National Surgical Adjuvant Breast Research Articles

Abstract PO4-01-03: Dual anti-HER2 Therapy with Pertuzumab and Trastuzumab versus Trastuzumab Alone in Addition to Anthracycline and Taxane-Based Neoadjuvant Therapy in Patients with HER2-Positive Early-Stage Breast Cancer; Real-World Data

Abstract Background: When use in the neoadjuvant setting, anti-HER2 targeted therapy had improved pathologic complete response rate (pCR) in patients with HER2-positive early-stage breast cancer (EBC). Here we present real-world data on the use trastuzumab with or without pertuzumab on the backbone of anthracycline and taxanes-based NSAPB-B27 chemotherapy regimen. Methods: We retrospectively reviewed records of patients with HER2-positive EBC who received neoadjuvant therapy using the National Surgical Adjuvant Breast and Bowel Project (NSABP)-B27 protocol (4 cycles of adriamycin and cyclophosphamide, followed by 4 more cycles of docetaxel; all given every 3 weeks) with anti-HER2 therapy from Jan 2014 to September 2021, treated at a tertiary care cancer center. The clinicopathological features, treatment received, and outcome were collected from patients’ electronic medical records. We estimated 3-year disease-free survival (DFS), a validated endpoint in HER2-positive EBC, using Kaplan-Meier with recurrence and/or death as events. Outcomes were reported in subgroups based on known prognostic factors. Results: The study comprised 528 patients with a median follow-up of 36 months. Median age was 48 (21-80) years. Hormone receptors (HR) were positive in 379 (71.8%), lymph node-involvement prior to neoadjuvant therapy was reported in 402 (76.1%) patients and 319 (60,4%) had grade-3 disease. Majority (n= 482, 91.3%) were labeled HER2-positive based on immunohistochemistry staining (IHC+3) and the rest were based on IHC+2 with positive FISH/ISH. Dual anti-HER2 therapy (trastuzumab and pertuzumab) was used in 316 (59.8%) patients, single agent trastuzumab in 173 (32.8 %) patients, while 39 (7.4%) others did not receive any anti-HER2 therapy. Except for 9 (1.7%) patients who progressed while on treatment, all patients underwent surgery. Among the whole group, 225 (43.4%) achieved pCR; significantly higher (n=80, 53.7%) in HR-negative compared to 38.3% among those with HR-positive disease, p=0.002. Additionally, pCR was higher in patients who received dual anti-HER2 (46.2%) compared to 39.3% for those treated with trastuzumab and 28.2% for those who did not receive anti-HER2 therapy. Following surgery, 463 (89.4%) of the patients received adjuvant trastuzumab, however, none of them received pertuzumab or TDM1 in adjuvant sitting. Estimated 3-year DFS was 86.1% with dual anti-HER2 and 83.0% with trastuzumab alone, p=0.19. However, DFS was better among those with node-negative disease; 96.5% compared to 80.9% in node-positive disease, p= < 0.001. Patients who achieved pCR had significantly better 3-year DFS; 89.3% compared to 80.2% in patients with residual disease, p= 0.006. Conclusions: Even with the wide use of pertuzumab in the neoadjuvant setting, the DFS was not improved compared to trastuzumab alone, and this highlights the importance of switching trastuzumab to TDM1, or to continue with pertuzumab in the adjuvant setting in patient with residual disease. Citation Format: Baha' Sharaf, Faris Tamimi, Osama Salama, Anas Zayed, Osama El Khatib, Suhaib Khater, Malek Horani, Suhaib Al-Sawajneh, Yosra AL-Masri, Hikmat Abdel-Razeq. Dual anti-HER2 Therapy with Pertuzumab and Trastuzumab versus Trastuzumab Alone in Addition to Anthracycline and Taxane-Based Neoadjuvant Therapy in Patients with HER2-Positive Early-Stage Breast Cancer; Real-World Data [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 PO4-01-03.

