bluuebunny/crossref_metadata_2025 huggingface dataset:
One-step nucleic acid amplification for detecting lymph node metastasis of head and neck cancer
Authors: Goda H. , Nakashiro K. , Yoshimura T. , Sumida T. , Wakisaka H. , Hato N. , Hyodo M. , Hamakawa H.
Published: August 2020

6028

Background: Lymph node stage is an important prognostic factor in squamous cell carcinoma of the head and neck (SCCHN). We previously reported the clinical usefulness of sentinel lymph node (SLN) biopsy diagnosed by concurrently performing histological examination using semiserial sections and genetic analysis by quantitative RT-PCR. However, these methods took about 3 hours. In this study, we have attempted to develop a more efficient method for intraoperative genetic detection of lymph node metastasis in SCCHN. Methods: A total of 291 lymph nodes (59 patients) resected on SLN biopsy for cN0 SCCHN or neck dissection for cN1/2 SCCHN were diagnosed by one-step nucleic acid amplification (OSNA) method using GD-100. The primary site was tongue, gingiva, oral floor, buccal mucosa, and pharynx in 44% (26), 37% (22), 10% (6), 5% (3), and 3% (2), respectively. OSNA consists of a short homogenization step followed by amplification of cytokeratin 19 (CK19) mRNA directly from the lysate. It is characterized by the use of 4 different primers specifically designed to recognize 6 distinct regions, so the CK19 primers do not amplify the known CK19 pseudogenes. The reaction process proceeds at a constant temperature (65°C) during strand displacement reaction. Amplification and detection of CK19 mRNA can be completed in a single step. Each lymph node was divided into two halves to diagnose metastasis. An alternative half was used for the OSNA assay with cytokeratin 19 (CK19) mRNA, and the remaining block was subjected to semiserial sectioning, sliced at 200-μm intervals and then examined by H&E and cytokeratin AE1/AE3 immunohistochemical staining. Results: Fifty-four of 291 lymph nodes were pathologically metastasis-positive. The optimal cut-off for the copy number of CK19 mRNA in assessing lymph node metastasis was 300 copies/μl, which had the highest diagnostic accuracy. The sensitivity and specificity of OSNA assay with CK19 mRNA was 92.6% (50/54) and 97% (230/237), respectively. An overall concordance rate between the OSNA assay and histopathology was 96.2%. The OSNA assay could be completed within 30 minutes. Conclusions: The OSNA assay showing high sensitivity and specificity can be used as a novel genetic detection tool of lymph node metastasis in SCCHN patients.

No significant financial relationships to disclose.
ERCC1 polymorphism in patients with locally advanced head and neck squamous cell carcinoma treated with concomitant chemoradiation: Prevalence and impact on treatment efficacy
Authors: Abboud O. , Weng X. , Guertin L. , Bissada É. , Abou Chacra Z. , Nguyen-Tan P. , Fortin B. , Tabet J. , Audet M. , Soulieres D.
Published: August 2020

6032

Background: Excision repair cross-complementation group 1 (ERCC1) is a gene coding for the nucleotide excision repair complex. Its increased expression and polymorphism at codon 118 have been linked to poor response to chemotherapy or chemoradiation in several types of cancer. ERCC1 removes the cisplatin adducts on the DNA of cells and its polymorphism appears to be a marker of chemotherapeutic resistance to platinum-based therapy. Objectives: To determine the prevalence of the polymorphism of ERCC1 (codon 118) in patients with locally advanced HNSCC treated with concomitant platinum-based chemoradiation therapy with or without prior surgery, and its effect on eficacy evaluated by locoregional control, disease-free survival and overall survival. Methods: Prospective data on efficacy was available on 460 consecutive patients treated with concomitant chemoradiation in our institution with a minimal follow-up of 2 years. Of these, 230 fixed and paraffin embedded biopsies or surgical specimens were collected. DNA was extracted from specimens and polymorphism of codon 118 was determined using a PCR technique. All analysis were performed using Kaplan-Meier survival curves, Fisher's test for categorical data and log-rank statistics for failure times. Results: DNA extraction was successful in 222 patients. Polymorphism mapping was possible in 178 specimens. Genotypic distribution in the population was the following : AAT/AAT:40% (Gr1), AAC/AAT: 48%(Gr2), AAC/AAC: 12% (Gr3). At 3 years, evaluation of efficacy for Gr1, Gr2, and Gr3 was determined. Locoregional control was respectively 77%, 83%, and 67% (p = NS), DFS was 58%, 68% and 55% (p=NS), and OS was 70%, 69%, and 70% (p = NS). Conclusions: ERCC1 polymorphism did not have an impact in our population on response to chemoradiation therapy. It can be postulated that ERCC1 does not seem to discriminate patients for whom another treatment option should be sought for patients with locally advanced SCCHN. Further data will be presented at the meeting including a multivariate analysis using different markers tested in our laboratory (KRAS, MGMT methylation, etc).

No significant financial relationships to disclose.
A phase IIb 4-arm open-label randomized study to assess the safety and efficacy of h-R3 monoclonal antibody against EGFR in combination with chemoradiation therapy or radiation therapy in patients with advanced (stage III or IVA) inoperable head and neck cancer
Authors: Krishnamurthyreddy B. , Vidyasagar M. S. , Koteshwar R. , Shenoy A. , Viswanath L. , Thimmaiah N. , Babu G. , Joseph B. , Bonnathiya R. , Bapsy P. P.
Published: August 2020

