Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab-deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2-Immune-DNA repair deficiency- subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379 .

Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379 .

Pembrolizumab Plus Carboplatin and Paclitaxel as First-Line Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-B10): A Single-Arm Phase IV Trial.

PURPOSE: Standard-of-care first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is pembrolizumab plus platinum and fluorouracil (FU). However, FU is associated with potential challenges (continuous 4-day infusion, high administration costs, and cardiovascular and gastrointestinal toxicities), creating a clinical need for alternative chemotherapy combinations. We evaluated the efficacy and safety of first-line pembrolizumab plus carboplatin and paclitaxel for R/M HNSCC in the open-label, single-arm, phase IV KEYNOTE-B10 study (ClinicalTrials.gov identifier: NCT04489888). METHODS: Eligible adults had previously untreated, histologically or cytologically confirmed R/M HNSCC regardless of PD-L1 status, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received pembrolizumab 200 mg intravenously once every 3 weeks for ≤35 cycles and carboplatin AUC 5 mg/mL/min intravenously once every 3 weeks for ≤6 cycles and investigator's choice of paclitaxel 100 mg/m2 on days 1 and 8 or 175 mg/m2 on day 1, intravenously once every 3 weeks. The primary end point was objective response rate per RECIST v1.1 by BICR. RESULTS: Between October 27, 2020, and April 29, 2022, 149 patients were screened and 101 received treatment. As of February 20, 2023, the median follow-up was 18.9 months (range, 9.1-27.0). At this final analysis, 49 (49%) of 101 patients had an objective response (95% CI, 38.4 to 58.7), including seven patients (7%) with a confirmed complete response. Of the 101 treated patients, grade 3-5 and serious treatment-related adverse events occurred in 76 (75%) and 27 (27%), respectively. There were no new safety signals. CONCLUSION: Pembrolizumab plus carboplatin and paclitaxel showed promising antitumor activity and a manageable safety profile in first-line R/M HNSCC, suggesting this combination may be an alternative option for this patient population.

Clipping the Positive Lymph Node in Patients with Clinically Node Positive Breast Cancer Treated with Neoadjuvant Chemotherapy: Impact on Axillary Surgery in the ISPY-2 Clinical Trial.

BACKGROUND: For patients with clinically node-positive (cN+) breast cancer undergoing neoadjuvant chemotherapy (NAC), retrieving previously clipped, biopsy-proven positive lymph nodes during sentinel lymph node biopsy [i.e., targeted axillary dissection (TAD)] may reduce false negative rates. However, the overall utilization and impact of clipping positive nodes remains uncertain. PATIENTS AND METHODS: We retrospectively analyzed cN+ ISPY-2 patients (2011-2022) undergoing axillary surgery after NAC. We evaluated trends in node clipping and associations with type of axillary surgery [sentinel lymph node (SLN) only, SLN and axillary lymph node dissection (ALND), or ALND only] and event-free survival (EFS) in patients that were cN+ on a NAC trial. RESULTS: Among 801 cN+ patients, 161 (20.1%) had pre-NAC clip placement in the positive node. The proportion of patients that were cN+ undergoing clip placement increased from 2.4 to 36.2% between 2011 and 2021. Multivariable logistic regression showed nodal clipping was independently associated with higher odds of SLN-only surgery [odds ratio (OR) 4.3, 95% confidence interval (CI) 2.8-6.8, p < 0.001]. This was also true among patients with residual pathologically node-positive (pN+) disease. Completion ALND rate did not differ based on clip retrieval success. No significant differences in EFS were observed in those with or without clip placement, both with or without successful clip retrieval [hazard ratio (HR) 0.85, 95% CI 0.4-1.7, p = 0.7; HR 1.8, 95% CI 0.5-6.0, p = 0.3, respectively]. CONCLUSION: Clip placement in the positive lymph node before NAC is increasingly common. The significant association between clip placement and omission of axillary dissection, even among patients with pN+ disease, suggests a paradigm shift toward TAD as a definitive surgical management strategy in patients with pN+ disease after NAC.

Internal Mammary Lymphadenopathy Does Not Impact Oncologic Outcomes in Patients Treated with Neoadjuvant Chemotherapy: Results from the I-SPY2 Clinical Trial.