Racial and Ethnic Disparities in Outcomes After Breast-Conserving Therapy and Endocrine Therapy for DCIS: A Post-Hoc Analysis of the NSABP B-35 Randomized Clinical Trial.

Racial and ethnic disparities in outcomes after treatment for ductal carcinoma in situ (DCIS) are largely unknown. The objective of this study was to examine breast cancer outcomes by race and ethnicity in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 clinical trial. The NSABP B-35 trial randomized postmenopausal women with hormone receptor-positive DCIS treated with breast-conserving therapy to 5 years of tamoxifen or anastrozole. In total, 3104 women were enrolled between 2003 and 2006. For this analysis, patients without complete self-reported race and ethnicity or with immediate trial dropout were excluded. Kaplan-Meier curves and adjusted Cox-proportional hazards models were used for analyses. Of the 3061 women included, 2614 (85.4%) were non-Hispanic white (NHW), 255 (8.3%) were non-Hispanic Black (NHB), 95 (3.1%) were Hispanic, and 96 (3.1%) were Asian or Pacific Islander (API). Endocrine therapy assignment and duration were well balanced between racial and ethnic groups. Median follow-up was 9 years; unadjusted Kaplan-Meier curves did not show any racial differences in disease events. Adjusted Cox-proportional hazards models found API (versus NHW) race to be associated with higher local recurrence [hazard ratio (HzR) 2.45, p = 0.035] and NHB race to be associated with higher distant recurrence (HzR 5.03, p = 0.020) and breast cancer mortality (HzR 3.83, p = 0.046). Despite similar locoregional treatments and standard endocrine therapy in a clinical trial population, racial and ethnic disparities exist in long-term outcomes for hormone-receptor-positive DCIS. These findings suggest that factors outside of access and treatment may impact DCIS outcomes by race and ethnicity.

Racial Disparities in Locoregional Recurrence in Postmenopausal Patients with Stage I-III, Hormone Receptor-Positive Breast Cancer Enrolled in the NSABP B-42 Clinical Trial.

There are limited data examining racial disparities in locoregional recurrence (LRR) among women with access to high-quality care. We aimed to examine differences in late LRR by race in patients with stage I-IIIA, hormone receptor-positive (HR+) breast cancer enrolled in the National Surgical Adjuvant Breast and Bowel (NSABP) B-42 trial. From 2006 to 2010, 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were disease-free after 5 years of endocrine therapy were randomized to an additional 5 years of endocrine therapy or placebo. Patients were excluded if multi-racial or if race was unknown. Kaplan-Meier curves were used to estimate 6-year LRR from the time of trial registration and according to race. Cox proportional hazards models were used for adjusted survival analyses. Overall, 3929 NSABP B-42 patients were included: 3688 (93.9%) White, 151 (3.8%) Black, and 90 (2.3%) Asian patients. Median follow-up was 75.2 months. Overall estimated 6-year LRR from trial registration was 1.8% and differed by race: LRR rates were 1.7% in White women, 4.9% in Black women, and 0% in Asian women (p=0.046). Adjusted Cox proportional hazards analysis found Black race to be independently associated with LRR (hazard ratio [HzR] 2.36, 95% confidence interval [CI] 1.01-5.49; p=0.047). Node-positivity was also associated with increased LRR (HzR 1.75, 95% CI 1.07-2.86; p=0.025). Adjusted Cox analysis found LRR (HzR 2.32, 95% CI 1.33-4.06; p=0.003) to be associated with increased overall mortality; however, race was not independently associated with mortality. Among postmenopausal patients with stage I-IIIA HR+ breast cancer in the NSABP B-42 trial, racial differences in late LRR were present, with the highest LRR in Black women.

Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor–Positive Breast Cancer

PURPOSE The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor–positive, lymph node–negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. METHODS The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy–treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. RESULTS A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant ( P = .038). Patients with high-RS (≥ 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (< 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, −1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. CONCLUSION The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor–positive breast cancer, but also predicts the magnitude of chemotherapy benefit.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials

For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.

