5% had melanoma recurrence, respectively. Of the patients with recurrent melanoma, those in the experimental group were older (65.75 versus 59.20), had higher Breslow depths (3.72 mm versus 3.31 mm), and had advanced tumor staging (89.5% versus 71.4% of patients presenting clinical stage ≥ II) compared to the control group at primary diagnosis. However, melanoma recurrence was detected earlier (25.50 months versus 35.35 months) in the experimental group at a lower overall tumor burden (73.10 mm versus 27.60 mm). A higher percentage of experimental patients started immunotherapy when offered (76.3% and 67.9%). Patients who received routine imaging after high-risk GEP test scores had an earlier recurrence diagnosis with lower tumor burden, leading to better clinical outcomes.

Has the advent of modern adjuvant systemic therapy for melanoma rendered sentinel node biopsy unnecessary?

The prognostic value of sentinel node biopsy (SNB) is well established and SNB was therefore adopted as a requirement for pathological staging of melanomas>1 mm thick in the American Joint Committee on Cancer (AJCC) 8th edition. Consequently, a negative SNB status became an eligibility criterion for clinical trials of adjuvant systemic therapy in resected stage IIB/C melanoma. However, since the Keynote 716 trial demonstrated an improvement in relapse-free survival (RFS) in patients with Stage IIB/C melanoma, all of whom had SNB staging, some have argued that SNB is no longer required for patients with T3 and T4 primary melanomas. The rationale for omitting SNB is that these patients will be able to access adjuvant immunotherapy regardless of SNB status, avoiding the costs and potential complications of SNB. However, this argument overlooks the prognostic value of knowing a patient’s nodal status and the therapeutic benefit of SNB in regional disease control. Based on extrapolation of data from multiple sources, we demonstrate that the risk of regional node-field relapse with SNB and immunotherapy for T3b and T4 melanomas is around 7–9% but is 20–27% without SNB. Similarly, the node-field recurrence rate with SNB alone is around 14% compared to around 40% with no SNB or immunotherapy. Consequently, in the absence of prospective data, we propose that the optimal management of the regional node-field for high-risk T3b and T4 primary melanomas is likely to be achieved by combining SNB and adjuvant immunotherapy for those patients who are suitable, rather than either treatment alone.

Abstract PD3-05: Early results of the French multicenter, randomized SHARE trial comparing whole breast irradiation versus accelerated partial breast irradiation in postmenopausal women with early-stage breast cancer