BACKGROUND: Internal mammary lymphadenopathy (IML) plays a role in breast cancer stage and prognosis. We aimed to evaluate method of IML detection, how IML impacts response to neoadjuvant chemotherapy (NAC), and oncologic outcomes. METHODS: We evaluated patients enrolled in the I-SPY-2 clinical trial from 2010 to 2022. We captured the radiographic method of IML detection (magnetic resonance imaging [MRI], positron emission tomography/computed tomography [PET/CT], or both) and compared patients with IML with those without. Rates of locoregional recurrence (LRR), distant recurrence (DR) and event-free survival (EFS) were compared by bivariate analysis. RESULTS: Of 2095 patients, 198 (9.5%) had IML reported on pretreatment imaging. The method of IML detection was 154 (77.8%) MRI only, 11 (5.6%) PET/CT only, and 33 (16.7%) both. Factors associated with IML were younger age (p = 0.001), larger tumors (p < 0.001), and higher tumor grade (p = 0.027). Pathologic complete response (pCR) was slightly higher in the IML group (41.4% vs. 34.0%; p = 0.03). There was no difference in breast or axillary surgery (p = 0.41 and p = 0.16), however IML patients were more likely to undergo radiation (68.2% vs. 54.1%; p < 0.001). With a median follow up of 3.72 years (range 0.4-10.2), there was no difference between IM+ versus IM- in LRR (5.6% vs. 3.8%; p = 0.25), DR (9.1% vs. 7.9%; p = 0.58), or EFS (61.6% vs. 57.2%; p = 0.48). This was true for patients with and without pCR. CONCLUSIONS: In this large cohort of patients treated with NAC, outcomes were not negatively impacted by IML. We demonstrated that IML influences treatment selection but is not a poor prognostic indicator when treated with modern NAC and multidisciplinary disease management.

Observations on the Representation of Asians in Surgical Training and Leadership.

INTRODUCTION: Diversity in medicine has a positive effect on outcomes, especially for Asian patients. We sought to evaluate representation of Asians across entry and leadership levels in surgical training. METHODS: Publicly accessible population data from 2018 to 2023 were collected from the US Census Bureau, the Association of American Medical Colleges, and the American Board of Surgery (ABS). Frequencies based on self-identified Asian status were identified, and proportions were calculated. RESULTS: The US census showed Asians constituted 4.9% of the US population in 2018 versus 6% in 2023. The proportion of Asian medical students rose from 21.6% to 24.8%; however, Asian surgical residency applicants remained constant at 20%. ABS certifications of Asians have increased from 13.7% to 18.5%. ABS examiners increased from 15.7% to 17.1%. CONCLUSIONS: In 5 years, Asians have made numeric gains in medical school and surgical training. However, Asian representation lags at Board examiner levels compared to the medical student population. The ABS has made recent efforts at transparency around examiner and examinee characteristics. A pillar of ensuring a well-trained surgical workforce to serve the public is to mandate that all surgical trainees and graduates undergo fair examinations, and are fairly assessed on their qualifications. Observed progress should further invigorate all surgical applicants, residents and leadership to take an even more active role in making surgery more diverse and welcoming to all, by including careful analyses of diversity at all levels.

Overall Volume of Upper Gastrointestinal Surgery Positively Impacts Gastric Cancer Outcomes at Centers with Low Gastrectomy Volume.

BACKGROUND: The relationship between hospital volume and surgical mortality is well documented. However, complete centralization of surgical care is not always feasible. The present study investigates how overall volume of upper gastrointestinal surgery at hospitals influences patient outcomes following resection for gastric adenocarcinoma. PATIENTS AND METHODS: National Cancer Database (2010-2019) patients with pathologic stage 1-3 gastric adenocarcinoma who underwent gastrectomy were identified. Three cohorts were created: low-volume hospitals (LVH) for both gastrectomy and overall upper gastrointestinal operations, mixed-volume hospital (MVH) for low-volume gastrectomy but high-volume overall upper gastrointestinal operations, and high-volume gastrectomy hospitals (HVH). Chi-squared tests were used to analyze sociodemographic factors and surgical outcomes and Kaplan-Meier method for survival analysis. RESULTS: In total, 26,398 patients were identified (LVH: 20,099; MVH: 539; HVH: 5,760). The 5-year survival was equivalent between MVH and HVH for all stages of disease (MVH: 56.0%, HVH 55.6%; p = 0.9866) and when stratified into early (MVH: 69.9%, HVH: 65.4%; p = 0.1998) and late stages (MVH: 24.7%, HVH: 32.0%; p = 0.1480), while LVH had worse survival. After matching patients, postoperative outcomes were worse for LVH, but there was no difference between MVH and HVH in terms of adequate lymphadenectomy, margin status, readmission rates, and 90-day mortality rates. CONCLUSIONS: Despite lower gastrectomy volume for cancer, postoperative gastrectomy outcomes at centers that perform a high number of upper gastrointestinal cancer surgeries were similar to hospitals with high gastrectomy volume. These hospitals offer a blueprint for providing equivalent outcomes to high volume centers while enhancing availability of quality cancer care.