To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

Combinational chemotherapy for the treatment of colon cancer

The second leading cause of cancer-related death is colon cancer. Combination chemotherapy can lessen the chance of re-occurrence and demise due to recurred or illness that has spread in patients who have had curative surgery. According to the findings of the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) and the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trials, combination regimens that include fluoropyrimidine and oxaliplatin are the current standard of care. Targeted medicines for combination adjuvant treatment in the second and third stages of colon cancer are an assuring area, there is no proof to support its use in this situation at this stage. Postoperative therapy has a well-established role in the elderly population, though the most appropriate regimen is still to be established. Improved surgical and radiotherapy techniques may help the patients achieve better results. Further studies should be undertaken in order to determine patient subgroups prone to recurrence, predict response to therapy, and develop better treatment strategies for individuals with colon cancer

Health-related quality of life outcomes after neoadjuvantchemoradiotherapy for rectal cancer in NRGOncology/NSABP R-04.

BackgroundThere has been limited evaluation of health‐related quality of life (HRQOL) in rectal cancer patients receiving neoadjuvant chemoradiotherapy. HRQOL outcomes in the National Surgical Adjuvant Breast and Bowel Project R‐04 trial are examined in this article.MethodsBetween 2004 and 2010, R‐04 patients were invited to enroll in the HRQOL substudy, with questionnaires administered before randomization, after completion of chemoradiotherapy, and 1‐year after surgery. HRQOL measures included: Functional Assessment of Cancer Therapy for colorectal cancer (FACT‐C); Short Form‐36v.2 Vitality scale; a treatment‐specific symptom scale; and the FACT neurotoxicity scale. A 5‐year postsurgery assessment was added to the protocol in 2012. Mixed‐effects models examined neoadjuvant therapy treatment effects in the 1‐year sample and models that explored associations of host factors and treatment impact on 5‐year HRQOL.ResultsA total of 1373 patients completed baseline HRQOL and at least one additional assessment. The average age was 58 years (range, 23–85 years), male (68%), and 59% Stage II. There were no statistically significant differences in HRQOL outcomes by treatment arm, but HRQOL worsened from baseline to postneoadjuvant chemoradiotherapy, with statistically significant effect sizes changes ranging from 0.6 (Vitality) to 0.9 (FACT‐C Trial Outcome Index). Neurotoxicity was greater in the oxaliplatin‐treated groups. Obese/overweight patients had statistically significantly worse FACT‐C Trial Outcome Index scores than did underweight/normal weight groups. At 5 years, younger patients and those with normal baseline weight had statistically significantly better physical function scores and older patients had better mental health outcomes.ConclusionsHRQOL did not differ across the four R‐04 treatment arms; however, host factors explained significant variation in posttreatment HRQOL. ClinicalTrials.gov: NCT00058474 (https://ClinicalTrials.gov/ct2/show/NCT00058474).Lay summary This article reports on the health‐related quality of life (HRQOL) outcomes of patients treated with four different chemotherapy regimens combined with radiation in rectal cancer patients before definitive surgical treatment.There were no significant differences in HRQOL by treatment regimen, but all patients experienced decreased vitality (energy) and physical functioning. By 1 year after treatment, most patients had returned to pretreatment vitality and physical functioning, with the exception of increased neurotoxicity.In a subsample of patients assessed at 5 years after surgery, physical function was better in those who at pretreatment were younger, normal weight, and had better performance status. Mental function was better in those who at pretreatment were older and had better performance status.

Development of the Breast Surgical Oncology Fellowship in the United States.

