bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of tumor progression during neoadjuvant chemotherapy in breast cancer
Authors: Caudle A. S. , Gonzalez-Angulo A. M. , Kelly H. K. , Liu P. , Pusztai L. , Symmans W. F. , Kuerer H. M. , Mittendorf E. A. , Hortobagyi G. N. , Meric-Bernstam F.
Published: August 2020

603

Background: While most patients with breast cancer receiving neoadjuvant chemotherapy (NCT) have some tumor response, a small proportion progress during therapy. Although several groups have looked at markers for response, none have specifically evaluated markers for progression. The goal of this study was to identify predictors of tumor progression during NCT with the ultimate aim of identifying the subset of patients who may benefit from a first-line surgical approach. Methods: Patients with stage I-III breast cancer treated at a single comprehensive cancer center with NCT between 1994 and 2007 were included. Data was obtained from a review of medical records of patients in a prospectively acquired database. Chemotherapy consisted of anthracycline and/or taxane-based regimens. Statistical analysis was performed using univariate and multivariate analysis with logistic regression analyzing patients with some response or stable disease versus patients with progression. Results: 1928 patients received NCT: 1762 (91%) had some response (minor, partial, or complete), 107 (6%) had stable disease (SD), and 59 (3%) progressed (PD) on at least one NCT regimen. Clinical factors that correlate with PD in univariate analysis include presenting T (T3 vs T1, p = 0.002) and AJCC stage (stage IIIb/IIIc vs I/II/III, p = 0.02). Predictive histopathological features were high tumor grade (p = 0.005), high Ki-67 (p = 0.002), and negative ER and PR status (p < 0.0001 and p = 0.0006). Patients with PD were more likely to be treated with a taxane (79% vs 88%, p = 0.04). In the post-NCT surgical specimens, patients with PD were more likely to have higher T stage (p < 0.0001), lymph node metastasis (p = 0.01), and lymphovascular invasion (p = 0.02). On multivariate analysis, pre-NCT T status and ER status were the most important predictors of progression. Conclusions: Pre-treatment characteristics predictive of disease progression on NCT include advanced tumors, high tumor grade, high Ki-67, and negative ER or PR status. Since high grade and negative ER/PR status have also been associated with a complete pathologic response to NCT, there is a clear need for more specific molecular predictors of response and progression in order to select appropriate treatment in these patients.

No significant financial relationships to disclose.
Multiagent concurrent chemoradiotherapy (MACCRT) and gefitinib in locoregionally advanced head and neck squamous cell cancer (HNSCC)
Authors: Rodriguez C. P. , Adelstein D. J. , Saxton J. P. , Rybicki L. A. , Lorenz R. R. , Wood B. G. , Scharpf J. , Lee W. T. , Ives D. I.
Published: August 2020

6037

Background: In patients (pts) with stage III-IV HNSCC, MACCRT has led to excellent locoregional control. Distant metastases (DM) are now the most common cause of treatment failure. This phase II study tested whether the oral EGFR inhibitor gefitinib (G) added to our Cleveland Clinic MACCRT regimen would decrease DM and improve survival. Methods: Between 4/03 and 9/07, 60 previously untreated pts with stage III-IV (M0) HNSCC, and a performance status of <1 were enrolled on this study. Pts received hyperfractionated radiation (72–74.4 Gy at 120cGy bid) and concurrent chemotherapy with cisplatin (20 mg/m2/day) and fluorouracil (1,000 mg/m2/day), both given as 96-hour continuous IV infusions during weeks 1 and 4. G 250 mg daily was begun on day 1 of the radiation and continued for 2 years. The results were retrospectively compared to our previous study of 44 pts treated with the same MACCRT regimen without G between 1/96 and 9/00. Results: The study population included a preponderance of Caucasian (97%) males (88%) with stage IV (80%) oropharynx tumors (68%), and with a median age of 58 (range 24–75) years. Patient and tumor characteristics were similar to the non-G treated historical cohort. When comparing the G vs. non-G treated pts, acute toxicities including transient renal dysfunction (28% v. 5% p = 0.002) and all-cause re-hospitalization (83% v. 64%, p = 0.022) were worse. Myelosuppression was similar. G-specific toxicity included > grade 1 rash in 60% and diarrhea in 35%. There were 5 deaths during treatment in the G group v. one in the non-G group (p = 0.19). Only a projected 44% of pts will complete the 2-year course of G. With a median follow-up in this trial of 37 (range 13–64) months, 3-year Kaplan-Meier outcome estimates do not differ between the study and the historical cohorts. Local control without surgery is 80% v. 88% (p = 0.21), DM control is 86% v. 76% (p = 0.19), freedom from recurrence is 72% v. 71% (p = 0.79), and overall survival is 67% v. 68% (p = 0.63) respectively. Conclusions: The addition of G to our MACCRT regimen was difficult for pts to complete. It did not improve any measured outcome and was associated with increased toxicity when compared to historical controls.