Natural history of undifferentiated pleomorphic sarcoma: Experience from the US Sarcoma Collaborative.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS. METHODS: From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at seven academic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR), time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed. RESULTS: Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLR recurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation. CONCLUSION: For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.

Disparate impact of the COVID-19 pandemic on delays in colorectal cancer treatment: A National Cancer Database study.

BACKGROUND: Timely treatment for patients with colorectal cancer may have been disrupted by the COVID-19 pandemic. We evaluated the impact of the pandemic on delays to treatment with surgery or systemic therapy for patients with colorectal cancer and delineated factors predictive of delayed treatment. METHODS: Using the National Cancer Database, patients diagnosed with colorectal cancer were categorized by year of diagnosis as COVID-19 era (2020) versus pre-COVID-19 (2018-2019). Categorical variables were compared by χ2 analysis. Multivariate logistic regression was used to assess odds ratios for delayed time to surgery or chemoimmunotherapy, defined as >60 days. RESULTS: In total, 50,689 patients colorectal cancer were diagnosed patients who were pre-COVID-19 vs 21,331 within the COVID-19-era. Patients diagnosed with COVID-19 had a higher stage at diagnosis. There were no differences in the proportion of delayed time to surgery for patients diagnosed in 2020, but patients who were tested for COVID-19 had increased proportions of delayed time to surgery (P < .0001). In multivariate analysis, Black race (P = .0026) and uninsured/underinsured status (P = .0017) were associated with delayed time to surgery. Diagnosis during COVID-19 did not increase delayed time to chemoimmunotherapy, regardless of COVID-19 testing or positivity; however, delays were seen for Black (P < .0001), Hispanic (P < .0001), and uninsured/underinsured patients (P < .0001). CONCLUSION: Although the pandemic did not delay treatment for colorectal cancer overall, vulnerable and underserved populations were disproportionately affected by delays to all forms of therapy. The difference in colorectal cancer outcomes in the coming years as a result of delays in treatment may be significant for these patients.

Trends in access to minimally invasive pancreaticoduodenectomy for pancreatic cancers.

BACKGROUND: Minimally invasive pancreaticoduodenectomy (MIPD), including robotic (RPD) and laparoscopy (LPD), is becoming more frequently employed in the management of pancreatic ductal adenocarcinoma (PDAC), though the majority of operations are still performed via open approach (OPD). Access to technologic advances often neglect the underserved. Whether disparities in access to MIPD exist, remain unclear. METHODS: The National Cancer Database (NCDB) was queried (2010-2020) for patients who underwent pancreatoduodenectomy for PDAC. Cochran-Armitage tests assessed for trends over time. Social determinants of health (SDH) were compared between approaches. Multinomial logistic models identified predictors of MIPD. RESULTS: Of 16,468 patients, 80.03 % underwent OPD and 19.97 % underwent MIPD (22.60 % robotic; 77.40 % laparoscopic). Black race negatively predicted LPD (vs white (OR 0.822; 95 % CI 0.701-0.964)). Predictors of RPD included Medicare/other government insurance (vs uninsured or Medicaid (OR 1.660; 95 % CI 1.123-2.454)) and private insurance (vs uninsured or Medicaid (OR 1.597; 95 % CI 1.090-2.340)). Early (2010-2014) vs late (2015-2020) diagnosis, stratified by race, demonstrated an increase in Non-White patients undergoing OPD (13.15 % vs 14.63 %; p = 0.016), but not LPD (11.41 % vs 13.57 %;p = 0.125) or RPD (14.15 % vs 15.23 %; p = 0.774). CONCLUSION: SDH predict surgical approach more than clinical stage, facility type, or comorbidity status. Disparities in race and insurance coverage are different between surgical approaches.

Association of Race, Ethnicity, Language, and Insurance with Time to Treatment Initiation Among Women with Breast Cancer at an Urban, Academic, Safety-Net Hospital.

INTRODUCTION: Initial treatment for nonmetastatic breast cancer is resection or neoadjuvant systemic therapy, depending on tumor biology and patient factors. Delays in treatment have been shown to impact survival and quality of life. Little has been published on the performance of safety-net hospitals in delivering timely care for all patients. METHODS: We conducted a retrospective study of patients with invasive ductal or lobular breast cancer, diagnosed and treated between 2009 and 2019 at an academic, safety-net hospital. Time to treatment initiation was calculated for all patients. Consistent with a recently published Committee on Cancer timeliness metric, a treatment delay was defined as time from tissue diagnosis to treatment of greater than 60 days. RESULTS: A total of 799 eligible women with stage 1-3 breast cancer met study criteria. Median age was 60 years, 55.7% were non-white, 35.5% were non-English-speaking, 18.9% were Hispanic, and 49.4% were Medicaid/uninsured. Median time to treatment was 41 days (IQR 27-56 days), while 81.1% of patients initiated treatment within 60 days. The frequency of treatment delays did not vary by race, ethnicity, insurance, or language. Diagnosis year was inversely associated with the occurrence of a treatment delay (OR: 0.944, 95% CI 0.893-0.997, p value: 0.039). CONCLUSION: At our institution, race, ethnicity, insurance, and language were not associated with treatment delay. Additional research is needed to determine how our safety-net hospital delivered timely care to all patients with breast cancer, as reducing delays in care may be one mechanism by which health systems can mitigate disparities in the treatment of breast cancer.