The surgical treatment of breast cancer has rapidly evolved over the past 50 years, progressing from Halsted's radical mastectomy to a public campaign of surgical options, aesthetic reconstruction, and patient empowerment. Sparked by the research of Dr. Bernard Fisher and the first National Surgical Adjuvant Breast and Bowel Project trial in 1971, the field of breast surgery underwent significant growth over the next several decades, enabling general surgeons to limit their practices to the breast. High surgical volumes eventually led to the development of the first formal breast surgical oncology fellowship in a large community-based hospital at Baylor University Medical Center in 1982. The establishment of the American Society of Breast Surgeons, as well as several landmark clinical trials and public campaign efforts, further contributed to the advancement of breast surgery. In 2003, the Society of Surgical Oncology (SSO), in partnership with the American Society of Breast Surgeons and the American Society of Breast Disease, approved its first fellowship training program in breast surgical oncology. Since that time, the number of American fellowship programs has increased to approximately 60 programs, focusing not only on training in breast surgery, but also in medical oncology, radiation oncology, pathology, breast imaging, and plastic and reconstructive surgery. This article focuses on the happenings in the United States that led to the transition of breast surgery from a subset of general surgery to its own specialized field.

Racial disparity in distant recurrence-free survival in patients with localized breast cancer: A pooled analysis of National Surgical Adjuvant Breast and Bowel Project trials.

Black race is associated with worse outcome in patients with breast cancer. The distant relapse-free survival (DRFS) between Black and White women with localized breast cancer who participated in National Cancer Institute-sponsored clinical trial was evaluated. Pooled data were analyzed from 8 National Surgical Adjuvant Breast and Bowel Project (NSABP) trials including 9702 women with localized breast cancer treated with adjuvant chemotherapy (AC, n = 7485) or neoadjuvant chemotherapy (NAC, n = 2217), who self-reported as Black (n = 1070) or White (n = 8632) race. The association between race and DRFS was analyzed using log-rank tests and multivariate Cox regression. After adjustment for covariates including age, tumor size, nodal status, body mass index and taxane use, and treatment (AC vs NAC), Black race was associated with an inferior DRFS in estrogen receptor-positive (ER+; hazard ratio [HR], 1.24; 95% CI, 1.05-1.46; P = .01), but not in ER- disease (HR, 0.97; 95% CI, 0.83-1.14; P = .73), and significant interaction between race and ER status was observed (P = .03). There was no racial disparity in DRFS among patients with pathologic complete response (pCR) (log-rank P = .8). For patients without pCR, Black race was associated with worse DRFS in ER+ (HR, 1.67; 95% CI, 1.14-2.45; P = .01), but not in ER- disease (HR, 0.91; 95% CI, 0.65-1.28; P = .59). Black race was associated with significantly inferior DRFS in ER+ localized breast cancer treated with AC or NAC, but not in ER- disease. In the NAC group, racial disparity was also observed in patients with residual ER+ breast cancer at surgery, but not in those who had pCR. Black women with breast cancer have worse outcomes compared with White women. We investigated if this held true in the context of clinical trials that provide controlled treatment setting. Black women with cancer expressing estrogen receptors (ERs) had worse outcome than White women. If breast cancers did not express ERs, there was no racial disparity in outcome. We also observed racial disparity in women who received chemotherapy before their cancer was removed, but only if they had cancer expressing ERs and residual disease on completion of treatment. If the cancer disappeared with presurgical chemotherapy, there was no racial disparity.

Evaluating Regional Nodal Irradiation Allocation and Association with Oncologic Outcomes in NSABP B-18, B-27, B-40, and B-41

