bluuebunny/crossref_metadata_2025 huggingface dataset:
A contemporary analysis of the ability of preoperative serum CA-125 to predict primary cytoreductive outcome in patients with advanced ovarian, tubal, and peritoneal carcinoma
Authors: Zivanovic O. , Chi D. S. , Eisenhauer E. L. , Sonoda Y. , Levine D. A. , Brown C. L. , Barakat R. R.
Published: March 2020

5572

Background: We previously reported that preoperative CA-125 may predict primary cytoreductive outcome in patients (pts) with stage III ovarian carcinoma. We performed a contemporary analysis of the ability of preop CA-125 to predict cytoreductive outcome in advanced ovarian, tubal and peritoneal carcinoma. Methods: In 1/01, we initiated a programmatic change in our primary surgical approach to advanced gynecologic malignancies using extensive upper abdominal procedures to achieve maximal cytoreduction. We reviewed the records of all pts with advanced ovarian, tubal or peritoneal carcinoma who underwent primary cytoreduction at our institution between 1/01 and 4/05. Results: The study cohort included 277 pts. Primary disease site was: ovary; 232 (84%); tubal, 9 (3%); and peritoneum, 36 (13%). Stage was: IIIA, 6 (2%); IIIB, 12 (4%); IIIC, 215 (78%); and IV, 44 (16%). Tumor grade was: I, 6 (2%); II, 30 (11%), III, 235 (85%), and unknown, 6 (2%). Cytoreductive outcome was: no gross residual disease (RD), 68 (25%); ≤ 1 cm RD, 153 (55%); and > 1 cm RD, 56 (20%). There was no threshold CA-125 level that accurately predicted cytoreductive outcome. With CA-125 values > 500 U/mL, 50% (57/113) of pts required extensive upper abdominal surgery to achieve RD ≤ 1 cm, compared to 27% (25/93) for those with CA-125 < 500 U/mL (P = 0.03). The table demonstrates the number of pts cytoreduced to = 1 cm RD in relation to preoperative serum CA-125 and the proportion of pts who needed extensive upper abdominal surgery to achieve this degree of cytoreduction. Conclusions: After the incorporation of extensive upper abdominal procedures, preop CA-125 did not predict the primary cytoreductive outcome of pts with advanced ovarian, tubal or peritoneal carcinoma. With preoperative CA-125 > 500 U/mL, extensive upper abdominal procedures were necessary in 50% of pts to achieve residual disease ≤ 1 cm. These data may be useful as part of preoperative surgical counseling and planning.

[Table: see text]

No significant financial relationships to disclose.
Phase II study for the suboptimally debulked advanced ovarian cancer: Intravenous platinum followed by interval debulking surgery and intravenous paclitaxel + intraperitoneal cisplatin (KCOG9812 study)
Authors: Tsubamoto H. , Ito K. , Itani Y. , Ito K. , Iijima T. , Hosokawa K. , Adachi S.
Published: March 2020

5576

Background: Intraperitoneral administration (IP) of cisplatin is recommended by National Cancer Institute for the patients with optimally debulked epitherial ovarian cancer (EOC). However, the advantage is not determined for the suboptimally debulked EOC after the initial surgery. We conducted a phase II study of cisplatin IP after the interval debulking surgery (IDS) following 3 cycles of intravenous platinum. Methods: The initial planned sample size was 30. Eligible patients had previously untreated, histologically confirmed EOC or primary peritoneal carcinoma (PPC) of FIGO stage IIIB-IV with suboptimal (> 1 cm) residual disease. Carboplatin AUC 4 iv d1 and cisplatin 50 mg/sqm iv d3 q21d for 3 cycles. After IDS, paclitaxel 175 mg/sqm iv d1 (or paclitaxel 60 mg/sqm iv d1,d8,d15) and cisplatin 75mg/m2 IP q21d for 4 cycles. Primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS) and toxicity. Results: 33 patients were enrolled since 1998 till 2005. The median age was 55 (range 19–77). ECOG PS 0/1/2 = 33%/36%/31%; stage IIIB/IIIC/IV = 6%/64%/30%; 91% serous papillary histology. Optimal interval debulking surgery was possible in 85%: none (61%), < 1 cm (24%). Grade 3 or 4 (CTCAE ver.3) non-hematologic toxicity was seen in one patient of neurotoxicity. Grade 3 or 4 hematologic toxicities include: neutropenia (37%), infection (4%), thrombocytopenia (11%). 55% were completed the treatment schedule. The reasons for discontinuing were drug resistance (12%), subileus (4%), elevation of serum creatinine (12%), G3 neurotoxicity (4%), IP catheter block (12%) and infection (4%). Primary recurrent sites of total 20 patients before the second line chemotherapy or surgery were peritoneal cavity (30%), distant metastasis (45%), retroperitoneal lymph nodes (15%), and elevation of serum CA125 (10%). Median PFS was 24 months; median overall survival was 48 months; median follow-up was 36 months (range 15–100). Conclusions: This treatment including cisplatin IP after IDS for the patients with the initially suboptimally debulked EOC was feasible, and showed good prognosis with the small number of the intraperitoneal recurrence.