[Table: see text]
Gefitinib for advanced cutaneous squamous cell carcinoma of head and neck: Phase II trial
Authors: Weber R. S. , Lustig R. A. , El-Naggar A. K. , Rosenthal D. I. , Kim E. S. , Wistuba I. I. , Tang X. M. , Wan F. F. , Taylor S. A. , Glisson B. S.
Published: August 2020

6054

Background: Advanced head and neck cutaneous squamous cell carcinoma (HN cSCC) carries a 30–40% risk of death by 2 years with standard therapies. Small molecular inhibitors of the epidermal growth factor receptor (EGFR) may have an impact. We evaluated gefitinib as an induction therapy in a high-risk patient (pt) group prior to definitive therapy to determine efficacy, toxicity and feasibility. Correlative studies of EGFR expression, gene mutation, and ploidy may serve as predictors of response. Methods: Eligible pts must have HN cSCC >2cm, regional nodal metastases, peri-neural invasion, or deep invasion and must be candidates for definitive locoregional therapy with surgery and/or radiation. Two 30-day induction cycles of gefitinib (250mg po qd). Pts are assessed clinically after 15 days. If a response is noted, gefitinib is continued. For pts with stable disease, the dose is escalated to 500mg qd. Pts with progressive disease go off study. Total and phosphorylated (p) EGFR protein expression was analyzed by immunohistochemistry and gene copy number by fluorescent in-situ hybridization (FISH). Results: To date, 23 pts are enrolled and 22 are evaluable for responses and toxicities. Complete responses (CR) were noted in 3 pts, partial response (PR) 7, stable disease (SD) 5, and progressive disease (PD) 7 (68.1% response per RECIST criteria). Minimal side effects are associated with gefitinib (cutaneous and GI related). EGFR and p-EGFR protein overexpression were observed in 5 of 11 (45.5%) pts tested thus far. Eight of the pts were FISH negative with respect to EGFR gene expression: 7 had low trisomy and 1 had low polysomy. Two were FISH positive and expressed high polysomy. No gene amplification was detected. No statistically significant correlations between EGFR gene or protein expression and responses to administration of gefitinib were found at this point in the analysis. Protein and gene expression analyses are ongoing. Conclusions: The preliminary results from our study are encouraging and suggest that anti-EGFR therapy may have a role in the adjuvant treatment of HN cSCC. Correlative studies may help identify pts most likely to respond to anti-EGFR therapy.

No significant financial relationships to disclose.
Phase II trial evaluating imatinib (I) in patients (pts) with anaplastic thyroid carcinoma (ATC)
Authors: Ha H. T. , Lee J. S. , Urba S. , Koenig R. J. , Sisson J. , Giordano T. , Worden F. P.
Published: August 2020

6057

Background: There is no standard treatment for ATC. Response to doxorubicin ranges between 5–22%; median survival ranges between 3–6 months. Affymetrix gene chip showed PDGFR overexpression in ATC. In p53 mutated/deficient ATC cell lines, c-Abl is overexpressed, and selective inhibition of c-Abl resulted in cytostatic effect. (I) inhibits tyrosine kinase activity of Bcr-Abl and PDGF. We hypothesize that ATC that overexpress PDGFR or Abl will respond to (I). Methods: Pts ≥ 18 years old with histologically confirmed ATC, overexpressing PDGFR or c-Abl by immunohistochemistry who had measurable disease were eligible. Pts must have Zubrod performance status ≤ 1, and adequate hepatic and renal function. Prior chemotherapy, chemoradiation, radiation therapy, or surgery must have been completed at least 28 days prior to registration. (I) was administered at 400mg orally twice daily without drug holiday. Response to treatment was assessed after every 8 weeks. Pts with complete response (CR)/partial responses (PR)/stable disease (SD) were treated until disease progression. The study was terminated early due to poor accrual. Results: From February 2004 to May 2007, eleven pts from our institution were enrolled and were started on (I) (6 men; 5 women) with a median age of 63 years (ranges 53–80). At baseline, 4/11 pts (36%) had locoregional disease, 5/11 pts (45%) had distant metastases, and 2/11 pts (18%) had both. Nine pts had prior chemoradiation, and 7 pts had thyroidectomy. Out of 11 pts, 8 were evaluable for response; 3 were excluded for lack of follow up radiological evaluation. The overall responses at 8 weeks were CR 0/8; PR 2/8 (25%); SD 4/8 (50%); and PD 2/8 (25%). The median time to follow up was 26 months (ranges 23–30 months). The estimate of 6-month progression free survival was 27% (95% CI, 7–54%). The estimate of 6-month overall survival was 46% (95% CI, 17–71%). The most common G3 toxicity was lymphopenia in 45%; other G3 toxicities included edema (27%), anemia (18%), and hyponatremia (18%). There was no G4 or higher or treatment related death. Conclusions: (I) appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing pts with a rare malignancy at a single institution, investigation of (I) in ATC may be warranted in a multi-institution setting.

No significant financial relationships to disclose.
Phase II trial of sorafenib (bay 43–9006) in patients with advanced anaplastic carcinoma of the thyroid (ATC)
Authors: Nagaiah G. , Fu P. , Wasman J. K. , Cooney M. M. , Mooney C. , Afshin D. , Lavertu P. , Bokar J. , Savvides P. , Remick S. C.
Published: August 2020