The 2023 A. Hamblin Letton Lecture, Southeastern Surgical Conference Lecture "Choices Matter in Cancer Surgery: A Life's Journey".

Attaining a successful career in cancer surgery depends on many choices. In this paper based on the Letton Lecture from the 2023 Southeastern Surgical Conference, Dr. Jennifer Tseng reflects on the choices that enabled her current work.

Impact of the COVID-19 Pandemic on Delays to Breast Cancer Surgery: Ripples or Waves?

BACKGROUND: Adherence to current recommendations for optimal time from diagnosis to treatment for patients with breast cancer may have been disrupted by the COVID-19 pandemic. This study aimed to evaluate the impact of the pandemic on time to surgery or systemic treatment with chemotherapy or immunotherapy for patients diagnosed with breast cancer. METHODS: Using the National Cancer Database, patients diagnosed with breast cancer in 2020 were compared to those diagnosed from 2018-2019 (Pre-COVID). Sub-analyses were performed for patients who were tested for COVID-19 and those who had a positive result in 2020. Multivariate logistic regression was used assess odds ratios for delayed time to surgery (DTS, defined as > 90 days) or systemic therapy (defined as > 120 days). RESULTS: In total, 230,997 patients were diagnosed with breast cancer in 2018 and 2019 compared to 102,065 in 2020. Of the 2020 cohort, 47,659 (46.7%) received COVID-19 testing; of which, 3,158 (6.6%) resulted positive. A larger proportion of COVID-tested or COVID-positive patients had higher stage at diagnosis. DTS was more likely for patients who were diagnosed in 2020, uninsured or underinsured, non-white, Hispanic, less educated, or age < 70 years. Similar factors were predictive of delay to systemic therapy (less age < 70 years); however, diagnosis in 2020 was not. CONCLUSION: The COVID-19 pandemic was associated with significant DTS for breast cancer but spared time to systemic therapy. Delays disproportionately impacted vulnerable and underserved patient populations. The true clinical effects of these delays may yet be realized for breast cancer patients.

The Evaluation of Gallstone Disease in the Year Before Pancreatic Cancer Diagnosis.

INTRODUCTION: Patients with pancreatic cancer can present with a variety of insidious abdominal symptoms, complicating initial diagnosis. Early symptoms of pancreatic cancer often mirror those associated with gallstone disease, which has been demonstrated to be a risk factor for this malignancy. This study aims to compare the incidence of gallstone disease in the year before diagnosis of pancreatic ductal adenocarcinoma (PDAC) as compared to the general population, and evaluate the association of gallstone disease with stage at diagnosis and surgical intervention. METHODS: Patients with PDAC were identified from SEER-Medicare (2008-2015). The incidence of gallstone disease (defined as cholelithiasis, cholecystitis and/or cholecystectomy) in the 1 year before cancer diagnosis was compared to the annual incidence in an age-matched, sex-matched, and race-matched noncancer Medicare cohort. RESULTS: Among 14,654 patients with PDAC, 4.4% had gallstone disease in the year before cancer diagnosis. Among the noncancer controls (n = 14,654), 1.9% had gallstone disease. Both cohorts had similar age, sex and race distributions. PDAC patients with gallstone disease were diagnosed at an earlier stage (stage 0/I-II, 45.8% versus 38.1%, P < 0.0001) and a higher proportion underwent resection (22.7% versus 17.4%, P = 0.0004) compared to patients without gallstone disease. CONCLUSIONS: In the year before PDAC diagnosis, patients present with gallstone disease more often than the general population. Improving follow-up care and differential diagnosis strategies may help combat the high mortality rate in PDAC by providing an opportunity for earlier stage of diagnosis and earlier intervention.

2023 A. Hamblin Letton Lecture.

For this lecture, I was inspired by Dr. Bryan Richmond's Southeastern Surgical Congress presidential address, "Finding your own unique place in the house of surgery." I struggled to find my own place in cancer surgery. The choices available to me and those who came before me enabled the wonderful career I am blessed to enjoy. What I share as part of my own story. My words do not represent those of my institutions or any organizations of which I am privileged to belong.