[Table: see text]
Evaluation of the prognostic significance of human kallikrein 8 protein expression levels in advanced ovarian cancer by using automated quantitative protein analysis
Authors: Kountourakis P. , Psyrri A. , Scorilas A. , Markakis S. , Kowalski D. , Camp R. L. , Diamandis E. P. , Dimopoulos M. A.
Published: March 2020

5581

Background: Kallikreins, a subgroup of the serine protease enzyme family, are considered important prognostic biomarkers in cancer. Here, we sought to determine the prognostic value of kallikrein 8 (hkl8) in ovarian cancer using a novel method of compartmentalized in situ protein analysis. Materials and Methods: A tissue array composed of 150 advanced stage ovarian cancers, uniformly treated with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of kallikrein 8 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Results: Mean follow-up time of the cohort was 34.35 months. One hundred twenty six of 150 cases had sufficient tissue for AQUA analysis. There was association between tumor mask hk8 protein expression levels and clinicopathological variables including grade (p=0.0011), residual disease (p=0.0063),clinical response to chemotherapy (p=0.0346). In univariate survival analysis there was a correlation between hk8 tumor mask expression and 5 years progression-free survival. Low hk8 expression correlated with better outcome (top vs. bottom quartile, p = 0.0319). In multivariate survival analysis, adjusting for well-characterized prognostic variables, tumor hkl8 expression level retained its prognostic significance for disease free survival (95%CI: 0.341–1.027, p=0.0468). Conclusions: Human Kallikrein 8 is an adverse prognostic factor in patients with ovarian cancer.The possibilities that hK8 may be suitable candidate as diagnostic, prognostic marker and therapeutic target merit further investigation.

No significant financial relationships to disclose.
Novel phase II study design of MORAb-003, a monoclonal antibody against folate receptor alpha in platinum-sensitive ovarian cancer in first relapse
Authors: Phillips M. , Armstrong D. , Coleman R. , Weil S. , Arseneau J. , Glenn D. , Puls L. , Senzer N. , Torres J. , White A.
Published: March 2020

5583

Background: Folate receptor alpha (FRA) is over-expressed in the majority of epithelial ovarian cancers (EOC) but largely absent from normal tissue. MORAb-003 (M3) is a humanized monoclonal antibody to FRA. Binding of M3 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-positive tumor cell killing; and suppresses tumor growth in xenograft models. High-dose M3 is non-toxic in monkeys. A phase 1 study showed no significant AEs and suggestions of efficacy in platinum-resistant EOC. This phase 2 efficacy study will determine the efficacy of M3 in platinum-sensitive EOC in first relapse, either as a single agent (SA) in asymptomatic relapse, or in combination with platinum and taxane (P/T) in symptomatic relapse, and to maintain a second response. Methods: Subjects with EOC in first relapse are eligible. For CA125 elevation without symptoms (± measurable disease) the subject receives SA M3 until progression. For symptomatic relapse the subject receives P/T and M3. Subjects with CR or PR receive SA M3 maintenance therapy with the objective of prolonging the second remission longer than the first. Endpoints include CA125 and CT scans. ORR and PFS will be determined for each arm. Results: To date, 15 subjects have been treated, 8 in combination therapy and 7 on single-agent M3. No significant drug-related adverse events have been reported. All subjects treated with the combination of M3 and P/T for symptomatic relapse who have reached at least the first evaluation point have achieved a normalization of CA125 and reduction of tumor size (CR or PR) by CT scan using RECIST criteria, including 3 of 3 subjects with first remissions of 6 to 9 months. Early responses have been observed in the SA M3 treatment arm. Conclusions: This first phase 2 study will determine the efficacy of M3, either as SA or in combination with P/T chemotherapy to achieve a meaningful response rate in EOC in first relapse, and to maintain the second remission longer than the subject’s own first remission. These data will be used to define the most effective phase of disease in which to use M3, and to focus a pivotal study on the area of greatest efficacy. The early results continue to demonstrate activity of M3 in EOC.

No significant financial relationships to disclose.
Comparative phase II study of intraperitoneal (IP) versus intravenous (IV) carboplatin administration with IV paclitaxel in patients with bulky residual disease after primary debulking surgery for epithelial ovarian or primary peritoneal cancer: A Sankai Gynecology Study Group (SGSG) study
Authors: Fujiwara K. , Nagao S. , Kigawa J. , Noma J. , Akamatsu N. , Miyagi Y. , Numa F. , Okada M. , Aotani E. , Terakawa N.
Published: March 2020

5584

Background: To assess the anti-tumor effect and safety of IP carboplatin (C) administration comparing with IV C administration in combination with IV infusion of paclitaxel (P). Methods: This is a non-randomized comparative phase II trial. Eligible patients were those with histologically confirmed epithelial ovarian or primary peritoneal cancer who received initial surgery and ended up with residual disease >= 2 cm. They must have reasonable hematological, hepatic, renal function before receiving chemotherapy. The patients received either of the following treatment arms; IP Arm: IV P 175 mg/m2 over 3h followed by IP C AUC6, IV Arm: IV P 175 mg/m2 over 3h followed by IV C AUC6. The treatments were scheduled to repeat 6–8 cycles. Interval debulking surgery was allowed after 3 to 5 cycle of treatment. Each participating institution had to declare, before the study was opened, which of the treatment arms the patients from the institution would be entered. Primary endpoint was a response. Secondary endpoints were toxicity and progression-free survival (PFS) and overall survival (OS). Target accrual was 30 patients in each arm. Results: Total accrual was 26 patients for IP arm and 30 patients for IV arm between 2001 and 2005. The study was closed early, because of the conflict of protocols for IP treatment. Eligible patients were 24 in IP Arm and 25 for IV arm. Median number of treatment cycle was 6 for both arms. Although the difference was not statistically significant, response rate was better in the IP Arm. Response rates were 83.3% (95%CI: 62.6%-95.3%) for IP Arm and 60.0% (95%CI: 38.7%-78.9%) for IV Arm. As of median followup of 31 months, median PFS is 25 months for IP Arm and 21 months for IV Arm,. Median OS is not reached for IP Arm, and 52 months for IV arm. Incidences of hematological and non-hematological toxicities were essentially the same on both arms. Conclusions: IP administration of C may be a better treatment strategy for epithelial ovarian and primary peritoneal cancer patients. A randomized phase III trial including bulky residual disease for comparison of IP and IV carboplatin treatment.