6058

Background: Sorafenib (bay 43–9006) is an oral, small molecule tyrosine kinase inhibitor of the raf-1 protein kinase receptor, VEGFR2 and PDGFR-β with antiangiogenic properties. We are conducting an open label, phase II study of sorafenib in patients with biopsy-proven ATC to evaluate if its objective response rate is >20% and to further characterize its safety profile. Methods: Patients with progressive ATC, after cytotoxic chemotherapy with or without radiation were given sorafenib, on a fixed dosing schedule of 400 mg PO bid on 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or patient refusal. Response was evaluated every 8 weeks with body scans using RECIST criteria. We employed a 2-stage study design: if none of the first 18 patients respond the study is terminated, otherwise accrual is continued to a total of 36 patients at which point if ≤3 of the patients respond, the treatment option is rejected. Results: To date 16 patients (10 male) have enrolled in the study. Median age is 55 years; with (range 28–79). Median time on study is 2 months. Median number of cycles given is 2 (range 1–27). Two of 15 evaluable patients (13%) have partial response (PR) and 4 patients (27%) have stable disease (SD). Median duration of PR/SD is 5.1 months (range 1–24.7months). Median time to progression is 1.5 months. Median duration of survival is 3.5 months (range 1–26 months). All patients at time of reporting are deceased. Most common toxicities are lymphopenia (81%) and fatigue (62%). Grade 3 toxicities include lymphopenia (25%), rash with desquamation, weight loss, and chest pain (all 12%). Grade 4 toxicities include dyspnea (6%) and lymphopenia (6%). There has been no significant cardiovascular toxicity. One patient died on study with rapidly progressive disease. Conclusions: Sorafenib demonstrates objective tumor response in the first 15 evaluable and pretreated patients with advanced ATC. This trial is ongoing and supported in part by NIH grant nos. CA62502.

[Table: see text]
Coronary heart disease (CHD) and stroke risk associated with breast cancer (CA) irradiation (RT) based on patient baseline cardiac risk profile
Authors: Chen R. C. , Hankinson S. E. , Harris J. R. , Chen W. Y.
Published: August 2020

606

Background: Although population-based studies showed increased fatal and non-fatal CHD risk associated with left-sided breast RT, presumably from “bystander” cardiac dose, how RT interacts with underlying cardiac risk factors to influence these outcomes is unclear. We used data from the Nurses’ Health Study (NHS) to examine the effect of RT on fatal and non-fatal CHD, stratified by baseline CHD risk factors. Methods: 121,700 female registered nurses enrolled in 1976. Ongoing biennial medical information collected includes CHD risk factors, cardiac events, CA diagnosis, treatment, and cause of death. Medical record review confirms CA diagnoses and cardiac events. Numerous publications establishing the causes of CHD and cardiac mortality have resulted. 3863 women have developed stage 0-III breast CA and received RT. Proportional hazards models were used to assess the association between left-sided RT and CHD development, after adjusting for age and CHD risk factors. Results: During 38,538 person-years follow-up after breast CA diagnosis, 126 CHD events developed. In age- adjusted univariate models, left-sided RT (vs. right-sided), diabetes, parental CHD before age 60, and smoking were significantly associated with fatal and non-fatal CHD; aspirin and postmenopausal hormone use were protective. Crude incidence of CHD after left-sided RT was 396 per 100,000 person-years, compared to 259 after right-sided RT. A multivariable model that accounted for the above plus other risk factors (hypertension, hyperlipidemia, physical activity, alcohol use) and stage showed that left-sided RT was independently associated with CHD development (rate ratio, RR 1.5, 95% CI 1.1–2.2). Stratified analyses by the presence of hypertension, hyperlipidemia, and smoking showed similar RR from left-sided RT in all subgroups. In contrast, left-sided RT did not affect risk of stroke in multivariable analysis (RR 0.7, 95% CI 0.4–1.2). Conclusions: Left-sided RT is an independent CHD risk factor, and indicates a similar RR to patients in all subgroups of baseline CHD risk, though absolute risk increase was larger in women who had additional risk factors. Breast CA survivors after left-sided RT may need long-term cardiac follow-up and management.

No significant financial relationships to disclose.
The incidence and impact of comorbidity on survival and selection of initial treatment in elderly patients (pts) with head and neck cancer (HNC)
Authors: Ghobadi A. , Athar M. , Dowell J.
Published: August 2020

6065

Background: Comorbidity has been shown to be a determinant of survival and treatment selection in various cancers including HNC. Higher comorbidity index is associated with higher utilization of non-curative intent treatment. Methods: In this retrospective study we analyzed 182 consecutively treated HNC pts >65 years (y) old at the Dallas VAMC from January 2000 through June 2007. Comorbidity was assessed with the Charlson Comorbidity Index (CCI). Treatment was classified as curative intent versus non-curative intent. The goals were 1) to demonstrate burden of comorbidity and 2) to demonstrate the impact of comorbidity on overall survival and selection of initial treatment in elderly HNC pts. Results: Pts characteristics: 100% male; 80% white, 19.5% Black, 0.5% Hispanic; median age 72y (range 65–87); 3% stage 0, 26% stage I, 20% stage II, 18% stage III, 30% stage IV, 2% unknown; primary site - 30% oral cavity, 4% hypopharnyx, 22% oropharynx, 38% larynx, 4% other, 1% unknown; treatment - 26% radiation only, 44% surgery (S), 21% chemoradiation (CR), 9% no treatment; Median CCI -2 (range 0–11); 61% had CCI score 0–2 and 39% had CI score > 3. Median overall survival was 883 days (SE 19.31 days). Rate of curative vs. non-curative intent treatment was 80% vs. 20% respectively. Pts with CCI score 0–2 had a non-significant higher rate of curative intent treatment than pts with CCI score > 3 (83.8% vs. 74.6% p = 0.13). In multivariate analysis including CCI, age, race, alcohol use, primary site, treatment, and stage, only advanced clinical stage had significant prognostic importance (HR 1.66; 95% CI, 1.29 to 2.14; p < 0.0005). The HR for CCI was 1.11 (95% CI, .99–1.24; p = 0.08). In separate multivariate analyses of pts treated with S and pts treated with CR, CCI was not a significant predictor of survival with HR of .88 (95% CI, .69–1.11; p = 0.29) and 1.13 (95% CI, .83–1.53; p = 0.44), respectively. Conclusions: In our population of elderly HNC pts, CCI and age had no significant impact on survival or selection of curative intent treatment. Additional study is required to better define appropriate candidates for curative intent treatment in this population.