6041

Background: Patients (pt) with advanced inoperable squamous cell carcinoma of the head and neck (SCCHN) have poor radiotherapy alone (RT) outcome. EGFR is over-expressed in >90% SCCHN. h-R3mAb (BIOMAb/nimotuzumab/TheraCIM) is a humanized monoclonal antibody, a validated oncotherapeutic-targeting EGFR. Objective: To investigate the safety and efficacy of concurrent h-R3mAb in combination with chemoradiotherapy of SCCHN. Methods: September 2004–2005, pt 18–70 yrs, SCCHN stageIII-IVA, 113 screened, 92 enrolled and randomly asssigned to, Group A: radical radiotherapy (pt) and Group B: chemoradiotherapy (pt). Randomization within Group A: [RT]v/s[RT+h-R3mAb] and within Group B: [RT+CT]v/s[RT+CT+ h-R3mAb] (n = 23 in each arm). Protocol: Radiotherapy: TD: 66 Gy,2Gy/Fr,5Fr/w,6.5wks. Radiation sensitizer (chemotherapy): CDDP-50mg/wk x 6wks. Study Drug (h-R3mAb): 200 mg/wk I.V.60min x 6weeks. Results: Evaluable (n = 76) in Group A-36 and Group B-40. F/u Analysis at 30 months after end of RT. Survival rate ITT: Group B: CT+RT+hR3- 69.5% v/s CT+RT-21.7% (p - 0.0011), Group A: RT alone - 21.7% v/s RT+ hR3–39.1% (ns). Progression-free survival: RT alone - 3(13.04 %) v/s RT+hR3mAb-8 (34.78 %), RT+CT-5 (21.74 %) v/s RT+CT+hR3mAb-13 (56.52%). Median overall survival (OS): CT+RT+hR3 - NR* v/s CT+RT- 21.96 months (hazard ratio [HR]-0.337, p - 0.0018) and RT alone - 25.02 v/s RT+hR3 - NR*(HR-0.678, p - 0.39). Disease-free survival: CT+RT+hR3- NR*v/sCT+RT-21.30 mths (HR-0.344, p - 0.0052) and RT alone-25.02 v/s RT+hR3- NA* (HR-0.599, p - 0.32). (NR*- median OS is yet to be reached). Safety: few grade - 1/2AE, no HAMA observed. OS per protocol - adding h-R3mAb to chemoradiation resulted in a reduction in risk of death (rrd) by 85% (HR 0.15, p - 0.0006) and to RT a 36 % rrd (HR0.64, p - 0.33). Conclusions: Concurrent use of h-R3mAb with RT or RT+CT is safe and efficacious. It enhances radiation and chemotherapy responses. Concurrent use of h-R3mAb with chemoradiotherapy enhances long-term loco-regional control and survival. Adding biological agents to physically targeted modality improves long-term therapeutic outcome of SCCHN.

No significant financial relationships to disclose.
Phase II trial of combination docetaxel and cisplatin in patients with locally advanced nasopharyngeal carcinoma
Authors: Yamouni M. , Benhadji K. A. , Beldjilali Y. , Lahfa I. , Khellafi H. , Abdelaoui A. , Djellali L. , Bouzid K.
Published: August 2020

6044

Background: The standard treatment of locally advanced nasopharyngeal carcinoma is cisplatin-based chemotherapy followed by locoregional radiotherapy. The purpose of this study is to assess the antitumor activity and toxicity of a new neoadjuvant chemotherapy regimen combining docetaxel (D) and cisplatin (C). Methods: Previously untreated patients (pts) with histologically diagnosed locally advanced nasopharyngeal carcinoma (stages IVA and IVB, TNM/UICC 1997) received D 75 mg/m2 and C 75 mg/m2 both on day 1, with cycles repeated every 21 days. All pts received three cycles in a neoadjuvant setting before radiotherapy (4 to 6 weeks after the third cycle of DC, 65–70 Gy 5 fractions/week). Pts were evaluated by clinical examination, CT scan of the nasopharynx, and nasofibroscopy with biopsy. The primary end point was tumor response. Secondary end points were disease-free survival (DFS), toxicity, and overall survival (OS). Results: 93 pts (65 male, 28 female) were enrolled. Median age was 42 years (range 18–69), WHO performance status was 0–1 in 87 pts and 2 in 6 pts. 75 pts (81%) had an undifferentiated carcinoma of nasopharyngeal type (UCNT) and 18 pts (19%) a differenciated carcinoma of the nasopharynx. 31 pts had stage IVA disease and 62 pts had stage IVB. Toxicity, tumor response, and survival at 5 years (median follow up 49.5 months) were assessable in 90 pts. After 270 cycles, grade 3–4 toxicities (WHO) were: neutropenia (12 %), febrile neutropenia (2%), anemia (1%), nausea and vomiting (23%), diarrhea (8%), mucositis (1%), reversible alopecia (70%). Two pts had onycholysis. Response rates for the 90 pts were: complete response 32.2% (29 pts), partial response 54.4% (49 pts), stable disease 11.1% (10 pts), and progressive disease 2.2% (2 pts). The overall response rate (ORR) was 86.6% and 89% amongst the UCNT. After radiotherapy, 88 pts had a complete response and one patient had stable disease. DFS and OS at 5 years were 52% and 55%, respectively. Conclusions: DC chemotherapy followed by radiation therapy is an effective regimen for the treatment of advanced UCNT and has an acceptable safety profile. These data need to be compared with concurrent chemoradiotherapy to assess the best strategy for the management of advanced UCNT.

No significant financial relationships to disclose.
Multicenter phase II study of cetuximab plus docetaxel in 84 patients with recurrent or metastatic, platinum-pretreated SCCHN
Authors: Knoedler M. K. , Gauler T. , Matzdorff A. , Jordan O. , Schroeder M. , Gruenwald V. , Dietz A. , Arnold D. , Hennemann B. , Keilholz U.
Published: August 2020

6048

Background: Cetuximab and docetaxel are both active in squamous cell carcinoma of the head and neck (SCCHN). We investigated the efficacy of cetuximab plus docetaxel as second-line treatment in platinum-pre-treated patients with recurrent and or metastatic SCCHN. Methods: 84 patients were enrolled and received cetuximab (initial dose of 400 mg/m2, followed by subsequent weekly doses of 250 mg/m2) and docetaxel (35 mg/m2 on days 1, 8, 15 of a 4-week cycle) for a maximum of 6 cycles. Patients with stable disease continued to receive cetuximab until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate according to RECIST criteria. Secondary endpoints were response rate in relation to platinum sensitivity, progression-free survival, overall survival, and toxicity. Results: According to RECIST there were 10 PR (12%) and 23 SD (27%), resulting in a disease control rate of 39%. Response to protocol treatment was unrelated to previous platinum sensitivity. Median progression-free survival was 4 months (95% CI, 2.9 to 5.1) and median overall survival was 7 months (95% CI, 5.5 to 8.5). The duration on protocol treatment exceeded 12 months in 6 (8%) patients. Grade III/IV toxicities included gastric perforation (n = 1), pneumonia (n = 7), mucositis and skin toxicities. Conclusions: Cetuximab plus docetaxel was an active second-line treatment regimen with acceptable toxicity in patients with platinum-pretreated SCCHN. The responsiveness was independent of previous platinum sensitivity.