There is a lack of level I evidence to guide radiation therapy recommendations for patients receiving neoadjuvant chemotherapy for breast cancer. We used 4 neoadjuvant chemotherapy trials to determine which patients benefit from regional nodal irradiation (RNI). We obtained data from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-18, B-27, B-40, and B-41 clinical trials. B-40 and B-41 allowed RNI at physician's discretion. We evaluated locoregional recurrence (LRR), distant recurrence, disease-free survival, and overall survival (OS). Kaplan-Meier, Peto-Peto, χ2, Fisher exact, and Wilcoxon rank-sum tests were used for survival estimates and comparison. Median follow-up for B-18, B-27, B-40, and B-41 was 13.7, 9.7, 4.5, and 5.1 years, respectively, including 742, 2254, 1154, and 504 patients for analysis. On multivariable analysis, factors significantly associated with RNI included tumor size, ypN status, and tumor subtype; Hispanic patients were less likely to receive RNI. Patients with ypN+HER2+ disease who received RNI had improved OS. B-40 patients with ypN+HR+ disease had improved LRR. On multivariable analysis for the B-40 and B-41 study population, RNI was not associated with significantly improved OS, disease-free survival, distant recurrence, or LRR. RNI was associated with a clinical benefit for patients with ypN+HER2+ and ypN+HR+ disease. RNI was not significantly associated with a clinically beneficial outcome for the entire cohort. Prospective phase 3 clinical trials are needed to establish guidelines for patients who should receive RNI after neoadjuvant treatment, and action is necessary to eliminate the disparity in care delivery shown for Hispanic women.

A Short History of Bernard Fisher's Contributions to Randomized Clinical Trials.

Dr. Bernard Fisher (1918-2019) was an early proponent of evidence-based medicine using the mechanism of prospective, multicenter, randomized clinical trials to test biological and clinical hypotheses. In this article, I trace how his early scientific work in striving to understand the nature of cancer metastasis through animal experiments led to a new, testable, clinical hypothesis: that surgery to remove only the tumor and a small amount of tissue around it was as effective as the more disfiguring operations that were then the standard treatment. Fisher's work with the National Surgical Adjuvant Breast and Bowel Project (NSABP) using large, randomized clinical trials to demonstrate the veracity of this hypothesis led to a new paradigm in which the emphasis was placed on how systemic therapies used at an early stage of disease could effectively eradicate breast cancer for many patients. This new therapeutic approach led to the successful development of new treatments, many of which are widely used today. Ultimately, the new paradigm led to successfully preventing breast cancer in women who were at high risk for the disease but who had not yet been diagnosed with the disease. Throughout his entire career, Fisher championed the use of large prospective, randomized clinical trials despite criticism from many in the medical community who strongly criticized his use of randomization as a mechanism for testing clinical hypotheses. The approach he and the NSABP employed is still considered to be the highest standard of evidence in conducting clinical studies.

Radiotherapy Standardisation and Artificial Intelligence within the National Cancer Institute's Clinical Trials Network

Artificial intelligence in healthcare refers to the use of complex algorithms designed to conduct certain tasks in an automated manner. Artificial intelligence has a transformative power in radiation oncology to improve the quality and efficiency of patient care, given the increase in volume and complexity of digital data, as well as the multi-faceted and highly technical nature of this field of medicine. However, artificial intelligence alone will not be able to fix healthcare's problem, because new technologies bring unexpected and potentially underappreciated obstacles. The inclusion of multicentre datasets, the incorporation of time-varying data, the assessment of missing data as well as informative censoring and the addition of clinical utility could significantly improve artificial intelligence models. Standardisation plays a crucial, supportive and leading role in artificial intelligence. Clinical trials are the most reliable method of demonstrating the efficacy and safety of a treatment or clinical approach, as well as providing high-level evidence to justify artificial intelligence. The National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group and the Gynecologic Oncology Group collaborated to form NRG Oncology (acronym NRG derived from the names of the parental groups). NRG Oncology is one of the adult cancer clinical trial groups containing radiotherapy specialty of the National Cancer Institute's Clinical Trials Network (NCTN). Standardisation from NRG/NCTN has the potential to reduce variation in clinical treatment and patient outcome by eliminating potential errors, enabling broader application of artificial intelligence tools. NCTN, NRG and Imaging and Radiation Oncology Core are in a unique position to help with standards development, advocacy and enforcement, all of which can benefit from artificial intelligence, as artificial intelligence has the ability to improve trial success rates by transforming crucial phases in clinical trial design, from study planning through to execution. Here we will examine: (i) how to conduct technical and clinical evaluations before adopting artificial intelligence technologies, (ii) how to obtain high-quality data for artificial intelligence, (iii) the NCTN infrastructure and standards, (iv) radiotherapy standardisation for clinical trials and (v) artificial intelligence applications in standardisation.