No significant financial relationships to disclose.
Longitudinal oncology registry of head and neck carcinoma (LORHAN): First report of outcomes
Authors: Curran W. J. , Chen A. Y. , Garden A. S. , Harari P. , Murphy B. A. , Wong S. , Bellm L. A. , Schwartz M. , Dawson D. , Ang K. K.
Published: August 2020

6071

Background: Registries can be invaluable for describing patterns of care and outcomes for a population of patients (pts). We report the initial survival findings from LORHAN, a prospective, longitudinal, observational national registry of head and neck carcinoma (HNC) pts. Methods: Pts are eligible for LORHAN if they have newly diagnosed HNC, are scheduled to receive radiotherapy (RT) or drug therapy, are ≥18 years of age and have provided written informed consent. Data are entered in the registry electronically and transferred via Secure HTTP protocols. Patient confidentiality is strictly maintained. Pts are followed from time of initial diagnosis and for a minimum of 2 and up to 10 years. When information is complete and has been verified and signed off by the investigator, a record is locked. Only locked records are summarized and reported. Results: 2,354 pts have been enrolled in LORHAN since Dec. 2005. Of these, 1,326 pts have completed initial cancer treatment and have locked records. 1- and 2-year follow-up data are available for 583 and 56 pts, respectively. Baseline characteristics were similar between settings, except that pts treated at academic centers were significantly younger (58 vs. 62 years of age), had poorer performance status (mean Zubrod: 0.9 vs. 0.7), had fewer laryngeal tumors (17% vs. 27% of pts) but more oropharyngeal tumors (42% vs. 37% of pts) and presented with more advanced disease (stage IV: 70% vs. 48% of pts) compared to pts treated in community. Treatment did not differ by setting. Treatment and survival data are shown below. Conclusions: LORHAN demonstrates it is feasible to collect more detailed information about patient and tumor features and treatment other than surgery. Changes in the pattern of care and survival findings are expected to emerge as newer regimens, including IC and targeted agents, are incorporated more broadly into clinical practice, and data in LORHAN matures.

[Table: see text]

[Table: see text]
Reporting of endpoints and tracking of failures in randomized trials of radiotherapy or concurrent chemoradiotherapy for locally advanced head and neck squamous cell cancer (LA-HNSCC)
Authors: Le Tourneau C. , Michiels S. , Gan H. , Siu L.
Published: August 2020

6072

Background: Due to their anatomical complexity, the interactive effects of multiple treatment modalities, the difficulties in differentiating scar tissues versus residual disease and second cancers versus tumor recurrence, LA-HNSCC represent a challenging disease for the reporting of endpoints and the tracking of failures. Methods: We retrieved all randomized trials that began accrual on or after 1978, and enrolled previously untreated nonmetastatic HNSCC patients receiving primary (chemo)radiotherapy. The reporting of endpoints and the tracking of failures in these trials were analyzed. Failures were defined as events meeting a pre-specified endpoint definition. Results: Forty trials involving 13,892 patients fulfilled our inclusion criteria. A total of 125 endpoints were identified: primary versus secondary = 34:91, survival-based (e.g., overall survival [OS]) versus surrogate (e.g. locoregional control [LRC]) = 47:78. In 6 trials, no primary endpoint was identified. LRC and OS accounted for 70% of primary endpoints. All but one trial reported at least one secondary endpoint, with a median of 2 per trial (range: 0–5), and as many as 17 different types of secondary endpoints were reported. Among 72 endpoints tracking locoregional failures, 21/72 (29%) did not define locoregional failure, while 46/72 (64%) specified the absence of complete response as a failure. Whether salvage surgery or elective node dissection was performed or not was reported in less than half of the trials. Furthermore, it was usually not specified if residual disease found during these procedures would account for failure or not. The means (i.e. clinical and/or radiological examinations) to ascertain failures and the protocol-specified timing to track failures were reported in 41% and 67% of surrogate endpoints, respectively. The tracking of other types of failure beyond the first failure is not reported by any of the trials. The reporting of second cancers was found in 15/40 (38%) trials, whereas the duration of follow-up was quantified in 31/40 (78%) trials. Conclusions: These results demonstrate the vast heterogeneity in endpoint reporting and tracking of failures in clinical trials of LA-HNSCC.