[Table: see text]
Analysis of the impact of growth factor on the haematological safety of dose-dense regimen in the randomized phase II adjuvant trial BO3
Authors: Delbaldo C. , Serin D. , Priou F. , Laplaige P. , Greget S. , Angellier E. , Teissier E. , Berdah J. , Fabbro M. , Quinaux E.
Published: August 2020

605

Background: In a randomized phase II study, P. Piedbois et al. explored a dose-dense docetaxel (T) followed by epirubicin/cyclophosphamide (EC) every two weeks versus the reverse sequence, versus standard-dose docetaxel, epiribucin and cyclophosphamide (TEC) every 3 weeks. The main purpose of this second analysis was to further explore the haematological safety of each regimen in patients receiving primary prophylactic pegfilgrastim. Methods: One hundred patients with node-positive invasive breast adenocarcinoma were randomized between (arm A) docetaxel 75 mg/m2, epiribucin 75 mg/m2 and cyclophosphamide 500 mg/m2 (TEC) every 3 weeks for 6 cycles (35 patients) or (arm B) epiribucin 100 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks for 4 cycles, followed by T 100 mg/m2 (EC→T) every 2 weeks for 4 cycles (31 patients) or (arm C) T→ EC (34 patients). Among the 99 patients who received chemotherapy, 79 received pegfilgrastim 6 mg subcutaneous day 1 from the first cycle (27 in arm A, 23 in arm B and 29 in arm C). The safety data of these 79 patients were reported here. Results: Our results showed grade 3/4: neutropenia (arm A 30 %, arm B 39 %, arm C 31 %) and febrile neutropenia (FN) (arm A 11 %, arm B 13 %, arm C 3 %), grade 2–4: anaemia (arm A 26 %, arm B 61 %, arm C 55 %) and thrombocytopenia (arm A 15 %, arm B 9 %, arm C 3 %), respectively. Crude proportion and time to toxicity summaries showed that in dose-dense arms, patients allocated to the EC→ T sequence were more exposed to FN than patients allocated to the T→ EC. In the Cox model taking into account all allocated treatment and age, treatment was a predictor of grade 2–4 anaemia, whereas age was significantly correlated to grade 2–4 thrombocytopenia. There was no clear relationship between haematological toxicity and dose intensity across all treatment arms. Except for nausea (17 % versus 3 %) and neurological toxicity (13 % versus 3 %), non-haematological toxicities were similar in arm B and C. Conclusions: These analyzes confirmed that dose-dense regimens EC→ T or T→ EC are feasible with pegfilgrastim primary prophylaxis. The T→ EC sequence seems to be associated with a better haematological tolerance, and should be the preferred dose-dense regimen providing similar efficacy. The trial was supported by Amgen.

No significant financial relationships to disclose.
Phase II trial of continuous dosing of sunitinib in advanced, FDG-PET avid, medullary thyroid carcinoma (MTC) and well-differentiated thyroid cancer (WDTC)
Authors: Carr L. , Goulart B. , Martins R. , Keith E. , Kell E. , Wallace S. , Capell P. , Mankoff D.
Published: August 2020

6056

Background: Due to the low efficacy of chemotherapy in progressive, WDTC and MTC, novel treatment approaches are needed. Thyroid cancers have elevated levels of vascular endothelial growth factor and higher microvessel density than normal thyroid tissue. Sunitinib inhibits several tyrosine kinase receptors involved in angiogenesis as well as the RET kinase frequently mutated in thyroid cancer. Here we report the results of a phase II trial investigating the use of continuous dosing sunitinib in patients with metastatic WDTC and MTC. Methods: Patients were eligible for enrollment if they had metastatic, iodine-refractory WDTC or MTC. To target those patients with more aggressive thyroid cancer, enrollment was limited to FDG-PET avid disease. Sunitinib was administered at 37.5 mg po qday on a continuous basis. Planned sample size is 35 patients. The primary end-point is response rate per RECIST criteria. Secondary end-points include FDG-PET response rate (defined as 20% reduction from baseline SUV) after 7 days of treatment, toxicity, overall survival, duration of response, and time to progression. Results: To date 33 patients have been enrolled (7 MTC:26 WDTC), and 29 patients have been evaluated for disease response. Median time on study is 7.5 months. Response rates to date: CR 7% (2/29), duration of response (9m+ and 14m+), PR 25% (8/29) (median 12 months), SD 48% (14/29) (median 6 months). Rate of disease control at 3 months (SD+PR+CR) 83% (24/29). 15 patients remain on study. Among those who have progressed the median time to progression is 6.5 months. FDG-PET was performed on 22 patients following 7 days of treatment, 36% (8/22) have a PET response. Of these patients 7 have disease control per RECIST criteria. Grade 3 toxicities seen in more than one patient include: anemia (2/33), fatigue (4/33), neutropenia (12/33), hand/foot syndrome (4/33), diarrhea (5/33), and leukopenia (11/33). One patient on lovenox therapy died of gastrointestinal bleeding. Conclusions: Continuous dosing of sunitinib is active (disease control rate 83%) in patients with high risk, metatstatic WDTC and MTC, as defined by FDG-PET avid disease.

