Search

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear., Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy., Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy., Exposure: TIL abundance in breast tissue from resected primary tumors., Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center., Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6)., Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

Importance: Benign breast disease (BBD) comprises approximately 75% of breast biopsy diagnoses. Surgical biopsy specimens diagnosed as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) are associated with increasing breast cancer (BC) risk; however, knowledge is limited on risk associated with percutaneously diagnosed BBD., Objectives: To estimate BC risk associated with BBD in the percutaneous biopsy era irrespective of surgical biopsy., Design, Setting, and Participants: In this retrospective cohort study, BBD biopsy specimens collected from January 1, 2002, to December 31, 2013, from patients with BBD at Mayo Clinic in Rochester, Minnesota, were reviewed by 2 pathologists masked to outcomes. Women were followed up from 6 months after biopsy until censoring, BC diagnosis, or December 31, 2021., Exposure: Benign breast disease classification and multiplicity by pathology panel review., Main Outcomes: The main outcome was diagnosis of BC overall and stratified as ductal carcinoma in situ (DCIS) or invasive BC. Risk for presence vs absence of BBD lesions was assessed by Cox proportional hazards regression. Risk in patients with BBD compared with female breast cancer incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) program were estimated., Results: Among 4819 female participants, median age was 51 years (IQR, 43-62 years). Median follow-up was 10.9 years (IQR, 7.7-14.2 years) for control individuals without BC vs 6.6 years (IQR, 3.7-10.1 years) for patients with BC. Risk was higher in the cohort with BBD than in SEER data: BC overall (standard incidence ratio [SIR], 1.95; 95% CI, 1.76-2.17), invasive BC (SIR, 1.56; 95% CI, 1.37-1.78), and DCIS (SIR, 3.10; 95% CI, 2.54-3.77). The SIRs increased with increasing BBD severity (1.42 [95% CI, 1.19-1.71] for NP, 2.19 [95% CI, 1.88-2.54] for PDWA, and 3.91 [95% CI, 2.97-5.14] for AH), comparable to surgical cohorts with BBD. Risk also increased with increasing lesion multiplicity (SIR: 2.40 [95% CI, 2.06-2.79] for ≥3 foci of NP, 3.72 [95% CI, 2.31-5.99] for ≥3 foci of PDWA, and 5.29 [95% CI, 3.37-8.29] for ≥3 foci of AH). Ten-year BC cumulative incidence was 4.3% for NP, 6.6% for PDWA, and 14.6% for AH vs an expected population cumulative incidence of 2.9%., Conclusions and Relevance: In this contemporary cohort study of women diagnosed with BBD in the percutaneous biopsy era, overall risk of BC was increased vs the general population (DCIS and invasive cancer combined), similar to that in historical BBD cohorts. Development and validation of pathologic classifications including both BBD severity and multiplicity may enable improved BC risk stratification.

Importance: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown., Objective: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC., Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022., Interventions: Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2)., Main Outcomes and Measures: Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%., Results: All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%])., Conclusions and Relevance: This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable., Trial Registration: ClinicalTrials.gov Identifier: NCT02860000.

Importance: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS)., Objective: To examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response., Design, Setting, and Participants: The study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence., Interventions: Participants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery., Main Outcomes and Measures: The presence of DCIS and EFS, DRFS, and LRR., Results: The study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS., Conclusions and Relevance: The analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS., Trial Registration: ClinicalTrials.gov Identifier NCT01042379.

Importance: The 1996 Tonsillectomy and Adenoidectomy Inpatient Guidelines of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Pediatric Otolaryngology Committee recommended that children younger than 3 years be admitted following tonsillectomy. Recommendations for hospital observation were not included as a key action statement in the 2011 AAO-HNS Clinical Practice Guidelines for Tonsillectomy in Children., Objective: To examine the association between posttonsillectomy complication rate and the age and weight of the child at the time of surgery., Design, Setting, and Participants: This was a multicenter case series study with medical record review of 2139 consecutive children ages 3 to 6 years who underwent tonsillectomy at 1 tertiary care academic center and 5 acute care centers in New Orleans, Louisiana, between 2005 and 2015. Children with moderate to severe developmental delay, bleeding disorders, and other major medical comorbidities were excluded., Main Outcomes and Measures: Complications examined included respiratory distress, dehydration requiring intravenous fluids, and bleeding., Results: Of the 2139 patients, 1817 met inclusion criteria. A total of 1011 (55.6%) were male. The mean (SD) age at the time of the procedure was 46 (14) months (range, 12-72 months). The mean weight at the time of the procedure was 17 (5) kg (range, 9-43 kg). A total of 95 patients (5.2%) had a postoperative complication. Of the 455 children younger than 3 years in the study, 32 (7.0%) had complications compared with 63 (4.6%) of the 1362 patients 3 years or older. The odds of having a complication in children younger than 3 years was 1.5 times greater than it was in children 3 years or older (odds ratio [OR], 1.56; 95% CI, 1.00-2.42). When examining total complications, children younger than 3 years were more likely to experience a complication within the first 24 hours after surgery than children 3 years or older (25% vs 9.5%; OR, 3.17; 95% CI, 1.00-10.11). The children admitted to the hospital had a greater risk of complication than those treated as an outpatient, independent of age (6.9% vs 93.0%; OR, 3.49; 95% CI, 2.0.18-6.05). No association between weight and complications was found on logistic regression (area under the curve = 0.5268; P = .66)., Conclusions and Relevance: Healthy children younger than 3 years may be at an increased risk for complication following tonsillectomy. Those children may also be at increased risk for complications within the first 24 hours after surgery compared with children 3 years or older. Our data suggest that complications are independent of weight in these patients. In our cohort, those patients selected for overnight observation were associated with an increased number of adverse events following tonsillectomy, suggesting that clinician judgment is crucial in determining which patients are safe for outpatient tonsillectomy.