No significant financial relationships to disclose.
Association between human papillomavirus (HPV) status with serum cytokine and angiogenic factor (CAF) profile after induction chemotherapy in head and neck squamous cell carcinoma (HNSCC)
Authors: Byers L. A. , Heymach J. V. , Lee J. J. , Lin H. , El-Naggar A. K. , Papadimitrakopoulou V. , Lippman S. M. , Hong W. K. , Holsinger F. C. , Kies M. S.
Published: August 2020

6081

Background: Human papillomavirus has been implicated in the development of head and neck squamous cell carcinoma and is associated with a more favorable clinical outcome. Previously, we identified a serum hypoxia signature associated with HNSCC progression (Byers et al, Proc ASCO. 2008). We investigated the association between HPV status, serum biomarkers, and clinical outcome in patients treated with induction chemotherapy. Methods: 47 previously untreated patients with locally advanced nodal disease (T0–4, N2b/c/3, M0) received 6 weekly cycles of paclitaxel (135 mg/m2), carboplatin (AUC 2), and cetuximab (400 mg/m2 week 1; 250 mg/m2 weeks 2–6) followed by definitive local therapy. 46 (98%) patients had a complete or partial response to induction chemotherapy (Kies et al, Proc ASCO. 2006), and 6 have had tumor progression (PD) after a minimum follow-up of two years. Formalin fixed biopsies were available for HPV testing by in situ hybridization with non-radioisotopic chromogen for 25 patients (including 5/6 with PD). 38 CAFs were measured by multiplex bead assay before and during treatment. Results: 12/25 patients were HPV-positive, all male and six were never smokers; of the 13 HPV-negative patients, four were male and three were never smokers. Among those with available data, all 5 patients with PD were HPV-negative (p = 0.02). There were four study deaths, all in the HPV-negative group. Overall survival was superior in HPV-positive patients (p = 0.04). There was no significant association between HPV status and serum CAF markers. However, among HPV-negative patients, PD was associated with the CAF hypoxia signature (5/8 patients with the hypoxia signature progressed versus 0/5 signature-negative). Of the individual CAFs, osteopontin was significantly elevated in all HPV-negative patients with PD. Conclusions: HPV positivity was associated with a longer progression-free survival and overall survival. Among HPV-negative patients, only those with a serum hypoxia signature had disease progression. These data suggest that the combination of HPV status and CAF profiling may identify patients at risk for relapse after sequential therapy.

No significant financial relationships to disclose.
The clinical impact and outcomes of immunohistochemistry-only metastases in breast cancer
Authors: Pugliese M. S. , Stempel M. M. , Patil S. M. , Hsu M. , Cody H. S. , Morrow M. , Gemignani M. L.
Published: August 2020

613

Background: Modern surgical and pathologic techniques can detect small volume axillary metastases in breast cancer. The clinical significance of these metastases was evaluated in comparison to patients with negative sentinel lymph nodes (Neg-SN). Methods: Retrospective database review from 1997 through 2003 for eligible patients with unilateral breast cancer and no history of significant non-breast malignancy identified 232 patients with sentinel lymph node (SLN) metastases identified only by immunohistochemical stains (IHC-SN). They were compared to 252 Neg-SN controls selected at random from the same database population. Statistical analysis was performed with 2-sample tests, Kaplan-Meier, and Cox regression methods. Results: IHC-SN patients had worse prognostic features and received more systemic therapy than controls (Table). Age and ER status were similar. In 123 IHC-SN patients treated with axillary dissection (ALND), 16% had macrometastases in the non-SLNs. Only one axillary recurrence occurred in the group of IHC-SN patients without ANLD (n=109). With median follow up of 5 years (range 0.01–12.0), 28 recurrences and 25 deaths occurred. There were no differences between cases and controls for recurrence-free survival (RFS) or overall survival (OS) both by univariate and multivariate models that included variables such as age, tumor size, chemotherapy and hormone therapy [HR 0.99 (95%CI 0.43–2.28, p=0.99) for RFS, HR 2.06 (95%CI 0.79–5.35) p=0.14 for OS]. In IHC-SN patients treated with ALND, patients with positive non-SLNs (n=20) tended to have worse RFS than those with negative non-SLNs (n=103) [RFS 89% vs. 97% at 5 yrs (p=0.06)]. Conclusions: A significant number of IHC-SN patients had a macrometastasis identified at ALND. In patients not undergoing dissection, axillary recurrence was a rare event. However, failure to identify additional metastases by omitting ALND may result in understaging and inadequate systemic treatment in some patients.

[Table: see text]

No significant financial relationships to disclose.
Determinants of therapeutic delays and their impact on axillary node involvement in operable invasive breast cancer (BC) patients (pts)
Authors: Dionysopoulos D. , Berrada N. , Chevalier J. , Rimareix F. , Mathieu M. , Balleyguier C. , Gouy S. , André F. , Vielh P. , Delaloge S. , Delaloge S.
Published: August 2020

615

Background: International guidelines recommend rapid diagnostic and therapeutic procedures for suspect breast lesions. However, the impact of the interval between screening and treatment (trt) (STI) on the severity of the disease remains unclear. We explored the potential impact of STI on a surrogate of survival, axillary nodal involvement (N+), among 1,000 recently diagnosed BC pts, as well as the causes of potential delays. Methods: We collected complete data of prospectively recorded community BC cases in a single regional cancer center between January 1, 2005, and October 10, 2007. Pts were eligible if they i. had a final diagnosis of invasive BC ii. were operated as first trt for BC, iii. had no history of other previous malignancy within the past 5 year period. Logistic regression analyses (SAS) were used to determine factors predictive of N+ and those influencing intervals between first description of the lesion and first therapeutic surgery (STI). Candidate factors included socio-economic variables (marital status, occupation, county of living, country of birth), personal and familial medical history parameters, as well as BC characteristics. Results: 990 pts met the inclusion criteria and had full data available. Med age: 59 years, BI-RAD ACR3/4/5: 2/41/55%, med pathological tumor size (pT): 16 mm (2–100), N+: 41%, med delay between first description of the lesion and surgery: 67 days. Factors predicting longer STI were: Birad ACR<5 vs 5 (p = 0.0004), not palpable lesion vs palpable (p = 0.01), microcalcifications vs solid lesion (p = 0.0008), presence of important comorbidities (p=.04), single life vs couple (p = 0.001). However, STI had no effect on N+: med STI was 68 days in N- vs 66 days in N+ pts. Factors predictive of N+ were lymphovascular invasion (LVI) (p=.0001) and pT (p = 0.0001), while age, social conditions, screening mode, per-cutaneous biopsy vs FNAC, grade, HR and HER-2 status, had no effect. Among pts with grade III BC, LVI (p = 0.0001) and pT (p = 0.02) were the sole predictors of N+ as well. Conclusions: This study identifies for the first time factors able to negatively influence STI of women with invasive BC. However, longer STI does not appear to influence axillary nodal invasion, even in pts with high grade BC.