[Table: see text]
Treatment (tx) with tyrosine kinase inhibitors (TKIs) for patients (pts) with differentiated thyroid cancer (DTC): The M. D. Anderson Cancer Center (MDACC) experience
Authors: Cabanillas M. E. , Waguespack S. G. , Bronstein Y. , Williams M. , Feng L. , Sherman S. I. , Busaidy N. L.
Published: August 2020

6060

Background: DTC is a relatively common tumor and about 20% will develop distant metastases (mets) of which at least 50% will not respond to standard tx. Until recently, tx for pts with progressive, RAI negative disease was limited. However, the identification of biologic targets in DTC has led to several trials with TKIs. Objectives: We sought to describe the MDACC experience with off-label use of TKIs to determine which pts benefit the most. Methods: Adult pts with a diagnosis of DTC treated with single agent sorafenib (SOR) or sunitinib (SUN), and who had a baseline and at least 1 follow-up (f/u) scan after 3 months (mos) of therapy, were included. All imaging data, as well as the TSH-suppressed thyroglobulin (TG) levels corresponding to each scan date were collected. RECIST was used to determine response. Results: We identified 33 pts from our clinical database. 15 pts met inclusion criteria: 9 women, 6 men. No pts were excluded due to progression or death before 3 mos. Median age 61 years (range, 38–83). 7 patients had papillary, 6 follicular (including 2 insular subtypes), 2 Hurthle cell. Most patients had RAI negative disease. SOR was used in 13, SUN in 2. Both SUN pts had been on SOR; 1 failed and 1 had intolerable side effects to SOR. Median time on tx was 42 weeks. All pts had evidence of PD prior to start of tx. Best response was 3 (20%) PR, 9 (60%) SD, 3 (20%) PD. Clinical benefit (PR+SD) = 80%. The SUN pt who was refractory to SOR had a 38% reduction in tumor size. The most noticeable activity occurred in lung (median change: -16%), whereas lymph nodes had PD or SD (median change: +3%). The 2 pts with pleural mets had PD. Four pts had bone mets: 2 had XRT and had SD in bone, while the other 2 did not have XRT and had PD in bone. At 12 mos PFS was 65% and OS was 85%. Median f/u time was 16 mos. All histologic types had similar responses. Log (TG) correlated with response (p = 0.0005). Conclusions: SOR and SUN are effective in pts with widely metastatic, progressive DTC, with most pts achieving SD or PR. The most noticeable responses occurred in the lungs in contrast with minimal changes in nodal mets, suggesting a tissue-specific response to tx. Log (TG) significantly correlated with response to tx and therefore may have value as a surrogate marker of response.

[Table: see text]
Differential tumor and normal mucosa biomarker modulation by epidermal growth factor receptor (EGFR) inhibition using erlotinib in oral cavity squamous cell carcinoma (OCSCC)
Authors: Tsien C. , Nyati M. , Chepeha D. , Worden F. , Helman J. , Bradford C. , Wolf G. , Lawrence T. , Eisbruch A.
Published: August 2020

6077

Background: Targeted therapy may improve the therapeutic index in locally advanced head neck cancer if differential EGFR inhibition in tumors compared to the normal mucosa is demonstrated. Based on prior published data, EGFR degradation is an important biomarker of cytotoxicity in a preclinical model. The aim of this pilot study was to determine if there are differences in biomarker modulation between tumor and the normal mucosa and confirm our initial preclinical findings regarding EGFR degradation. Methods: Patients with primary OCSCC requiring surgical resection had normal mucosa and tumor biopsies prior to a test course of erlotinib. Patients received one week of erlotinib 150 mg qd. Repeat tumor and normal mucosal biopsies were obtained at the time of surgical resection to evaluate the effect of the EGFR inhibitor on both tumor and the normal mucosa. Changes in known preclinical markers of EGFR activity (phospho, total EGFR, AKT, STAT3) were measured by immunoblotting assays. In addition, changes in distribution of these biomarkers were analyzed by immunohistochemical analysis. Results: 12 pts were enrolled; 7 pts with paired tumor and normal mucosa biopsies. Tumor specimens showed over-expression of EGFR compared to the normal mucosa (p = 0.005). Erlotinib treatment led to marked inhibition of both pEGFR and EGFR protein (p = 0.004 and p = 0.007, respectively) in tumor biopsies. In contrast, we found heterogeneity in EGFR inhibition in the normal mucosa following erlotinib. (p = 0.1 [pEGFR], and p = 0.07 [EGFR)]) We noted dramatic reduced levels of pSrc and pSTAT3 following erlotinib in tumors compared to untreated matched tumor samples. In addition, levels of p27 were enhanced. Conclusions: Differential EGFR inhibition in tumors compared to the normal mucosa, may suggest that the addition of EGFR inhibitors to chemo-RT or accelerated RT, whose dose limiting toxicity is acute mucositis, may select patients who will benefit from targeted therapy. Our results demonstrate that EGFR inhibition by erlotinib led to marked reduction in EGFR protein levels. EGFR degradation may be an important biomarker in selecting patients predicted to have a response to TKI. These results need further validation.

No significant financial relationships to disclose.
Comparison of neoadjuvant paclitaxel and carboplatin with neoadjuvant letrozole in postmenopausal patients with receptor-positive locally advanced breast cancer (LABC)
Authors: Sinha D. , Bahadur A. K. , Singh K. , Rathi A. K.
Published: August 2020