No significant financial relationships to disclose.
Increased risk of cervical cancer in high-risk families with and without mutations in the BRCA1 and BRCA2 genes
Authors: Rhiem K. , Fischer C. , Bosse K. , Wappenschmidt B. , Schmutzler R. K.
Published: March 2020

5588

Background: In BRCA germline mutation carriers increased risks for cancer at other sites than breast and ovary have been reported. Methods: To evaluate the risk of BRCA-associated cancers, we conducted a cross-section analysis in 4405 individuals from 409 families with BRCA1 (n=86) or BRCA2 mutations (n=53) and 270 high risk BRCA1/2 negative families ascertained by the Familial Breast and Ovarian Cancer Center Cologne. We considered proven mutation carriers, individuals affected by breast and ovarian cancer and their first degree relatives and identified 921 individuals from BRCA1 (604 female; 317 male), 571 from BRCA2 (365 female; 206 male) and 2913 from BRCA1/2 negative (1938 female; 975 male) families that suffered from 677 cancers other than breast and ovarian cancers. Relative risks (RR) of the study group compared to the general population were evaluated by the standardized incidence ratio (SIR), using data from two German Cancer Registries. Results: The risk for cervical cancer is significantly increased in women from BRCA1 and BRCA2 positive (RR=4.59, 95% CI=2.20 to 8.44, and RR=3.69, 95% CI=1.20 to 8.61; p=<0.001) and from BRCA1/2 negative families (RR=2.97, 95% CI=1.88 to 4.45). Moreover, the risk for pancreatic cancer in women from BRCA2 positive and BRCA1/2 negative families as well as the risk for prostate cancer in men from BRCA2 positive families is increased (RR=5.10, 95% CI=1.65 to 11.90; RR=1.98, 95% CI=1.02 to 3.46; RR=2.09; 95% CI=1.00 to 3.84). Conclusions: We here report an increased risk of cervical cancer for women from BRCA1 and BRCA2 positive and from BRCA1/2 negative high risk families, respectively. These results are in line with other studies in BRCA1 and 2 positive individuals and should be considered in the clinical risk management of these individuals.

No significant financial relationships to disclose.
Role of -2518 MCP-1 polymorphism in cervical cancer development
Authors: Coelho A. P. , Nogal A. , Pereira D. , Matos A. , Sousa B. , Araújo A. , Catarino R. , Medeiros R.
Published: March 2020

5594

Background: Cervical cancer (ICC) and squamous intraepitelial lesions of the cervix uteri (SIL) constitute serious health problems to women worldwide. ICC occupies the second place in the list of tumours afflicting women. Around 470,000 new cases are diagnosed annually, 80% of which in less developed countries and near half of them resulting in death of the women. MCP-1 chemokine is the main determinant of tumour associated macrophages (TAM) content in the squamous cell carcinoma of the uterine cervix. The aim of our study was the evaluation of the association between the -2518 MCP-1 polymorphism (a biallelic G/A functional polymorphism) and susceptibility to cervical intraepithelial lesions and cervical cancer development. Methods: We analyzed 898 samples of DNA, of which 420 corresponded to healthy women (control group), 130 to women with low and high-grade cervical intraepithelial lesions and 348 to women with cervical cancer. The analysis of the polymorphism and the evaluation of the corresponding genotypes were performed with the PCR-RFLP methodology. Analysis of data was performed using the computer software SPSS for windows. Results: The analysis of the genotipic frequencies of the -2518 MCP-1 genotypes indicates that women carrying genotypes with the G allele present a 29.2% protection for the development of intraepithelial lesions of the cervix uteri (OR=0.708; 95% CI: 0.503–0.998; P=0.048) and a 33.5% protection for the development of squamous cell carcinoma of the cervix uteri. It was also possible to observe an association between the waiting time to onset of cervical cancer and the polymorphism: 59 years for women carrying genotypes with the G allele (95% CI: 56–61years) and 53 years for women with the AA genotype (95% CI: 52–57 years; P=0.005). Also, women with genotypes carrying the G allele present a 2.5 fold higher risk for the progression from early stages of invasive cervical carcinoma (I/II) to clinically more advanced stages (III/IV) (OR=2.26; 95% CI: 1.09–4.67; P=0.026). Conclusions: These findings suggest a role of the -2518 MCP-1 polymorphism in the molecular mechanisms that lead to cervical cancer development and progression.

No significant financial relationships to disclose.
A pilot study of adjuvant bevacizumab after neoadjuvant chemotherapy for high-risk breast cancer
Authors: Mayer E. L. , Miller K. D. , Rugo H. S. , Peppercorn J. M. , Carey L. A. , Ryabin N. , Winer E. P. , Burstein H. J.
Published: March 2020