No significant financial relationships to disclose.
Sentinel and axillary nodes of the breast distinguished from those of the arm by 3D-CT lymphography and selectively dissected by endoscopic surgery
Authors: Yamashita K. , Haga S. , Shimizu K.
Published: August 2020

616

Background: In early breast cancer, the presence of metastasis in axillary lymph nodes (AN) is an important factor in prognosis and further treatment. However, AN dissection causes many complications such as contracture of shoulder joint, lymph edema, and paralysis of upper extremities. Sentinel node (SN) biopsy provides us valuable information about no need to dissect AN for node-negative patients. However, on node-positive patients, the conventional AN dissection has been performed. 3D-CT lymphography (LG) can show the precise individual lymphatic flow not only from the breast tumor to SN but also from SN to venous angle, which means breast lymphatic channel. We applied 3D-CT LG to distinguish them from the arm channel to avoid any arm complications. Methods: 3D-CT LG was performed on the day before surgery to mark SN on the skin. Above the tumor and near the areola and the arm pit, 2 ml of Iopamidol 300 was injected subcutaneously. Images of 16-channel multidetector-row helical CT scan were taken at 1, 3, and 5 min after injection. They were reconstructed to produce a 3D image of lymph ducts and lymph nodes. SN biopsy and AN sampling were performed by dye-staining method using endoscopy. Results:We performed SN biopsy with 3D-CT LG on 160 patients. 3D-CT LG clearly showed the precise lymphatic flow from the tumor to SN. It can show SN at only one min after injection. But following up to 5 min, we can follow the lymph ducts beyond SN into the second to the fifth node groups toward the venous angle with complex plexus, observed in the surrounding anatomical architecture. Detection rate was 100% for SN; 80% for the third group; and 30% for the fifth group. The arm lymph flow was distinguished by the connections between the breast and the arm flow, observed 39% and 71% in the fourth and the fifth group. SN was shared from between the breast and the arm in 5 patients (3.1%). They complained arm edema only by SN biopsy. We can distinguish and sample AN drained from the breast, guided by 3D-CT LG and dye-staining using endoscopy. Conclusions:By 3D-CT LG, we can recognize the accurate and more precise lymph flow in the surrounding anatomical architecture. It helps us easily to pursuit lymph flow and to remove SN and AN from the breast selectively using endoscopic surgery.

No significant financial relationships to disclose.
Surgical practice patterns following NCCTG N0338 “Phase II trial of docetaxel and darboplatin administered every two weeks as induction therapy for stage II and stage III breast cancer.”
Authors: Apsey H. , Roy V. , Pockaj B. , Northfelt D. , Sticca R. , Nikcevich D. A. , Mattar B. , Fitch T. , Perez E. A.
Published: August 2020

623

Background: Neoadjuvant therapy plays an important role in breast cancer treatment. Unlike patients who undergo surgery followed by adjuvant therapy,there are no established guidelines for surgical management following neoadjuvant therapy. Methods: Surgical practice patterns from 50 patients in N0338 “Phase II trial of Docetaxel and Carboplatin administered every two weeks as induction therapy for Stage II and Stage III breast cancer” were reviewed. The protocol did not mandate surgical therapy leaving the decision to the treating surgeon and patient. Results: 66% of patients underwent mastectomy (M) and 33% underwent breast conservation therapy (BCT). Three (9%) had immediate reconstruction. Eight (24%) underwent contralateral prophylactic M. Residual tumor size did not always impact primary surgical therapy. In the M group 4 (12%) had no residual disease, 15 (45%) < 2cm and 14 (42%) > 2cm; whereas, in the BCT group 1 (6%) had no residual disease, 12 (70%) < 2cm and 4 (24%) > 2cm. Axillary lymph node (ALN) staging varied tremendously. Three (6%) patients presented with palpable lymphadenopathy and proceeded to complete axillary lymph node dissection (ALND) after chemotherapy (CT). Fine needle aspiration (8) or core needle biopsy (7) of the axilla was performed in 15 (30%) patients before CT; 1 was negative and went on to have sentinel lymph node biopsy (SLNB) after CT; 14 (94%) were positive with 13 (86%) going on to ALND and 1 SLNB after CT. Five (10%) underwent SLNB prior to CT. One (20%) was positive and went on to have ALND after CT; 4 (8%) were negative and had no further ALN staging. A total of 19 (39%) had SLNB after neoadjuvant therapy; 13 (68%) were positive and underwent ALND; 1 SLNB failed; 2 of 5 that were negative underwent ALND with 1 having a positive lymph node. Ten (20%) underwent ALND with no pre-operative staging with 8 being positive for ALN metastases. Conclusions: Review of study data from multiple institutions revealed no consistent criteria in selection of surgical intervention for the breast tumor or ALN staging. There remains a need for further research in this area to establish standard practice guidelines. Support from NIH, sanofi-aventis, Amgen, Breast Cancer Research Foundation.