608

Background: For the treatment of LABC using a regimen with the highest likelihood of shrinking the tumor should improve the outcome. Paclitaxel was the first taxane to show activity in breast cancer. The advent of endocrine therapy in the neoadjuvant setting allows downstaging of tumors with less morbidity. The aromatase inhibitors are now the treatment of choice in neoadjuvant setting for elderly patients with estrogen receptor-positive breast cancer. Methods: This prospective, randomized, comparative study assessed the effect of three cycles of neoadjuvant chemotherapy vs. three months of neoadjuvant hormonal therapy in terms of loss of clinical and pathological primary tumor size. Inclusion criteria required postmenopausal patients with non-metastatic, ER and/or PR positive LABC with no co-morbidity. Forty eligible patients were randomly assigned into 2 groups of 20 patients each: Group A treated with 3 cycles of 3 weekly injections of paclitaxel (175 mg/m2) and carboplatin (AUC 6) assessed after each cycle; group B received oral Letrozole 2.5mg once daily for 3 months assessed every 4 weeks. Surgery was done and primary specimen was pathologically examined. Results: Clinically mean loss in primary residual tumor compared to volume at presentation in group A vs. group B at 1st review was 45% vs. 35% (p: 0.536), 63% vs. 57% at second (p: 0.176), and 71% vs. 74% at third review (p: 0.062).Clinical complete response (WHO criteria) and stable disease each were seen in 14% in either group of patients (p: 0.632), partial response in 65% group A and in 72% group B (p: 0.117); no progressive disease was seen in either. All patients underwent surgery. The mean pathological primary cell kill in group A vs. group B was 81% vs.78 %(p:0.918). Resected nodes were pathologically positive for tumor in 47% group A and 60% group B patients (p: 0.269). Conclusions: Neoadjuvant hormonal therapy using oral Letrozole in receptor positive LABC in post menopausal women is as effective as three weekly paclitaxel and carboplatin in downstaging the tumor.

No significant financial relationships to disclose.
Correlation of dynamic contrast enhanced magnetic resonance imaging (DCE MRI) with 18f-fluoromisonidazole positron emission and computed tomography (18F-FMISO PET/CT) in assessing tumor hypoxia in a series of head and neck cancer (HNC) patients with nodal metastases
Authors: Lee N. , Jensen J. , Schoder H. , Wang Y. , Fury M. , Pfister D. G. , Stambuk H. , Humm J. , Koutcher J. , Shukla-Dave A.
Published: August 2020

6083

Background: 18F-FMISO PET/CT is a noninvasive hypoxia imaging modality. Hypoxia can develop within the tumor which typically corresponds to regions with poor blood perfusion. DCE-MRI can yield results on tumor perfusion. The present study compares hypoxic and perfusion status of HNC with nodal metastases using DCE-MRI and 18F-FMISO PET/CT imaging. Methods: 13 HNC (7 base of tongue, 5 tonsil, 1 larynx) patients with nodal metastases underwent both DCE-MRI and 18F-FMISO PET/CT scans prior to chemoradiotherapy. MRI was performed on a 1.5 Tesla GE Excite scanner. DCE-MRI studies were acquired using a fast multi-phase spoiled gradient echo sequence. Antecubital vein catheters delivered a bolus of 0.1 mmol/kg Gd-DTPA at 2 cc/s. For 18F-FMISO PET/CT,∼10.0 mCi of 18F-FMISO was administered IV and images were acquired ∼2 hours later. PET images were reconstructed; CT data were used for attenuation correction. Region of interests (ROIs) were manually drawn by a neuroradiologist. Quantitative DCE-MRI analyses were done using the 2-compartment Tofts model. The analyses calculated the pixel Ktrans(distribution rate constant), ve(extravascular-extra-cellular volume fraction), and kep(redistribution rate constant). 18F-FMISO PET/CT images were analyzed and the uptake by the tumor was scored as: no uptake (score 0); moderate-severe uptake (score 1). Semi-quantitative analysis included standardized uptake value (SUV) measurements. Statistical significance was calculated using a 2-sided Student's t-test, with p < 0.05. Results: A total of 17 nodes were analyzed. For the nodes that showed no hypoxia on PET imaging (n = 7), the mean (±SD) values were: 18F-MISO SUV (1.1 ± 03), Ktrans(0.33 ± 0.18), ve(0.53 ± 0.23), and kep(0.66 ± 0.25). For the nodes that showed moderate to severe 18F-MISO uptake (n = 10) the values were: 18F-FMISO SUV (2.8 ± 08), Ktrans(0.24 ± 0.07), ve(0.61 ± 0.13), and kep (0.43 ± 0.17). A significant lower kep for nodes with 18F-MISO uptake (p = 0.042). Conclusions: Preliminary result supports the hypothesis that the hypoxic nodes are poorly perfused nodes (lower kep values) versus nodes with no hypoxia.

No significant financial relationships to disclose.
Surgery versus primary endocrine therapy for elderly women with estrogen receptor-positive early operable primary breast cancer: Survival analysis and correlation with oestrogen receptor positivity
Authors: Syed B. M. , Johnston S. J. , Wong D. W. M. , Morgan D. A. L. , Ellis I. O. , Cheung K. L.
Published: August 2020

612

Background: A recent Cochrane review of seven randomised trials involving 1,446 elderly women (unselected for oestrogen receptor (ER) status) has shown no significant difference in overall survival between surgery (with or without adjuvant tamoxifen) and primary endocrine therapy using tamoxifen. We now report results of a large series from a single centre with a dedicated elderly breast cancer service, with long term follow-up. Methods: During a period of > 20 years, 1,031 elderly (> 70 years) women with ER positive (H-score >50) early operable primary breast cancer received either surgery (with or without adjuvant endocrine therapy) (N = 436) or primary endocrine therapy (N = 595) (>80% using tamoxifen) as initial treatment, with complete follow-up information till deaths. The initial treatment was decided based on fitness for surgery and patient choice. Analysis was carried out on breast cancer specific survival and degree of ER positivity. Results: After a median follow up of 49 months (range 0 - 261 months), patients between 70 - 80 years, treated by surgery, had better 5-year breast cancer specific survival compared to their counterparts treated by primary endocrine therapy (95% versus 85%; p < 0.001). For patients > 80 years, there was however no statistical difference between the two groups (90% versus 90%; p = 0.813). The median survival has not reached yet in all groups. Patients in the latter group (> 80 years) were found to have a higher chance of having strongly ER positive tumours (57% versus 50% in patients between 70 - 80 years with H-score >200; p- < 0.02). Conclusions: In a selected group of elderly women (> 80 years) who tend to have strongly ER positive tumours, surgery and primary endocrine therapy did not appear to produce any difference in breast cancer specific survival. This subject is currently being investigated in a national randomised trial in the UK.