561

Background: Patients with residual breast cancer after neoadjuvant chemotherapy are at increased risk of recurrence and may have chemotherapy-resistant disease. We sought to explore the role of novel antiangiogenic therapy in this patient population. Methods: This phase II trial evaluated the feasibility and toxicity of adjuvant antiangiogenic therapy. Eligible patients had stage II-III breast cancer with residual invasive carcinoma at surgery following anthracycline-containing neoadjuvant chemotherapy. Treatment consisted of bevacizumab 15 mg/kg given every three weeks for one year, starting no less than 1 month after surgery or 2 weeks after radiation. Concurrent endocrine and/or trastuzumab therapy was allowed. The primary endpoint was feasibility and tolerability of single agent bevacizumab. Results: 40 patients were treated with bevacizumab monotherapy. Median age was 50 years, 45% were stage III, 58% were hormone receptor positive, and 8% were HER2+. There were 11 delays in treatment administration (average delay = 7.2 days). To date, patients are on average through 10.4 of 17 planned cycles of therapy, with 3 patients completing treatment and 3 patients with tumor recurrence on study. Treatment-related toxicities include mild arthralgias (50%), headache (50%), epistaxis (20%), and hypertension (23%). One patient experienced reversible posterior leukencephalopathy related to hypertension, one patient had GI bleeding, and 4 subjects voluntarily removed themselves from the protocol. No cardiac dysfunction has been observed. Definitive feasibility/safety data and preliminary correlative studies will be available by June 2007. Conclusions: Adjuvant bevacizumab after neoadjuvant chemotherapy appears tolerable and feasible with side effects including hypertension, arthralgias, epistaxis, and headache. Three recurrences within a median follow-up of 7.5 months underscore the need for novel treatments among such patients. Ongoing trials are evaluating bevacizumab with oral chemotherapy.

[Table: see text]
Detection of minimal residual disease (MRD) in peripheral blood of primary breast cancer patients: Translational research in the SUCCESS study
Authors: Jueckstock J. K. , Rack B. , Thurner-Hermanns E. , Forstbauer H. , Pantel K. , Ulmer H. , Beckmann M. , Lichtenegger W. , Janni W. J. , Friese K.
Published: March 2020

565

Background: Patients with detection of MRD in bone marrow are known to have an increased risk for recurrence and a poorer clinical outcome. However, peripheral blood would be the preferable compartment to monitor treatment efficacy due to increased feasibility. The translational research program of the German SUCCESS-trial was established to evaluate MRD in peripheral blood at 4 different time points during adjuvant systemic treatment of breast cancer patients. Here first results of the detection of MRD at primary diagnosis and after adjuvant chemotherapy will be presented. Patients and Methods: Cells were separated by Ficoll-Hypaque density- gradient centrifugation followed by labelling of epithelial cells with the anti-cytokeratine-antibody A45-B/B3 (directed against cytokeratines 8, 18 and 19) and immunohistochemically staining with neu-fuchsin. All preparations were screened by two independent persons. Results: 328 breast cancer patients were analyzed at primary diagnosis. Among those, 133 patients returned for a 2nd blood sampling after completion of adjuvant chemotherapy. Most of the tumors were small (43% pT1, 51% pT2, 4% pT3, 1% pT4) but of intermdediate or unfavourable grade, (G1 7%, G2 48%, G3 45%). 66% of the patients were node-positive (34% pN0, 38% pN1, 20% pN2, 8% pN3) and a positive hormone receptor status was seen in 71%. In 22% the Her2-status was positive. MRD in peripheral blood was found in 31% of all patients before and in 9% after chemotherapy. The mean number of detected cells was 2 (range 1- 9). In 87,2 % of the patients who showed MRD at the first measurement no MRD was detected after chemotherapy. 16% of patients without detection of MRD at primary diagnosis showed MRD after chemotherapy. Neither tumor size (p= 0.624), lymph node metastases (p= 0.450), histopathological grading (p= 0.168), hormone receptor status (p= 0.270) or Her2/neu status of the primary tumor (p= 0.893) correlated with the presence of MRD. Conclusions: The detection of MRD in peripheral blood can be widely used and is suitable for repeated measurements. Further follow-up will show, if this method can be used for risk stratification and monitoring of treatment efficacy in adjuvant breast cancer.

No significant financial relationships to disclose.
Prognostic (Px) significance of Ki67 before and after neoadjuvant chemotherapy (CT) in early breast cancer
Authors: Jones R. L. , Salter J. , Nerurkar A. , Parton M. , A’Hern R. , Smith I. E. , Dowsett M.
Published: March 2020

573

Background: High levels of the proliferation marker Ki67 are associated with a higher response rate to CT but poorer long-term outcome. The Px significance of Ki67 before CT and at surgical excision was compared. Methods: 103 patients treated with CT with pre- and post- (excision) CT tissue and a further 181 with only excision tissue available were identified, 37 and 76 of these respectively were ER+ and also received tamoxifen. The following factors were considered pre-CT and at excision (where relevant) for their relationship with relapse-free (RFS) and overall (OS) survival: ER, PR, HER2, grade, Ki67, histological type, vascular invasion, age/menses, T and N stage, pre-therapy operability, clinical response, CT regimen, type of surgery, adjuvant therapy, pathological tumour size and nodal involvement. Results: In the paired cohort univariate analysis of RFS the following factors were associated with poorer Px (a) pre-CT: ER- (p=0.003); increasing T stage (p<0.001), N stage (p=0.002) and Ki67 (p<0.001); (b) at excision: increasing grade (p=0.01), tumour size (p=0.02), nodal status (p<0.001) and Ki67 (p<0.001); no adjuvant endocrine therapy (p<0.001). On multivariate analysis only excision Ki67 (p<0.001) was significant although there was a suggestion pre-therapy Ki67 was important (p<0.10). On univariate analysis of OS the following factors associated with poorer Px (a) pre-CT: ER- (p=0.006); increasing T stage (p<0.001) and Ki67 (p<0.001); (b) at excision: increasing grade (p=0.04), tumour size (p=0.005), nodal status (p<0.03) and Ki67 (p<0.001); no adjuvant endocrine therapy (p=0.001). On multivariate analysis both pre-CT and excision Ki67 were significant independent predictors but the latter was more highly significant. (p<0.02 + p<0.0001, respectively) Assessing the combined group of 284 patients, after 5 years the highest and lowest tertiles of excision Ki67 had strikingly different Px: RFS 36% and 73%; OS 50% and 85%, respectively. Conclusions: Ki67 after CT is a strong predictor of long-term outcome. The greater significance of Ki67 in the excision sample may be due to this identifying patients in whom residual highly proliferative disease remains after CT.