No significant financial relationships to disclose.
A novel approach for sentinel lymph node identification using fluorescence imaging and image overlay navigation surgery in patients with breast cancer
Authors: Tagaya N. , Abe A. , Tachibana M. , Kubota K.
Published: August 2020

624

Background: We reported a novel technique of sentinel lymph node (SLN) identification using fluorescence imaging of indocyanine green injection. Furthermore, to obtain safe and accurate identification of SLN during surgery, we introduce the image overlay navigation surgery and evaluate its efficacy. Methods: This study enrolled 30 patients with a tumor less than 3 cm in diameter. Initially we obtained three-dimensional (3-D) imaging from MD-CT by volume rendering of Osirix (Macintosh, Apple Inc.). It was projected on the patient’ operative field with the clear visualization of LN through the micro projector (Mpro 110, Sumitomo 3M). And then the dye of indocyanine green was injected subdermally in the areola. Subcutaneous lymphatic channels draining from the areola to the axilla were visible by fluorescence imagings (Photodynamic eye: PDE, Hamamatsu Photonics Co.) immediately. Lymphatic flow was reached after LN revealed on 3-D imaging. After incising the axillary skin on the point of LN mapping, SLN was then dissected under the guidance of fluorescence and 3-D imaging with adequate adjustment of sensitivity. Results: Lymphatic channels and SLN were successfully identified by PDE in all patients. And the sites of skin incision were also identical with the LN being demonstrated by 3-D imaging in all patients. The mean number of SLN was 2.8. The adjustment of sensitivity of PDE provide with the reduction of operation time. The image overlay navigation surgery was visually easy to identify the location of SLN from the axillary skin. There were no intra- or postoperative complications associated with SLN identification. Conclusions: This combined navigations of fluorescence and 3-D imagings revealed more easy and effective to detect SLN intraoperatively than fluorescence imaging alone. The operator's demand was satisfied with the introduction of image overlay navigation surgery consisted of augmented reality and mixed reality, and it may be practical in the various surgical fields.

No significant financial relationships to disclose.
Comparison of cytopathological and histological results in 1,053 fine-needle aspiration cytology of breast lesions performed in a one-stop clinic
Authors: Borget I. , Caramella C. , Balleyguier C. , Suciu V. , Uzan C. , Domont J. , Mathieu M. , Dromain C. , Delaloge S. , Vielh P.
Published: August 2020

635

Background: Fine-needle aspiration cytology (FNAC) has been used extensively in the diagnosis of breast lesions, but false-negative rates are a matter of concern. However, immediate onsite evaluation of breast lesions, combining FNAC results with clinical and radiological data allows to improve its diagnostic accuracy. The objective of this study was to evaluate the concordance between cytopathological and histological results in a large series of FNAC performed during the first 3-yr period of the dedicated one-stop clinic set up in our institution since 2004. Methods: We reviewed data of all patients (pts) seen in the one stop clinic between May 2004 and March 2007 who had a lesion diagnosed by FNAC and verified by histology. For benign lesions, histological verification of the lesion was mandatory each time there was no perfect concordance between clinico-radiologic features and FNAC results (such as benign FNAC but BI-RAD 5). Pts characteristics, radiological findings, cytopathological and histological (by per-cutaneous biopsy or surgery) results were extracted from the hospital computerized prospectively registered medical records. Results: A total of 1053 nodular breast lesions (mean size: 24±23 mm, BI-RAD ACR 1/2/3/4/5: 2/10/68/283/684) in 1015 pts (mean age: 59±13 years) were studied. FNAC was US-guided in 521 lesions (49.4%). FNAC classified lesions as malignant in 741 (70.4%), benign in 127 (12.0%), suspicious in 143 (13.6%), and unsatisfactory in 42 (4.0%) cases. Among definitive benign or malignant diagnosis, FNAC and histological results showed concordance in 840/868 (96.7%) cases (738 malignant and 102 benign cases). The numbers of false-negative and false-positive lesions were respectively 25/127 (19%) and 3/741 (0.4%). Among the 143 suspicious and 42 unsatisfactory specimens, 114 and 20 were malignant, respectively. Conclusions: FNAC performed in a one-stop clinic allows obtaining an immediate on-site diagnosis of breast cancer with a good concordance with histological results and low rate of unsatisfactory specimens. However, affirming benign lesion requires a multi-disciplinary team: whenever clinico-radiologic features and FNAC results are non concordant, histologic assessment is mandatory.

No significant financial relationships to disclose.
Identifying high-priority quality measures for breast cancer quality improvement using data from a nationally representative sample
Authors: Hassett M. J. , Weeks J. C.
Published: August 2020