Joseph R. Bertino: In Memoriam (1930–2021)

Joseph R. Bertino: In Memoriam (1930–2021)

The influence of preoperative biopsy on the surgical method in breast cancer patients: a single-center experience of 3,966 cases in China.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B32 trial reported that the detection rate of sentinel lymph nodes by core needle biopsy (CNB) is higher than that by segmental resection. However, there are few reports regarding the detection rate of sentinel lymph nodes by vacuum-assisted breast biopsy (VABB). Therefore, we analyzed the impact of preoperative biopsy methods on the surgical modes of 3,966 patients with breast cancer in our center. In total, 3,966 female breast cancer patients [clinical tumor node metastasis (TNM) stage I-III] were enrolled in this study. Preoperative pathological diagnosis methods included fine needle aspiration (FNA) biopsy, CNB, excision biopsy, and VABB. According to the time of diagnosis. The data were analysis by chi square test, variance analysis and the Kaplan-Meier time series in SPSS 22.0. There was a decrease in the number of patients that underwent excision biopsy (7.3% to 2.7%) and intraoperative freezing (89.4% to 28.9%) over time, while CNB exhibited an increasing trend (1.6% to 55.3%). The positive rates of VABB, CNB, excision biopsy, and FNA were 99.5%, 97.1%, 97.9%, and 82.2%, respectively, and the false negative rates were 0%, 1.8%, 0.34%, and 8.9%, respectively. The overall breast-conserving rate was 36.7%, while the breast-conserving rate for VABB was 57.1%. The axillary sentinel lymph node biopsy rate of cN0 patients was 48.3%, and the intraoperative frozen group (36.7%) and excision biopsy group (39.5%) were lower than the CNB (57.1%) and VABB (77.9%) groups. Until December 2019, there were 350 cases with tumor recurrence or metastasis. The methods of biopsy were not correlated to the cumulative survival time. Changes to the diagnosis and treatment of breast cancer has a profound impact on the method of tumor biopsy. VABB biopsy offers advantages such as accurate diagnosis, a greater volume of tissue taken at one time, minimally invasive and repeatable, and does not affect the surgical approach and prognosis of patients. It will gradually become the primary method of preoperative pathological evaluation of breast cancer.

Antimullerian Hormone as a Serum Biomarker for Risk of Chemotherapy-Induced Amenorrhea.

Antimullerian hormone (AMH) is a promising biomarker for ovarian reserve. In this study, we assessed AMH before and 1 year after initiation of adjuvant chemotherapy onNational Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology B-47 in female participants aged 42 years and younger (median age = 39 years). At baseline, median AMH was 1.2 ng/mL; 13 (4.7%) values were less than 0.1 ng/mL (the threshold for detectable levels, in the perimenopause and menopause range), and 57 values (20.6%) were less than 0.5 ng/mL. At 1 year, 215 (77.6%) were less than 0.1 ng/mL, and 264 (95.3%) were less than 0.5 ng/mL. Postchemotherapy menses were reported by 46.2% of participants. Multivariable logistic regression found that the odds of having postchemotherapy menses increased with younger age, higher body mass index, and higher prechemotherapy AMH, but not by trastuzumab administration or by the choice of chemotherapy (doxorubicin-cyclophosphamide followed by paclitaxel vs docetaxel-cyclophosphamide). We conclude that higher prechemotherapy AMH predicts a lower risk of chemotherapy-induced amenorrhea and that AMH 1 year after chemotherapy initiation is not informative in this setting because it is likely to be very low.