No significant financial relationships to disclose.
Determinants of outcome in elderly patients with positive sentinel lymph nodes
Authors: Gemignani M. , Karam A. , Hsu M. , Patil S. , Stempel M. , Traina T. , Ho A. , Cody H. , Morrow M.
Published: August 2020

614

Background: Older women are less likely to receive standard of care treatment for breast cancer. This undertreatment may be linked to the perception that elderly patients (pts) may not tolerate or derive benefit from treatment that is often viewed as “too toxic.” Methods: From July 1997 to July 2003, 1,470 pts with invasive cancer with positive sentinel lymph nodes (PSLN) by intraoperative frozen section or final pathologic exam by hematoxylin-eosin and/or immunohistochemistry (IHC). We examined sociodemographic, pathologic, and therapeutic variables that affected the outcome of elderly pts ≥70 years old. A comorbidity score was assigned using Adult Comorbidity Evaluation-27 system. Chi-square, Fisher's exact Wilcoxon tests, and multivariate logistic regression analysis were used. Results: The median age was 53 years (range 21–89) and median tumor size 1.6 cm (range 0.1–11). 1,265 (86.1%) pts were <70 years old and 205 (13.9%) pts were ≥70 years old. 183 (12.5%) pts had IHC only PSLN, 1,021 (69.5%) had 1–3 PSLN, and 266 (18%) ≥4 PSLN. Breast conservation therapy (BCT) was performed in 59.7% of pts. Elderly pts were more likely to have moderate to severe comorbidities (46% vs. 11%, p < 0.0001) and BCT (67% vs. 59%, p = 0.026), compared to pts <70 years old. Elderly pts were less likely to undergo completion ALND (73% vs. 89%, p < 0.0001), adjuvant chemotherapy (43% vs. 90%, p < 0.0001) and radiotherapy following BCT (82% vs. 90%) compared to pts <70 years old. The 5-year disease-free survival (DFS) was not significantly different for elderly pts compared to non-elderly pts (87.7% vs. 91.9%, p = 0.21), on the other hand the 5-year overall survival was significantly worse for elderly pts (80.4% vs. 93.2%, p < 0.0001), a difference that was mainly due to a significantly higher 5-year cumulative incidence of death due to other causes (13.2% vs. 1.9%, p < 0.0001). On multivariate analysis, ER or PR positive status, IHC only PSLN and T1 tumors were the only factors independently associated with improved odds of 5-year DFS. Conclusions: Tumor rather than patient factors were the primary determinants of breast cancer outcomes in our cohort of node positive breast cancer pts. Elderly breast cancer pts with an estimated life expectancy beyond 5 years should receive the same standard of care therapy as their younger counterparts.

No significant financial relationships to disclose.
Factors influencing 3D-MRI diagnosis in preoperative breast cancer patients
Authors: Hisamatsu K. , Takiyama W. , Sakabe R. , Satou Y. , Saeki S. , Mukaida H. , Yamashita Y. , Hirabayashi N. , Kaneko M. , Ono T.
Published: August 2020

620

Background: We presented 3D-MRI will be the useful breast imaging tool in diagnosing intraductal spread and tumor size in breast cancer patients. (ASCO 2008).To do breast conserving surgery, careful management was needed in cases with widely ductal spreading and multifocal lesion. This study was to evaluate factors influencing false negative diagnosis and multifocal types of 3D-MRI, retrospectively. Methods: From July 2000, pre-operative 3D-MRI was underwent 488 cases and images were obtained 479 cases (98%). These patients could be divided into three groups according to 3D-MRI images: pattern 1) localized type (273 cases), 2) widely enhanced type (106 cases) and 3) multi-focal type (100 cases). From April 2005, resected specimen was serially step cut and total specimens were microscopically evaluated. Tumor size in 3D-MRI was 1cm over smaller than resected specimens were defined false negative cases. Investigated factors influencing 3D-MRI were age, patterns of 3D-MRI images, presence of pre-operative chemotherapy, histological type, histological grade, microscopical invasive tumor size (mm) and presence of ductal spreading. Results: The rate of histological confirmed intraductal spread were seen in 58% (158/273cases), 89% (94/106 cases) of patients with 3D-MRI pattern 1) and 2), respectively. Tumor size was correlated between MRI and specimens, significantly (n = 162, r = 06706, p < 0.001). Factors influencing false negative diagnosis of 3D-MRI were presence of pre-operative chemotherapy (p < 0.05), presence of ductal spreading (p < 0.001) and patterns of 3D-MRI images (p < 0.05). In the cases with multi-focal 3D- images, there were only 11(11/41, 26%) cases with true multifocal lesions by total specimens examination. Selection for breast conserving surgery and margin width were based by 3D-MRI images. The proportion of breast-conserved surgery were obtained 90% (437/488 cases) and local failure seen only 6 cases (local failure rate 1.4%) in 3D-MRI guided surgery. (median follow up 52 months). Conclusions: These results suggest that MRI will be the useful breast imaging tool, but caution will be needed in cases with pre-operative systemic therapy, cases expected intraductal spread by imaging tools and cases with multi-focal 3D- images.

