bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of MORAb-003, a humanized anti-folate receptor-alpha monoclonal antibody, in platinum resistant ovarian cancer
Authors: Konner J. A. , Ahmed S. , Gerst S. , Vander Els N. , Pezzuli S. , Sabbatini P. , Hensley M. , Dupont J. , Tew W. , Aghajanian C.
Published: March 2020

5027

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 (MAb) to FRA. Binding of M3 to FRA can prevent phosphorylation of substrates specific for the Lyn kinase; suppress proliferation of cells over-expressing FRA; mediate FRA-positive tumor cell killing via antibody-dependent cellular and complement-dependent mechanisms; and suppress tumor growth in vivo of FRA-expressing tumors in rodent xenograft models. Toxicology studies in non-human primates found no evidence of toxicity with M3 at supra-pharmacological doses. This open-label, multiple-infusion, first-in-human, dose-escalation trial evaluates the safety, pharmacokinetics (PK), and antitumor activity of M3 in patients with platinum-resistant EOC. Methods: Sequential cohorts of patients receive four weekly infusions at escalating dose levels of M3, from 12.5 mg/m2 to 100 mg/m2. Human anti-human antibody (HAHA) and PK analyses are performed. Eligible patients have EOC that relapsed < 6 months after platinum-based therapy, acceptable organ function, Karnofsky Performance Status ≥ 70%, and measurable disease by GOG-RECIST criteria. Patients undergo pulmonary function testing (PFT) at baseline, and at end of study. Results: To date, 7 women have been treated with M3: 3 at the 12.5 mg/m2 dose, 3 at 25 mg/m2, and 1 at 37.5 mg/m2. Median age was 60. Neither dose limiting toxicity nor HAHA has been observed. Grade 1 rash occurred in 1 patient. Grade 1/2 fever following drug administration occurred in 2 patients. Grade 2 FEV1 decrease was observed in a patient with likely pulmonary lymphangitic metastasis. One subject at 25 mg/m2 had radiographically stable disease. At low doses, the PK analysis demonstrated the half-life to be shorter than anticipated based on animal studies, possibly due to tumor binding. Radiolableled imaging studies are underway to determine the distribution of M3. Conclusions: The FRA-specific MAb MORAb-003 appears to be well tolerated in patients with EOC. Enrollment continues and updated results will be presented.

No significant financial relationships to disclose.
Secondary cytoreductive surgery for localized recurrent epithelial ovarian cancer: Analysis of prognostic factors and survival outcome
Authors: Salani R. , Santillan A. , Zahurak M. , Giuntoli R. , Gardner G. J. , Armstrong D. K. , Bristow R. E.
Published: March 2020

5029

Background: To evaluate prognostic factors and survival outcome of patients undergoing secondary cytoreductive surgery for recurrent epithelial ovarian cancer with ≤ 5 sites of recurrence on pre-operative imaging studies. Methods: Patients undergoing secondary cytoreduction for recurrent epithelial ovarian carcinoma between 9/1997–3/2005 were retrospectively identified from tumor registry databases. Inclusion required: complete clinical response to primary therapy, ≥12 months between initial diagnosis and recurrence, and ≤5 recurrence sites on pre-operative imaging studies. Univariate and multivariate logistic regression analyses were used to evaluate the effect of clinico-pathologic variables on overall post-recurrence survival. Results: Fifty-five patients met study inclusion criteria. The median age at recurrence was 57.7 years and the median diagnosis-to-recurrence interval was 32 months (range 12 to 164 months). Complete cytoreduction was achieved in 41 patients (74.5%). On multivariate analysis, the statistically significant and independent predictors of overall survival were diagnosis-to-recurrence interval ≥18 months (median survival=49 months vs 3 months, p = 0.001), the number of radiographic recurrence sites (median survival: 1–2 sites=50.0 months vs 3–5 sites=12.0 months, p < 0.03) and residual disease (median survival: no gross residual=50 months vs macroscopic residual=7.2 months, p < 0.01). Age, tumor grade, histology, CA-125 level, ascites, and tumor size were not significantly associated with survival. Conclusions: These data support the definition of localized recurrent ovarian cancer as patients with 1–2 radiographic recurrence sites. In this select population, a diagnosis-recurrence interval ≥18 months and complete secondary surgical cytoreduction, which was achievable in the majority of cases, were associated with a median post-recurrence survival time of approximately 50 months.