Inference on quantile residual life for length-biased survival data

Length biased data occurs when a prevalent sampling is used to recruit subject into a study that investigates the time from an initial event to a terminal event. Such data are usually left-truncated and right-censored. While there have been accurate and efficient methods to estimate the survival function, not much work have been done regarding estimation of residual life time distribution or the summary parameters such as the median and quantiles of the residual life. In this paper we propose two ways to estimate the quantiles of the residual life time at fixed time points accounting for the length biased and censored na- ture of the data. We provide the asymptotic properties of these estimators and investigate them through simulation studies. Considering that the variance of these estimators require density estimation, we suggest an alternate approach to obtain the confidence intervals for the residual function. We apply these methods to a breast cancer dataset from National Surgical Adjuvant Breast and Bowel Project (NSABP).

Assessing the Quality of Rectal Cancer Pathology Reports in National Surgical Adjuvant Breast and Bowel Project Protocol R-04/NRG Oncology.

Accurate and comprehensive surgical pathology reports are integral to the quality of cancer care. Despite guidelines from the College of American Pathologists, variations in reporting quality continue to exist. The aim of this study was to evaluate the quality of rectal cancer pathology reports and to identify areas of deficiency and potential sources of reporting variations. This is a retrospective analysis of prospectively obtained pathology reports. This study is based at the hospitals participating in the National Surgical Adjuvant Breast and Bowel Project Protocol R-04 study. Patients with rectal cancer undergoing surgical resection between July 2004 and August 2010 were included. The primary outcomes measured were the adherence to the College of American Pathologists guidelines and the impact of synoptic reporting, academic status, rural/urban setting, and hospital bed size on reporting quality. We identified 1004 surgical pathology reports for rectal cancer surgery from 383 hospitals and 755 pathologists. The overall adherence rate to the College of American Pathologists guidelines was 73.3%. Notable reporting deficiencies were found in several key pathology characteristics, including tumor histologic grade (reporting rate 77.8%), radial margin (84.6%), distance from the closest margin (47.9%), treatment effect (47.1%), and lymphovascular (73.1%)/perineural invasions (35.4%). Synoptic reporting use and urban hospital settings were associated with better adherence rates, whereas academic status and hospital bed size had no impact. Reporting variations existed not only between institutions, but also within individual hospitals and pathologists. There was a trend for improved adherence over time (2005 = 65.7% vs 2010 = 82.3%, p < 0.001), which coincided with the increased adoption of synoptic reporting by pathologists (2005 vs 2010, 9.4% vs 25.3%, p < 0.001). Data were obtained from a restricted setting (ie, hospitals participating in a randomized clinical trial). Wide variations in the quality of pathology reporting are observed for rectal cancer. The National Accreditation Program for Rectal Cancer mandates that programs meet strict quality standards for surgical pathology reporting. Further improvement is needed in this key aspect of oncology care for patients with rectal cancer. See Video Abstract at http://links.lww.com/DCR/B238.ClinicalTrials.gov registration: NCT00058 EVALUACIÓN DE LA CALIDAD DE LOS INFORMES DE PATOLOGÍA QUIRÚRGICA EN CASOS DE CÁNCER DE RECTO DEL NSABP R-04/ ONCOLOGÍA DEL NRG: Un informe de patología quirúrgica preciso y completo es fundamental en la calidad de atención de pacientes con cáncer. A pesar de las normas establecidas por el Colegio Americano de Patología, la variabilidad en la calidad de los informes es evidente.Evaluar la calidad de los informes de patología en casos de cáncer de recto para así identificar las áreas con deficiencias y las posibles fuentes variables en los mencionados informes.Análisis retrospectivo de informes de patología quirúrgica obtenidos prospectivamente.Hospitales que participan del Protocolo del Estudio Nacional R-04 como Adyuvantes Quirúrgicos de Mama e Intestino.Todos aquellos pacientes con cáncer de recto sometidos a resección quirúrgica entre Julio 2004 y Agosto 2010.Cumplimiento de las normas del Colegio Americano de Patología, del impacto de los informes sinópticos, del estado académico, del entorno rural / urbano y el número de camas hospitalarias en en la calidad de los informes.Identificamos 1,004 informes de patología quirúrgica en casos de cirugía en cáncer de recto en 383 hospitales y 755 patólogos. La tasa general de adherencia a las directivas del Colegio Americano de Patología fue del 73.3%. Se encontraron deficiencias notables en los informes en varias características patológicas clave incluidos, el grado histológico del tumor (tasa de informe 77.8%), margenes radiales (84.6%), distancia del margen más cercano (47.9%), efecto del tratamiento (47.1%) invasión linfovascular (73.1 %) / invasion perineural (35.4%). El uso de informes sinópticos y los entornos hospitalarios urbanos se asociaron con mejores tasas de adherencia, mientras que el estado académico y el número de camas hospitalarias no tuvieron ningún impacto. Hubo variaciones en los informes no solo entre instituciones, sino también dentro de hospitales y patólogos individuales. Hubo una tendencia a una mejor adherencia a lo largo del tiempo (2005 = 65.7% v 2010 = 82.3%, p < 0.001), que coincidió con la mayor adopción de informes sinópticos por parte de los patólogos (2005 v 2010, 9.4% v 25.3%, p < 0.001)Datos obtenidos de un entorno restringido (es decir, hospitales que participan en un ensayo clínico aleatorizado).Se observaron grandes variaciones en la calidad de los informes de patología quirúrgica en casos de cáncer de recto. El Programa Nacional de Acreditación para Cáncer de Recto exige que los programas cumplan con estrictos estándares de calidad para los informes de patología quirúrgica. Se necesita una mejoría adicional en este aspecto clave de la atención oncológica para pacientes con cáncer de recto. Video Resumen en http://links.lww.com/DCR/B238.Registro de Clinical Trials.gov: NCT00058.