No significant financial relationships to disclose.
A correlative study of cardiac biomarkers and left ventricular ejection fraction (LVEF) from N9831, a phase III randomized trial of chemotherapy and trastuzumab as adjuvant therapy for HER2-positive breast cancer
Authors: Kutteh L. A. , Hobday T. , Jaffe A. , LaPlant B. , Hillman D. , Kaufman P. , Davidson N. , Martino S. , Moreno A. , Perez E.
Published: March 2020

579

Background: N9831 and other clinical trials have demonstrated the additive survival benefit of trastuzumab (H) therapy with chemotherapy for patients with resected HER-2 positive breast cancer. Cardiac toxicity (CTox) is increased by this strategy. Prediction of or early detection of CTox is important. Methods: 95 patients provided informed consent. Brain natriuretic peptide (BNP), C-reactive protein (CRP), troponin T (TnT) and I (TnI), TNF-alpha, IL-1b, and IL-6 were to be drawn at baseline, after initiation of doxorubicin/cyclophosphamide (AC), after initiation of paclitaxel (T), and after the initiation of H (may have been given concurrently with T). 67 patients with at least a baseline sample, a post-treatment sample, and a baseline and subsequent evaluation of LVEF were studied. No patient in this group had a grade 3 decline in LVEF. Only 3 of these patients did not receive H. Values above the 99th percentile were considered abnormal for troponin. 40 ng/ml was considered elevated for BNP. Results: Values of CRP, TNF-alpha, IL- 6 and IL1b changed in very few patients and without a discernible pattern. For further evaluation of BNP, TnI, and TnT, 2 definitions of CTox were tested: 1. a >10% drop in LVEF from baseline (n=27) and 2. a drop in LVEF of 10–15% to less than the institutional lower limit of normal (LLN) OR a >15% decline in LVEF (n=14). No pre-treatment marker appeared to predict a > 10% decline in LVEF (definition 1). For patients fulfilling definition 2, pre-treatment BNP > 40 was seen in 21% of patients vs 8% of normals (nls) (p= 0.18) and an abnormal TnI (>0.04) was seen in 21% vs 6% of nls (p=0.10). Only doubling of BNP appeared promising as a serial marker of CTox using definition 2 (27% vs 7% for nls (p = 0.09). Conclusions: Baseline BNP and TnI and serial measures of BNP may be promising for further investigation for the prediction and detection of treatment-related CTox. Due to limitations of the study including the small numbers of patients analyzed, the difficulty in defining CTox, and the variation in the timing of sample procurement and assessment, these data are considered exploratory. Supported by CA-25224, CA-2115, CA 38926, CA31946.

No significant financial relationships to disclose.
Comparison of vascularity measures from PET and MRI for improved breast tumor characterization and therapeutic response evaluation
Authors: Partridge S. C. , Eby P. R. , Doot R. K. , White S. W. , Kurland B. F. , Schubert E. K. , Dunnwald L. K. , Lehman C. D. , Mankoff D. A.
Published: March 2020

589

Background: Dynamic contrast-enhanced MRI (DCE-MRI) and positron emission tomography (PET) are two imaging modalities previously shown to be predictive of response to neoadjuvant therapy in breast cancer. As the two techniques are functionally very different, the extent of their agreement or discordance for tumor characterization is not well understood. The purpose of this study was therefore to investigate the association between quantitative DCE-MRI enhancement kinetics and 15O-water PET/18F-FDG PET blood flow and metabolic measures of breast tumors. Methods: We retrospectively evaluated exams for 20 patients with locally advanced breast cancer (LABC) who underwent both 15O-water/18F-FDG PET and DCE-MRI. PET measures included 15O-water blood flow, 18F-FDG transport rate constant from blood to tissue (K1), and FDG metabolic rate. DCE-MRI measures included functional tumor volume, initial peak enhancement (PE), and a delayed signal enhancement ratio (SER) assessing washout. Pearson’s correlations and multivariate stepwise regression analyses were performed; p<0.05 was considered significant. Results: PET 15O-water blood flow correlated significantly with DCE-MRI peak SER (r=0.8) and tumor volume (r=0.7). PET K1 measures correlated significantly with DCE-MRI peak PE (r=0.7), peak SER (r=0.6) and tumor volume (r=0.6). By multivariate analysis, SER was the strongest independent MRI correlate of PET blood flow, and PE the strongest MRI correlate for K1. No significant correlations were observed between 18F-FDG PET metabolic rate and the DCE-MRI kinetic parameters. Also, while blood flow and K1 were strongly correlated (r=0.9, p=0.0001), blood flow and metabolic rate were not (r=0.4, p=0.12). Conclusions: The associations between PET and MRI measures may lead to a better understanding of angiogenesis, vascular permeability, and glucose transport in LABC. A lack of correlation of metabolic rate with blood flow and DCE MRI kinetics suggests that 18F-FDG PET provides complimentary metabolic information independent of vascular factors. The combination of MRI and PET may be helpful in understanding tumor pharmacodynamics in response to novel therapy.