No significant financial relationships to disclose.
ABCF2 expression in endometrial cancer and breast cancer
Authors: Tsuda H. , Ogawa Y. , Nishimura S. , Kajitani K. , Kawamura N. , Hashiguchi Y. , Berkowitz R. S. , Mok S. C.
Published: March 2020

5035

Background: ABCF2 is a new member of the ATP-binding cassette transporter superfamily gene. We previously reported that ABCF2 protein is new biomarker in clear cell adenocarcinoma (CC) of the ovary and its expression may predict the response to chemotherapy and survival of CC patients (Proc ASCO 2005, Clin Cancer Res 2005). Both breast cancer (BC) and endometorial cancer (EC) are estrogen-dependent tumors, however, their biological behavior differ. In this study, we examined ABCF2 expression in EMCA and BC and evaluated the relationship between ABCF2 expression and clinical factor. Methods: Formalin-fixed surgical samples from 100 EMCA and 191 BC patients were included in this study. ABCF2 expression was investigated by immunohistochemistry. Positive expression of ABCF2 was > 10% based on the cytoplasmic staining. Results: Histologic types and stage were as followed: EMCA: (Endometrioid (EM): 92; Adenosquamous (AS): 8), (I: 63; II: 5; III: 30; IV: 2). BC: (Papillo tu (PP): 60; Solid tub (SL): 38; Scirrhous (SC): 77; Other (OT): 15). Breast cancer was sub-classified into 3 types according to the criteria of the Japanese Breast Cancer Society. The relationship between ABCF2 expression and histologic type was shown in table. In EMCA and BC, there were no significant relationship between ABCF2 expression and clinical factor like stage, histologic type, grade and estrogen receptor (ER). In EMCA, ABCF2 expression was not related with disease free survival (DFS). However, in BC, ABCF2-positive tumors had longer DFS than ABCF2-negative tumors (p = 0.03). The ABCF2 expression were correlated with further biological variables such as tumor stage, lympho node metastasis, nuclear grade and ER status for DFS by univariate and multivariate Cox regression analysis. Multivariate analysis revealed that ABCF2 was an independent prognostic factor (HR 0.46; p = 0.018). Conclusion: The role of ABCF2 protein may differ between EMCA and BC.

[Table: see text]

No significant financial relationships to disclose.
ABCF2 expression may predict the prognosis of cervical cancer
Authors: Nishimura S. , Tsuda H. , Kajitani K. , Hashiguchi Y. , Kawamura N. , Berkowitz R. S. , Mok S. C.
Published: March 2020

5045

Background: ABCF2 is a new member of the ATP-binding cassette transporter superfamily gene. We previously reported that ABCF2 protein is new biomarker in clear cell adenocarcinoma (CC) of the ovary and its expression may predict the response to chemotherapy and survival of CC patients (Proc ASCO 2005, Clin Cancer Res 2005). In this study, we examined ABCF2 expression in cervical cancer (CACX) and evaluated the relationship between ABCF2 expression and clinical factor. Methods: Formalin-fixed surgical samples from one hundred fourty CACX were included in this study. ABCF2 expression was investigated by immunohistochemistry. Positive expression of ABCF2 was >10% based on the cytoplasmic staining. Results: One hundred fourty patients were included in this study. The clinical stage was I in 86 patients, II in 38 patients, III in 10 patients, and IV in 6 patients. Histologic types were squamous cell carcinoma (SC) in 101 patients and non-squamous cell carcinoma (NSC) in 39 patients. The positive rate of ABCF2 in advanced stage (III + IV) was significantly higher than it in early stage (I + II) (p = 0.03). However, histologic type was not related with ABCF2 expression (SC 49.5% vs NSC 59.0%, p = 0.35). ABCF2-negative tumors had longer overall survival (OS) than ABCF2-positive tumors (p = 0.0014). The ABCF2 expression were correlated with further biological variables such as age, tumor stage, and histologic type for OS rate by univariate and multivariate Cox regression analysis. Multivariate analysis revealed that stage and ABCF2 were independent prognostic factor (Hazards ratio (HR) = 4.66, p = 0.0005; HR = 0.34, p = 0.025). Conclusions: The role of ABCF2 protein may predict the prognosis of CACX.