6507

Background: We previously developed a simple, data-based strategy for selecting high-priority quality measures, and applied it to practice performance data from eight National Comprehensive Cancer Network (NCCN) centers to identify high-priority measures for breast cancer care. We now seek to evaluate the generalizability of these results by identifying which measures rank highly when practice performance data from a nationally representative sample, rather than a select group of cancer centers, are used. Methods: Using SEER-Medicare data, we assessed practice performance for 9933 women 65–70 years old diagnosed 1998–2002 with non-metastatic invasive breast cancer. For each quality measure, we determined the number of eligible patients, the number who did not receive recommended therapy, and the overall and target (goal) concordance values. We entered these data into a previously described algorithm to derive a numerical prioritization score for each measure. Spearman correlations were used to analyze comparisons between datasets. Results: We were able to evaluate practice performance relative to most (18/30; 60%) of the measures included in our original NCCN analysis. The absence of oral hormone therapy and DCIS pathology data in SEER-Medicare precluded assessments of quality relative to the remaining measures. The highest-ranking measures recommended chemotherapy for hormone-receptor positive tumors >1 cm, axillary node surgery and radiation after lumpectomy for stage I-II cancer, and no radiation after mastectomy for node-negative cancer <5 cm. Excluding hormone therapy and DCIS measures, the 6 highest-ranking measures in the SEER-Medicare and NCCN analyses were identical. Correlation between the prioritization scores for the 18 measures common to both datasets was 0.74. Conclusions: While SEER-Medicare data only include patients >65 and NCCN data only represent select institutions, information from both can be used to identify high-priority quality measures. That the same measures rank highly in both analyses suggests these are comprehensive, generalizable, policy ready national standards, and that this is a valid method for identifying high-priority quality measures.

No significant financial relationships to disclose.
Excessive false-positive errors in single-arm phase II trials: A simulation-based analysis
Authors: Tang H. , Foster N. R. , Grothey A. , Ansell S. M. , Sargent D. J.
Published: August 2020

6512

Background: The use of randomized phase II designs with an experimental arm and a standard-treatment control arm (R2PII) instead of a conventional single-arm design is clearly increasing in oncology. In practice, sample size, related cost issues, the belief that historical controls are adequate, and the use of a standard-treatment control arm in a phase II setting are frequently raised objections to R2PII trials. As the expense and complexity of definitive phase III trials increase, the ability of phase II trials to provide reliable and accurate results is critical. Methods: We investigated the ability of single arm vs R2PII trials to provide accurate conclusions by modeling variability in historical controls, patient outcome drifts independent of the tested therapy, and patient selection effects. Simulations compared R2PII and single-arm designs with binary endpoints under realistic parameters (e.g. alpha = beta = 0.10, historical control success rate = 20%, target success rate = 40%). Results: In the absence of variability in historical controls, estimated false positive and negative rates in both designs mirror the designated specifications. However, even in the presence of a modest drift effect in the population (mean 5% absolute shift in true control success rate), the false positive rate in single-arm designs is inflated two to three fold (to 20%-30%), while the R2PII retains the desired error rates. Greater confidence in historical controls in the single-arm design corrects only a small portion of the deviations. Increasing the sample size in each trial inflates the false positive error rate further to as much as 50%. Varying several sets of parameters gave similar results. Conclusions: In the presence of variability in historical controls, patient drift and/or selection effects, the false positive error rate of a single arm design is unacceptably high. In contrast, the R2PII design is reliable and robust despite the complexities in patient outcome drift and selection effects, and variability in historical control success rates. Given the rapid improvements in outcomes of many tumor types, the R2PII design should be the preferred method to evaluate novel agents in oncology in spite of the associated costs and the use of a reference control arm.

No significant financial relationships to disclose.
The effect of pretreatment patient characteristics on the allocation of treatment for advanced epithelial ovarian cancer
Authors: Chase D. M. , Fedewa S. , Chen A. , Ward E. , Brewster W. R.
Published: August 2020

6514

Background: While the standard treatment of advanced ovarian cancer is maximum cytoreductive surgery followed by adjuvant platinum-based chemotherapy, some patients are treated with neoadjuvant chemotherapy (NCT) with or without surgery and others receive no therapy. The primary objective of this study was to identify pre-treatment characteristics associated with receipt of non-standard treatment. Methods: 11,155 patients with clinical stage recorded were selected from 25,784 patients diagnosed between 2003 and 2005 from the National Cancer Database, a registry sponsored by the American Cancer Society and the American College of Surgeons. Among the 11,155 patients, 9,015 were stage IIIC or IV. 383 (4.25%) were excluded due to missing treatment information leaving 8,632 patients for the analysis. Evaluable variables included demographics, health insurance, Charlson co-morbidity score, area-level income and facility characteristics. Multivariate logistic regression analyses were performed to assess factors associated standard care versus suboptimal care. Results: In this cohort, 5,517 (63.91%) of patients received optimal treatment. In multivariate analyses, Uninsured and Medicaid-insured patients were less like likely to receive optimal treatment as compared to privately insured patients (OR = 0.58, 95% CI 0.46–0.73; OR = 0.61, 95% CI = 0.49–0.76, respectively). Blacks and Hispanics were also less likely receive optimal treatment (OR = 0.60, 95% CI 0.50–0.72, OR = 0.72, 95% CI 0.57–0.90, respectively) compared to whites. Patients with a Charlson comorbidity score of 1, 2, or 3 were also less likely to receive optimal care (OR = 0.84 95% CI 0.74–0.96; OR = 0.46 95% CI 0.34–0.62; OR = 0.27 95% CI 0.13–0.55, respectively). Treatment in a comprehensive cancer facility or teaching hospital compared to community cancer hospitals was associated with optimal treatment (OR = 1.28 95% CI 1.10–1.48; OR = 1.66 95% CI 1.43–1.93). Conclusions: In this large retrospective multi-institutional cohort, approximately one-third of patients with clinical stage III and IV ovarian cancer did not receive optimal treatment. Pretreatment patient characteristics, such as race, insurance status, age, medical cormorbidities, and facility-type, were strongly associated with suboptimal treatment.

No significant financial relationships to disclose.