No significant financial relationships to disclose.
Pathologic complete response (pCR) following weekly (wkly) paclitaxel (cremophor or albumin-bound) and carboplatin (TC) ± trastuzumab (H), ± bevacizumab (B) in patients (pts) with doxorubicin/cyclophosphamide-resistant (AC-Res) and AC-sensitive (AC-S) large and inflammatory breast cancer
Authors: Mehta R. S. , Schubbert T. , Kong K. , Hsiang D. , Butler J. , Baick C.
Published: March 2020

591

Introduction: Historically, pCR is rare in AC-Res in contrast to AC-S BC except following TCH in HER2+ BC in preliminary analysis (SABCS-2004, #1110). Moreover, robust predictors of pCR are needed. Methods: 106 consecutive BC pts on neoadjuvant studies were treated with GM/G-CSF supported dose-dense AC (except 7**- Table ), 2 cycles if AC-Res and 4 if AC-S. Pts then received 9–12 wkly TC (3 wks on, 1 off) ± 6–8 bi-wkly B if HER2- or +12–16 wkly H if HER2+, followed by surgery. Fisher’s exact test was performed to compare pCR percentages by various characteristics. Results: pCR in breast and lymph nodes in 38 of 84 assessable tumors in the first 82 pts were documented. 67% (56/84) tumors were reduced to ≤5 mm. Overall, no difference in pCR rates were found between AC-S and AC-Res BC, but pCR rates were 2- to 4-fold higher in HER2+, AC-S (79%) and AC-Res (65%) subsets compared to HER2-, AC-S (32%) and AC-Res (16%) subsets. Higher pCR rates were associated with HER2+/hormone receptor- (HR-) > HER2+/HR+, HER2-/HR- (triple-) > HER2-/HR+, and within the HER2+ subset-IHC 3+/FISH+ or unknown > IHC 3+/FISH- or IHC 1–2+/FISH+, and ductal > other histology. No patient had clinical cardiac dysfunction or EF <50, except 1 on AC/TC. 13/106 (12%) progression or death at a median follow-up of 22 months (range 2–46) is mostly due to stage IV and CNS progression. Conclusion: Short course of TCH achieves a high rate of pCR in AC-Res and AC-S, HER2+ BC in contrast to TC ± B in AC-Res and AC-S, HER2- BC. This is the first demonstration of high rate of complete AC resistance reversal across stage II-IV, inflammatory and recurrent HER2+ BC. In vivo response adjusted 2–4 cycles of dose-dense AC limited clinical cardiac toxicity. HER2+ (IHC 3+/FISH+ or unknown), HR- and ductal histology are significant predictors of high pCR. HER2 and HR confer 4 predictive subtypes of BC.

[Table: see text]

No significant financial relationships to disclose.
Association of polymorphic drug metabolizing enzymes (DME) with outcomes in breast cancer patients treated on the ECOG 2190/Intergroup 0121 (E2190/Int0121) study
Authors: Gor P. P. , Gray R. J. , Horn M. , Rebbeck T. R. , Gimotty P. A. , Aplenc R. , Pins M. , Tallman M. S. , DeMichele A.
Published: March 2020

596

Background: Disparate outcomes of breast cancer patients after adjuvant chemotherapy may be influenced by variation in drug metabolism due to genetic polymorphisms in DME. Cyclophosphamide and thiotepa require activation by cytochrome P450 (CYP) and detoxification by glutathione-S-transferase, two highly polymorphic enzymes. We hypothesized that variants in CYP3A4(*1B), GSTM1 and GSTT1 would impact survival outcomes after adjuvant chemotherapy, with effects potentially modulated by chemotherapy dose. Methods: We performed a retrospective cohort study of patients enrolled on E2190/Int0121, a randomized trial of cyclophosphamide (C), doxorubicin (A), and fluorouracil (F) versus CAF + high dose chemotherapy (HDC) using cyclophosphamide and thiotepa followed by stem cell rescue; disease-free survival (DFS) and overall survival (OS) were equivalent in the clinical trial. PCR-based methods were used to genotype hematologic stem cells. Hazard ratios for genotypes were obtained using Cox regression. Results: Stem cell samples and clinical data from August 1, 1991 through August 1, 2005 were available for 347/540 of patients enrolled; 151 patients on CAF and 196 on CAF + HDC arms, respectively. Median follow-up was 9.8 years. See table . CYP3A4*1B allele carriers had significantly poorer DFS (HR 1.84) in the combined cohort and CAF arm (HR 1.87), but not in the HDC arm; OS was not significant by CYP3A4 genotype. GSTM1 null homozygotes in the combined cohort and HDC arm had significantly better DFS (HR 0.70 and 0.66, respectively) and OS (HR 0.67 and 0.57, respectively), but not in the CAF arm. GSTT1 null homozygotes had significantly worse DFS (HR 2.3) and OS (2.02) in the CAF arm, but not in the HDC arm or combined cohort. Conclusions: In the overall E2190/Int0121 cohort, polymorphisms in activating (CYP3A4*1B) and inactivating (GSTM1) DME significantly impact DFS and OS. The detrimental effect of GSTT1 in the CAF arm appears to be ameliorated by HDC.