Abstract Purpose: The aim of current analyses is to report toxicity and cosmetic outcomes at 3 and up to 9 years of follow-up of post-menopausal patients randomized to receive either standard external beam whole breast radiotherapy (WBI), including hypofractionated options, versus accelerated partial breast irradiation (APBI). Methods and materials: From December 2010 to July 2015, 1006 patients were enrolled in 34 French centers (503 in each arm). Among the whole population, 28 patients who did not meet the final selection criteria or withdrew consent were excluded leading to a modified intention to treat analysis dataset of 978 patients (WBI: n=488; APBI: n=490). Median age (65y) and tumor stage pT1 (99%) rates were similar in both arms. Patients had conservative surgery with clip placement in the tumor bed. Clear margins (&amp;gt; 2mm) were observed in 99% of the patients. In both arms, 96-97% of the patients had negative sentinel lymph node biopsy (SLNB; median number: 4 in WBI arm and 5 in APBI), luminal BC. Ductal histology was observed 82%. Only 2% and 1% of patients had grade III and pN(i+) disease. The median time interval between surgery and radiotherapy was 57d in WBI vs 62d in APBI. WBI schedules consisted of: 50Gy in 25fr + 16Gy boost (n=212) or 40Gy in 15fr (n=156) or 42.5Gy in 16fr (n=120), while APBI arm consisted of 38.5Gy or 40Gy in 10fr. Overall, 94 patients from the APBI arm finally received standard WBI. For statistical considerations, SHARE trial, sponsored by UNICANCER (NCT01247233) is a non-inferiority randomized controlled trial comparing APBI versus WBI in terms of local control as primary objective. Secondary endpoints were severe toxicity (NCI-CTCAE v4 grade ≥ 2), and cosmetic results, evaluated by doctors and by patients, over the entire follow-up. For both outcomes, we estimated the cumulative incidences (CI) using Kalbfleish and Prentice method, considering disease relapse, secondary cancer or death as competing events. Treatment effect (APBI vs WBI) was estimated by cause-specific Hazard Ratios (cs-HR) from Cox models adjusted on stratification factors. Results: Median follow-up was 5.8y (range, 0.13-9.5). The number of deaths was 27, and the number of local relapses was 8. Among the 978 patients, 582 and 396 had finally WBI and APBI, respectively. The rates of post-operative hematoma, edema and infection were low: 8-9%, 2%, 3-2%, respectively. When considering any type of severe toxicity, we observed a significant reduction rate in APBI compared to WBI: cs-HR=0.73 (95% confidence interval: 0.61-0.88); p=0.001, and 3-year cumulative incidence (CI) of severe toxicity at 45% (41-49) in WBI vs 36% (32-40) in APBI arm. The difference was also in favor of APBI when considering breast skin toxicity alone: cs-HR=0.55 (0.44-0.70), p&amp;lt; 0.001 and 3-year CI at 36% (32-40) in WBI vs 21% (18-25) in APBI arm. Conversely, for breast other toxicities, WBI was found less toxic than APBI: cs-HR= 2.10 (1.51-2.91), p&amp;lt; 0.001, and 3-year CI at 8% (5-10) vs 15% (12-19), respectively. When considering cosmetic results according to the investigator, we observed no significant difference between the two arms: cs-HR=1.04 (0.81-1.33), p=0.26 and 3-year probability of remaining with good to excellent cosmetic results at 77% (73-81) in WBI arm and 78% (74-81) in APBI arm. Findings were similar when considering results according to the patient: cs-HR=1.07 (0.85-1.37), p=0.23, and 3-year probability at 74% (70-78) and 75% (70-79), respectively. Conclusions Historically SHARE is the first APBI trial that included hypofractionated schedules in the standard arm. We reported increased risk of severe toxicity and skin breast toxicity in standard arm as compared with APBI arm without any difference in terms of cosmetic results. Longer follow-up is needed. Citation Format: Yazid Belkacemi, Isabelle Gabelle-Flandin, Marie-Cécile Le Deley, Adeline Petit, Philippe Guilbert, Julien Geffrelot, Christian Carrie, Eleonor Rivin Del Campo, Chantal Hanzen, Claire Charra-Brunaud, Isabelle Lecouillard, Nicolas Magne, Agnès Tallet, Nicolas Leduc, Blaha Belgadi, Philippe Fourneret, Alexandre Coutte, Esther Capelo, Franck Darloy, Muriel Garcia Ramirez, Philippe Dudouet, Pierre Clavere, Jean-Philippe Suchaud, Guillaume Auzac, Thomas Lacornerie, Jérôme Lemonnier, Céline Bourgier, Eric Lartigau. Early results of the French multicenter, randomized SHARE trial comparing whole breast irradiation versus accelerated partial breast irradiation in postmenopausal women with early-stage breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD3-05.

Ipilimumab and Nivolumab for Treatment of Eyelid Spindle Cell Melanoma

A 70-year-old man presented with recurrent left upper eyelid spindle cell melanoma. He was initially diagnosed with eyelid spindle cell melanoma three years prior and underwent excision with negative sentinel lymph node biopsy. He refused radiation and was observed without evidence of local or systemic disease. Seventeen months later, he developed a biopsy-proven local recurrence and presented for additional evaluation. Exam demonstrated a large, firm, amelanotic lesion encasing the entire left upper eyelid from the medial to lateral canthus and attaching to the brow tissues and frontal bone (A). Due to the extensive surgery required for complete excision, he opted for checkpoint inhibitor immunotherapy. He received ipilimumab 1 mg/kg and nivolumab 3 mg/kg intravenously every three weeks for 4 cycles. He had pseudoprogression after the first cycle within one week after receiving the first cycle (B) but demonstrated dramatic clinical improvement after his fourth cycle (C) that remained evident three months after he received his last cycle of combined ipilimumab and nivolumab (D). He continues to undergo treatment with intravenous nivolumab with plan for 3 additional cycles of nivolumab monotherapy given his improvement. Ipilimumab and nivolumab are checkpoint inhibitors that provide effective noninvasive treatment for malignant melanoma, especially in locations such as the periorbital region where Mohs surgery with possible extensive excision and subsequent reconstruction would result in high morbidity, including cicatricial lagophthalmos, ectropion, exposure keratopathy, or restrictive strabismus. In patients with extensive disease, including our patient, checkpoint inhibitor immunotherapy may reduce the need for orbital exenteration. Awareness that immunotherapy may lead to pseudoprogression, increased tumor size after immune cell infiltration of the tumor due to effective treatment response, is important to avoid premature cessation of efficacious immunotherapeutic agents.