No significant financial relationships to disclose.
Nipple areola skin-sparing mastectomy with TRAM flap reconstruction: Single-center study
Authors: Kim H. , Park E. , Lim W. , Sei J. , Koh B. , Son B. , Ahn S.
Published: August 2020

632

Background: Cosmetic aspect of breast cancer treatment becomes important. The originally described technique of Skin sparing mastectomy (SSM) included the removal of gland, nipple areola complex (NAC), and biopsy scar. However, the risk of tumor involvement of NAC in patients with breast cancer has been overestimated. The purpose of this study is to evaluate the oncological safety and technical outcomes of nipple areola skin sparing mastectomy (NA-SSM) compared with SSM. Methods: This retrospective study includes 522 patients who underwent immediate breast reconstruction using pedicled transverse rectus abdominis musculocutaneous (TRAM) flap between July 2001 and December 2006. The indication of NA-SSM in this study was defined as being for any stage, any tumor size and any tumor areola distance. Briefly, NAC was preserved when palpation and the outlook of the nipple was normal. 364 patients underwent SSM with immediate TRAM flap reconstruction and 152 underwent NA-SSM with immediate TRAM flap reconstruction. We compared complication rate, local recurrence rate (LRR), disease-free survival (DFS), and overall survival (OS) Between NA-SSM and SSM with immediate TRAM reconstruction cases. Results: Median follow up of NA-SSM and SSM was 60 and 67 months respectively. Complete or partial nipple areola necrosis developed in 26 (17.1%; complete, partial 15). The 5 year DFS was 89% for NA SSM and 87.4% for SSM (log rank p = 0.20), The 5 year OS was 99.3% for NA SSM and 98.3 % (log rank p = 0.33) The local failure occurred in 3 (2%) of 152 underwent NA SSM, 3 (0.8%) of 364 patients underwent SSM (p = 0.27). There were 2 (1.3%) nipple areola recurrence. Cosmetic outcome of NA SSM was better than that of SSM in the majority of patients. Conclusions: Our study demonstrates that NA-SSM with immediate TRAM reconstruction is oncologically as safe as SSM with immediate TRAM reconstruction and provides a good cosmetic outcome.

No significant financial relationships to disclose.
Histologic subtypes of ductal intraepithelial neoplasia (DIN) of the breast: Characteristic associations and biology
Authors: Schwartz J. D. , Christy C. , Grube B. , Rishi M. , Tavassoli F. , Bossuyt V. , Harris L. , DiGiovanna M. P. , Lannin D. R.
Published: August 2020

633

Background: Most invasive breast cancers are associated with more than one histologic subtype of DIN. The clinical and biologic significance of these DIN subtypes is under-appreciated. Methods: We reviewed 853 cases of DIN diagnosed at our University based Breast Center between 2003 and 2008, 568 (67%) of which were associated with an invasive cancer. Cases of pure invasive cancer without DIN were excluded. Results: A single histologic subtype was present in 41% of the cases, two subtypes in 43%, and three in 16%. The most common DIN subtypes present were solid (52%) and cribriform (50%), while the comedo (18%), micropapillary (11%), papillary (9%) and flat (6%) subtypes were less common. Comedo and solid DIN were frequently found together (Odds ratio [OR]) for coexpression 1.94, p< .001) as were micropapillary and papillary subtypes (OR 2.58, p< .005). Comedo DIN was much less likely to be found with papillary (OR .24, p< .005), flat (OR .34, p< .05), cribriform (OR .42, p< .001) or micropapillary (OR .48, p< .05) subtypes. We also examined multiple biological parameters and their association with the different DIN subtypes as shown in the table below. Solid and comedo subtypes tend to be hormone receptor negative, Her2 positive and high grade while the cribriform subtype tends to be hormone receptor positive, Her2 negative and low grade. Papillary and comedo DIN are most likely to be larger lesions. Papillary DIN is least likely to be associated with an invasive cancer. Conclusions: The histologic architecture provides clues to the underlying molecular changes and biological behavior of DIN. This study will begin to help us understand the molecular basis for the different histologic subtypes of DIN, their different clinical behaviors and tendencies to progress to invasive cancer.

[Table: see text]

No significant financial relationships to disclose.
Role of progesterone receptor status (PR) as predictive factor of pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) in breast cancer (BC) patients (pts)
Authors: Perez Garcia J. M. , Saura C. , Muñoz E. , Sanchez-Olle G. , Gomez P. , Peg V. , Sabadell D. , Cortes J. , Baselga J. , Bellet M.
Published: August 2020

637

Background: While estrogen receptor (ER) negativity has been consistently associated to higher pCR rates after NACT in BC, few data regarding the association of PR with pCR has been reported. PR positivity has been related to taxol resistance in in vitro chemosensitivity assays. Our aim was to investigate the putative role of PR in the prediction of pCR in a cohort of BC pts receiving NACT. Methods: Medical reports of all pts receiving NACT and breast surgery between 2004 and 2006 in our institution were reviewed. Baseline clinical and histological features, along with type of preoperative therapy were examined as variables for association with pCR (no invasive tumor in breast and axilla) using univariate and multivariate analyses. Results: 128 pts were included. 73.4% received anthracycline and taxanes (A&Tx) based CT and 9.4% also received trastuzumab (T). PR+ (≥ 10%) was significantly associated with low histological grade (HG), low Ki67 (<10%), HER-2- (Herceptest 0,1,or 2 with FISH-) and ER+ (≥10%). Overall pCR rate was 18.8%. No PR+ patient achieved pCR. In univariate analysis, high HG, ER-, PR-, HER-2-, high Ki67, T therapy, and number of CT cycles were significantly associated with pCR. In multivariate analysis only HER-2 and PR status were statistically significant. Similarly, PR and HER-2 status were independently related to pCR in the subgroup of pts receiving A&Tx (N = 94, 20.2%pCR). In the HER-2- subgroup (n = 89, 9%pCR) only ER independently predicted pCR, while in the HER-2+ subgroup (n = 33, 42.4%pCR, 57.1%pCR with T), both PR- and T therapy were the only predictive factors for pCR in the univariate and multivariate analyses. When the 24 HER-2+ pts treated with A&Tx (23 taxol/1 taxotere) ± T were separately analyzed, only PR retained statistical significance in the multivariate model. Conclusions: In our cohort of BC pts treated with NACT, PR status independently predicts pCR in the whole population as well as in the A&Tx-treated and in the HER-2+ subgroups. In the HER-2+ pts receiving A&Tx ± T PR negativity was the only factor associated with pCR. PR status merits further investigation as a predictive factor for pCR to NACT, in particular in HER-2+ population.