Contralateral Prophylactic Mastectomy in the Era of Financial Toxicity: An Additional Point for Concern?

Contralateral Prophylactic Mastectomy in the Era of Financial Toxicity: An Additional Point for Concern?

Evaluating Treatment Tolerability in Cancer Clinical Trials Using the Toxicity Index.

BackgroundThe National Cancer Institute Moonshot research initiative calls for improvements in the analysis and reporting of treatment toxicity to advise key stakeholders on treatment tolerability and inform regulatory and clinical decision making. This study illustrates alternative approaches to toxicity evaluation using the National Surgical Adjuvant Breast and Bowel Project R-04 clinical trial as an example.MethodsNational Surgical Adjuvant Breast and Bowel Project R-04 was a neoadjuvant chemoradiation trial in stage II–III rectal cancer patients. A 2 x 2 factorial design was used to evaluate whether the addition of oxaliplatin (Oxa) to 5-fluorouracil (5FU) or capecitabine (Cape) with radiation therapy improved local-regional tumor control. The toxicity index (TI), which accounts for the frequency and severity of toxicities, was compared across treatments using multivariable probabilistic index models, where Pr A < B indicates the probability that higher values of TI were observed for A when compared with B. Baseline age, sex, performance status, body mass index, surgery type, and stage were evaluated as independent risk factors.ResultsA total of 4560 toxicities from 1558 patients were analyzed. Results from adjusted probabilistic index models indicate that oxaliplatin-containing regimens had statistically significant (P < .001) probability (Pr) for higher TI compared with regimens without oxaliplatin (Pr 5FU < 5FU + Oxa = 0.619, 95% confidence interval [CI] = 0.560 to 0.674; Pr 5FU < Cape + Oxa = 0.627, 95% CI = 0.568 to 0.682; Pr Cape < 5FU + Oxa = 0.587, 95% 0.527 to 0.644; and Pr Cape < Cape + Oxa = 0.596, 95% 0.536 to 0.653). When compared with other existing toxicity analysis methods, TI provided greater power to detect differences between treatments.ConclusionsThis article uses standard data collected in a cancer clinical trial to introduce descriptive and analytic methods that account for the additional burden of multiple toxicities. These methods may provide a more accurate description of a patient’s treatment experience that could lead to individualized dosing for better toxicity control. Future research will evaluate the generalizability of these findings in trials with similar drugs.