[Table: see text]

No significant financial relationships to disclose.
Impact on overall survival of primary tumor extirpation in breast cancer patients who present with stage IV disease
Authors: Lang J. E. , Rao R. , Feng L. , Meric-Bernstam F. , Bedrosian I. , Kuerer H. M. , Singletary S. E. , Hunt K. K. , Hortobagyi G. N. , Babiera G. V.
Published: March 2020

598

Background: Limited data exists regarding optimal local therapy for patients who present with stage IV breast cancer with an intact primary tumor. Two retrospective series, from the National Cancer Data Base and the Geneva Cancer Registry, showed that surgery may improve overall survival in these patients. Our institutional experience demonstrated improved metastatic progression-free survival after a median follow-up of 32.1 months but did not show a survival benefit at short term follow-up. We evaluated the impact of local control on overall (OS) and disease-specific survival (DSS) in this population after a longer follow-up interval to determine if a survival benefit could be demonstrated from local surgical treatment for selected patients with stage IV breast cancer. Methods: We reviewed the records of all patients at our institution who presented from 1997–2002 with stage IV disease with an intact primary tumor. OS and DSS were estimated by the Kaplan-Meier method. The log-rank test was used to compare the difference in survival between surgical and non-surgical patients. Multivariate statistical analysis was performed using the Cox proportional hazards model. Results: Of 220 patients identified with stage IV disease with an intact primary tumor, 80 (36%) underwent surgical resection of the primary tumor; 39 (49%) had segmental mastectomy and 41 (51%) had a total mastectomy. There were 140 (64%) patients who did not undergo surgery. The median follow-up duration from time of presentation to our institution was 58.6 months and the median OS time after presentation was 45.8 months. After adjustment for covariates, surgery was associated with improved OS (p=0.03) and DSS (p=0.04) compared to the non-surgical group. Conclusions: With a median follow-up time of 58.6 months, patients who presented with stage IV breast cancer with an intact primary tumor treated surgically had significantly improved OS and DSS compared to patients who did not undergo surgery. Our findings may be limited by a selection bias. Therefore, we feel that the issue of surgical intervention for the primary tumor in stage IV breast cancer patients deserves to be carefully studied in a well-designed, prospective, multi-center trial.

No significant financial relationships to disclose.
No statistical impact of intra-tumoral overexpression of EGFR, VEGF and p53 on the overall survival in head and neck squamous cell cancer (HNSCC): Preliminary results of the GORTEC 99–02 randomized trial
Authors: Metges J. , Volant A. , Auperin A. , Gregoire V. , Maingon P. , Lesaunier J. , Calais G. , Bourhis J.
Published: March 2020

6010

Background: Predictive and prognostic factors are warranted to improve the management of HNSCC patients. We designed a prospective study to analyze the p53 status, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) tumoral overexpression of the patients included in the GORTEC 99–02 prospective phase III trial which compared conventional radiotherapy (RT) plus 5FU and carboplatin (FUP) vs RT with concomitant boost and FUP vs very accelerated RT Methods: This propective study has been designed to include 820 patients. We present here the results in a sub group of 219 patients for whom the immunohistochemical overexpression of EGFR, P53 and VEGF was analyzed. Association beetween these markers and TNM staging, age, sex,disease progression and survival was evaluated. Tumor overexpression was assessed by immunohistochemistry for EGFR (Dako EGFR pharmDx™ kit), VEGF (Santa Cruz Biotech), P53 (Dako). EGFR status was defined as positive or negative.If positive, we evaluated the percentage of cells presenting the same intensity of staining. Staining pattern was qualified as “diffuse” if more than 95% of cancer nests were stained with the same intensity, and as “mosaic” if the staining was heterogeneous Statistical analysis were performed using Spearman correlation coefficient, Kruskal-Wallis test for quantitative variables, chi2 and Fisher exact test for qualitative variables and Logrank test and cox model for survival analysis. Multivariate analysis of survival took into account T and N status, tumor localisation and the type of treatment. Results: Positive expression for P53, VEGF and EGFR were respectively found in 56.4%, 61.1% and 94%.Diffuse EGFR status was associated with higher T status (p=0.0141). VEGF(+) status was associated with increased EGFR staining (p=0.0017). Patients with p53+ status were younger than p53(-) (p=0.0362). P53,VEGF and EGFR expressions were not significatively related to survival Conclusions: These preliminary results don’t found any relationship between intra-tumoral markors and survival in HNSCC.Work supported by a french PHRC from the national Institute of Health

No significant financial relationships to disclose.
S0216: A Southwest Oncology Group (SWOG) phase II trial of docetaxel (T), cisplatin (P), and fluorouracil (F) induction followed by accelerated fractionation/concomitant boost (AF/CB) radiotherapy (RT) and concurrent cisplatin for advanced head and neck squamous cell cancer (HNSCC)
Authors: Adelstein D. J. , Moon J. , Hanna E. , Shankar Giri P. G. , Mills G. M. , Wolf G. T. , Urba S. G.
Published: March 2020

6014

Background: Randomized trials have suggested benefit from three-drug taxane-containing induction chemotherapy, and from AF/CB RT in patients (pts) with locoregionally advanced HNSCC. In an effort to optimize non-operative therapy, this SWOG phase II trial combined these two interventions with standard concurrent single-agent cisplatin. Methods: Eligibility required a diagnosis of untreated stage III or IV (M0) HNSCC deemed appropriate for RT with curative intent, a performance status of 0–1, and adequate hematologic, renal, and hepatic function. Two courses of induction TPF (T 75 mg/m2 day (d)1, P 100 mg/m2 d1, and F 1,000 mg/m2/d as a 24 hour continuous IV infusion d1–4) were given, 21 days apart. Stable or responding pts received definitive AF/CB RT; 54 Gy in 30 fractions (fx) to the total volume, with a concomitant boost of 18 Gy in 12 fx given on the last 12 treatment days. Concurrent cisplatin (100 mg/m2) was given on d1 and d22 of the RT. An accrual of 60 pts was planned using a one-stage study design. The primary endpoint was overall survival (OS). Secondary endpoints were toxicity and response. Results: Between 3/1/03 and 8/15/04, 76 pts were enrolled; 74 were eligible and evaluable. The median age was 54 years; 82% were male, and 77% white. 52 pts (70%) had stage IV disease. 40 pts (54%) experienced at least one grade (G)4 toxicity during induction, including neutropenia in 32, with fever in 13. 62 pts completed induction and began concurrent chemoradiotherapy (CCRT); 50 completed all planned treatment. 57 pts have been evaluated for toxicity from CCRT. At least one G4 toxicity was noted in 20 pts, including neutropenia in 6, with fever in 3. There were 2 treatment-related deaths during induction, and 2 during CCRT. With a median follow-up of 27 months, the 2-year projected OS is 72% (95% CI 62%-83%), with a projected progression-free survival (PFS) of 66% (95% CI 55%-77%). Conclusions: TPF induction followed by AF/CB RT and concurrent cisplatin is toxic but feasible within a cooperative group. In this cohort of pts with advanced HNSCC, OS and PFS are encouraging, and justify further study of this approach.