No significant financial relationships to disclose.
Routine preventive care and cancer surveillance in long-term survivors (LTS) of colorectal cancer: Results from NSABP Protocol LTS-01
Authors: Kunitake H. , Zheng P. , Yothers G. , Land S. , Fehrenbacher L. , Giguere J. K. , Wickerham D. L. , Ganz P. A. , Ko C. Y.
Published: August 2020

6500

Background: Little is known about the use of routine preventive care and cancer surveillance in long-term colorectal cancer survivors. NSABP LTS-01 is a study that examines the use of such services in long-term colorectal cancer survivors previously treated in NSABP adjuvant trials. Methods: Long-term colorectal cancer survivors (≥ 5 years) were recruited from five completed NSABP treatment trials (Protocols C-05, C-06, C-07, R-02, R-03) at 65 study sites. A survey battery for long-term survivors of colorectal cancer (LTS-01) was developed. A 1:4 comparison cohort case-matched by age, gender, race, and education was created from the 2005 National Health Interview Survey. Contingency tables and multivariate models were used to compare cohorts and determine predictors of preventive care and cancer surveillance. Results: 649 LTS-01 patients (625 colon, 24 rectal) completed the interview; 57% male, mean age 66.1yr (SD 10.5), median survival 8 yrs. LTS-01 patients were more likely to have a usual source of healthcare than the NHIS cohort (98% vs. 93%, p < 0.0001). The number of ER visits in the previous 12 months was not significantly different between the two groups. LTS-01 patients were more likely to have received a flu shot in the past 12 months (68% vs. 42%, p < 0.0001) and were also more likely to have undergone cancer screening by Pap smear (67% vs. 54%, p < 0.001), mammogram (85% vs. 71%, p < 0.001), and PSA test (84% vs. 75%, p < 0.001). For CRC surveillance, 3% did not have a colonoscopy, 13% had not had a CEA test, and 34% did not have a CT scan in the last 5 years. The best predictor of the receipt of these cancer screening tests was the presence of health insurance (OR 2.6–4.5). No factor was uniformly associated with colorectal cancer surveillance. Conclusions: Long-term survivors of colorectal cancer achieve better routine preventive care including cancer screening than the general population. However in these stage II and stage III cancer patients cancer surveillance is variably performed.

No significant financial relationships to disclose.
A study of physician investigator (PI) disclosure of alternatives of care and prognostic information to advanced cancer patients (ACP) enrolling in phase I trials
Authors: Daugherty C. , Kass N. E. , Roter D. , Larson S. , Sugarman J. , Kasza K. , Ratain M. J. , Hlubocky F. J.
Published: August 2020

6508

Background: ACP in phase I trials have been described as having an inadequate understanding of several elements of informed consent. However, actual PI disclosure of alternatives to trial participation and prognostic information, and subsequent ACP understanding of these elements, have not been described. Methods: Clinical encounters between 131 ACP entering phase I trials and 25 oncologists at three institutions (University of Chicago; Johns Hopkins; and Duke University) were audio-taped. ACP completed follow-up questionnaires one week later to assess understanding of informed consent elements. Audiotapes were analyzed using the Roter Interaction Analysis System (RIAS) and specifically coded for terms associated with trial alternatives and patient prognosis. Results: To date, 85 encounters have been analyzed. Average encounters length: 30.4 min (range: 5.7–77.8 min). For ACP: median age 60y (33–83); 55% female; 88% Ca; 55% <college educ; 52% income <$60,000. The PI was recorded as discussing options other than anticancer treatment in 47% of encounters. The terms “palliative” or “hospice” were used in 1% and 2.3% of encounters respectively. In 29% of encounters the PI described the option of “doing nothing”. The PI used the terms “death” or “terminal” in 5.8% encounters. The PI was never recorded using the term “dying”. Within these encounters, no ACP was recorded as using any of the following terms: “palliative,” “hospice,” “terminal,” “death,” “dying.” Within follow-up interviews, 30% reported no alternatives to trial participation were discussed; 1% reported that palliative care/hospice was discussed. Based on coding of qualitative responses, 53% of ACP said that either their prognosis was excellent or they didn't know their prognosis. An association was found between recorded physician statements regarding general prognosis and ACP subsequently reporting having discussion regarding life expectancy (59% v. 33%, p = 0.04). Conclusions: PI communication and subsequent measured understanding regarding alternatives to trial participation and prognosis remain inadequate in the setting of phase I trial enrollment.

[Table: see text]
The impact of the inclusion of clinical data review on overall radiographic response and progression in oncology clinical trials as assessed by blinded independent central review
Authors: Wangler N. , Borradaile K. , Ford R.
Published: August 2020

6511

Background: The United States Food and Drug Administration (USFDA) advocates blinded independent central review (BICR) of radiographic exams for oncology registration studies when the primary study endpoint is based on tumor measurements, such as progression-free survival, time to progression or objective response rate. However, a proportion of subjects progress clinically prior to radiographic evidence of disease progression and in certain indications, measurement of cutaneous lesions may be incorporated into response criteria calculations. Methods: BICR data from 4,183 subjects in the following indications: lymphoma, melanoma, breast cancer, and colorectal cancer, was blinded, pooled, and reviewed to determine the impact of clinical review on best response and date of progression following BICR of radiographic images. Results: Inclusion of clinical data and/or clinical photography impacted 27% (47/171) of lymphoma subjects, affecting the assessment of the best response (13%), best response date (16%) and/or the date of progression (19%); 12% (13/107) of melanoma subjects, affecting the assessment of the best response (6%), best response date (5%), and/or the date of progression (8%); 10% (308/2,947) of breast cancer subjects, affecting the assessment of the best response (4%), best response date (4%), and/or the date of progression (9%); 3% (32/958) of colorectal cancer subjects, affecting the assessment of the best response (2%), best response date (2%), and/or the date of progression (2%). Conclusions: When using BICR to determine endpoints in oncology clinical trials, inclusion of a clinical review may be relevant in 27% of subjects for lymphoma, 12% for melanoma, 10% for breast cancer, and 3% for colorectal cancer.

[Table: see text]