Importance: Limited information exists about the short-term morbidity of parotidectomy in children. This information is important when counseling parents and planning treatment for children with parotid masses., Objective: To examine 30-day perioperative outcomes after parotidectomy in the pediatric population., Design, Setting, and Participants: A prospective case series of 87 pediatric patients who underwent parotidectomy from January 1, 2008, to June 30, 2015, performed by 2 pediatric head and neck specialists in a tertiary care pediatric hospital., Main Outcomes and Measures: Thirty-day perioperative complications, postoperative facial nerve function, reoperation rates, and readmission rates were the main outcome measures. Secondary outcome measures were operative time and length of stay., Results: Ninety parotidectomies (71 superficial and 19 total) were performed in 87 patients (48 male and 39 female). Mean age at operation was 8.3 years. Eighty-five of the cases (94%) were performed for benign disease. Mean operative time was 4.09 hours (range, 1.58-10.43 hours) and mean length of stay was 2.24 days (range, 0.97-4.33 days). Immediate postoperative facial weakness was observed in 32 cases (36%); 10 of these cases (31%) involved the upper branch and 29 (90%) involved the lower branch. Immediate postoperative paresis occurred more often after total parotidectomy vs superficial parotidectomy (11 of 19 [58%] vs 21 of 71 [30%]; P = .03) but was unrelated to the etiologic cause of the patients' parotid disease. Thirty of 32 cases (94%) of facial nerve weakness were transient, and the mean time to resolution was 61 days. Eleven complications (12%) other than facial nerve weakness occurred during the 30-day postoperative period. Three patients (3%) required a return to the operating room for hematoma or wound dehiscence. One patient (1%) required readmission in the 30-day postoperative period for contralateral parotitis., Conclusions and Relevance: We observed a low rate of 30-day perioperative complications as a result of superficial or total parotidectomy for pediatric parotid disease. Major adverse events included return to the operating room and 1 wound infection. Only 1 patient required readmission. Transient weakness of the facial nerve is relatively common, observed more often in the lower division, and can be expected to resolve in most patients by an average of 2 months.

Importance: Human papillomavirus (HPV) is a preventable disease that plays a causative role in a significant proportion of malignant neoplasms of the head and neck. Inner-city populations are at risk for HPV-related oropharyngeal cancer, are least likely to receive HPV vaccination, and report a lack of information regarding HPV., Objective: To determine whether an educational platform affects knowledge, attitudes, and practices regarding HPV vaccination in an inner-city community., Design, Setting, and Participants: This prospective cohort study, conducted from March 1 to December 31, 2014, surveyed 128 participants at multiple inner-city community centers regarding their knowledge of, attitudes toward, and practices regarding HPV vaccination before and after a brief educational presentation. No eligible individuals refused to participate in the educational session. Surveys were excluded from analysis if they were incomplete., Interventions: Participants completed two 20-question surveys separated by a 15-minute educational session on HPV-related disease, including a short PowerPoint presentation., Main Outcomes and Measures: Presence of statistically significant differences in survey scores before and after the educational session., Results: Eighty-six participants met eligibility criteria (61 male [70.9%]; 68 with a high school education [79.1%]). Baseline knowledge of HPV, its causal association with cancer, and the existence of a vaccine against HPV were poor: of a total composite score of 20, the mean knowledge score before the educational session was 9.69. Participants' self-rated knowledge regarding HPV disease and vaccination improved significantly as a result of the educational session; the absolute increase in mean knowledge composite score from before the educational session to after the session was 3.52 (17.6%) (95% CI, -2.87 to 9.92; P < .01). Attitudes regarding government involvement in vaccination did not change as a result of the educational session (composite attitudes score before the educational session, 16.57 of 28; score after the session, 15.22; P = .98). Participants' intent to vaccinate their children increased significantly following the educational presentation: before the presentation, 34 respondents (40%) intended to have their children vaccinated; after the presentation, 60 (70%) intended to do so (P = .002)., Conclusions and Relevance: Lack of knowledge regarding HPV vaccination and unwillingness to undergo vaccination contribute to low rates of HPV vaccination within urban populations. Community-based educational sessions successfully teach the link between HPV and various cancers, provide information regarding the risks and benefits of vaccination, and increase participants' willingness to vaccinate their children against HPV. Attitudes regarding government involvement in health programs are resistant to change.