No significant financial relationships to disclose.
A phase II study of gefitinib in patients with advanced thyroid cancer
Authors: Pennell N. A. , Daniels G. H. , Haddad R. I. , Ross D. S. , Wirth L. J. , Fidias P. H. , Temel J. S. , Gurubhagavatula S. , Clark J. R. , Lynch T. J.
Published: March 2020

6020

Background: There are few effective treatments for locally advanced or metastatic thyroid cancers that are refractory to radioactive iodine (RaI). The epidermal growth factor receptor (EGFR) is highly expressed on normal and malignant thyroid tissue, and has been associated with a worse prognosis in well-differentiated thyroid cancer. The EGFR tyrosine kinase inhibitor gefitinib is effective in inhibiting the growth of thyroid cancer cells in vitro. This study sought to determine the efficacy and tolerability of gefitinib in patients with advanced thyroid cancer. Methods: In this open-label phase II trial, patients with RaI-refractory, locally advanced or metastatic thyroid cancer received 250mg of daily gefitinib. Anaplastic and medullary thyroid carcinoma were considered RaI refractory based on histology. The primary endpoint was overall response rate. Secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), and tumor marker responses. Tumor markers consisted of serum thyroglobulin (Tg) in the differentiated cancers and serum calcitonin and carcinoembryonic antigen in medullary thyroid cancer. Results: A total of 27 patients were enrolled. 59% were male and the median age was 65. Histologic subtypes included papillary (41%), follicular (22%), anaplastic (19%), medullary (15%), and Hürthle cell carcinoma (4%). There were no objective tumor responses among the 25 patients evaluated, at which point the trial was halted. However, 32% of patients had objective reductions in tumor volume that did not meet criteria for PR. 48%, 24%, and 12% of patients had stable disease (SD) after 3, 6, and 12 months of treatment. Median PFS and OS were 3.7 [95% CI; 1.8, 5.7] and 17.5 months [9.2, not yet reached]. Five patients with SD had a decrease in Tg to <90% of baseline level that was maintained for at least 3 months. Gefitinib was well tolerated, with 11% of patients experiencing grade 3 toxicity. Conclusions: Gefitinib therapy did not result in any objective tumor responses. However, reductions in tumor volume, falling Tg levels, and prolonged SD in a subset of patients may indicate biologic activity. The OS of 17.5 months was superior to historical rates in this population. However, the significance of this is difficult to interpret in the absence of a randomized comparison group.

No significant financial relationships to disclose.
EGFR expression by immunohistochemistry (IHC) and response to chemotherapy and cetuximab in squamous cell carcinoma of the head and neck (SCCHN)
Authors: Kies M. S. , Ghebremichael M. S. , Katz T. L. , Herbst R. S. , Youssoufian H. , Burtness B.
Published: March 2020

6024

Background: There is modest activity for cetuximab in recurrent SCCHN. Molecular markers for patient selection are desirable. Burtness et al (JCO 23:8646, 2005) reported that high EGFR expression predicted for tumor resistance to chemotherapy (CT) with or without cetuximab. We have studied an independent cohort of patients from the IMC-9816 study (Herbst et al, JCO 23:5578, 2005) using the same EGFR immunoreactivity staining technique. Methods: Slides were prepared from formalin fixed paraffin embedded tissue with the DAKO kit, with staining intensity graded on an ordinal scale 0–3 and staining density assessed according to the percentage of cells stained. High expression was defined as staining intensity 3 + on = 80% of cells. Tumor samples were available in 77 pts from the initial cohort of 132 patients with recurrent SCCHN who received cisplatin-based CT. Of the latter, 76 patients were assessed to have stable (SD 51) or progressive disease (PD 25) and then treated with cetuximab and cisplatin. An amendment permitted further enrollment of patients with PD after off study cisplatin therapy (N 54). Of a total of 130 pts who received cetuximab and cisplatin, tumor samples were available from 86. Results: There was no association of response with EGFR expression. Responses to CT are tabulated. Of the 86 SD and PD pts receiving CT and cetuximab, responses were observed in 3 of 44 and 7 of 42 pts with low and high EGFR expression, respectively (p=0.191). In a survival analysis of patients treated with cetuximab, the hazard ratio for subjects with high EGFR was 0.835, p=0.40. Conclusions: Conventional IHC, even when supplemented by staining intensity and staining density, does not predict for responsiveness of SCCHN to CT, with or without cetuximab. Future studies may require more quantitative methods, possibly subcellular localization, and measurement of other EGFR pathway targets, ligand content and probably “down-stream” effectors.

No significant financial relationships to disclose.

[Table: see text]