[Table: see text]

No significant financial relationships to disclose.
Report of first-stage accrual for NCI 5886, a phase II study of erlotinib, carboplatin and paclitaxel as first-line treatment of ovarian cancer
Authors: Blank S. V. , Curtin J. P. , Goldman N. A. , Runowicz C. D. , Speyer J. L. , Tiersten A. D. , Dancey J. , Wadler S. , Muggia F. M.
Published: March 2020

5076

Background: Abnormalities in the EGFR pathway are thought to play a major role in the dysregulated growth of ovarian and related epithelial cancers. The purpose of this study is to determine whether the addition of erlotinib (erl) to the standard first line regimen of paclitaxel (T) and carboplatin (CB) encourages pathologic complete response (pCR) in patients (pts) with ovarian (OC), fallopian tube (FTC) or primary peritoneal (PPC) cancers. Tolerability and toxicity data have been previously reported (ASCO 2005). Correlative studies of EGFR and related pathways are being performed, but data is insufficient currently for presentation. Methods: Pts with a histologic diagnosis of OC, FTC or PPC Stage III or IV with either optimal (≤ 1 cm) or suboptimal residual disease within 12 weeks of initial surgery were eligible for enrollment. Pts received T (175 mg/m2) and CB (AUC 6) every 21 days, along with erl (150 mg) by mouth, daily, continuously, for a planned 6 cycles, after which pts underwent surgical reassessment to determine pCR. Data were analyzed as two parallel phase II trials in the strata of Stage III optimal (Op) and Stage III suboptimal/Stage IV (S). Both trials followed Simon’s two-stage design, with planned first stage sample sizes of 28 (Op) and 19 (S). Early stopping rules applied for ≤ 11 pCR in Op pts, and ≤3 responses in S pts. Results: Since June 2003, 47 pts have been accrued, 29 Op and 18 S. In the Op stratum, 19 second looks (SL) were performed: 10 negative, revealing pCR, and 9 positive. Two patients elected not to have SL. Six Op pts discontinued treatment prior to completion, and four pts in this group continue treatment. In the S stratum, 7 pts were treated neoadjuvantly, and 1 pt is Stage IV. Surgical reassessment was performed in 5 of the 18 S pts, all of whom had dramatic responses, but not pCR. One pt’s disease did not respond enough to the regimen to warrant surgical reassessment. One pt was ineligible, 8 discontinued treatment, and 3 continue treatment. Conclusions: First stage accrual goals have been met, and demonstrate enough activity of erl, T and Cb in OC, FTC and PPC to proceed with second stage accrual. In the S cohort, criteria for proceeding with the study are being reassessed to account for early dropouts and neoadjuvant treatment.

No significant financial relationships to disclose.
A phase I study of pemetrexed (P) plus gemcitabine (G) in relapsed ovarian cancer (OC): Dosing results and evidence of activity
Authors: Hensley M. L. , Derosa F. , Gerst S. R. , Sabbatini P. , Dupont J. , Konner J. , Goss T. , Orlando M. , Wang Y. , Aghajanian C.
Published: March 2020

5083

Background: High expression of folate receptors on ovarian cancer cells may provide excellent targets for P. Preclinical data support synergism with G. Optimal doses of q 14 day P+G with vitamin support in pre-treated OC pts are not known. We sought to determine the maximally tolerated doses (MTD) and to assess for toxicity and activity in relapsed OC. Methods: Pts with relapsed OC, no prior P or G, KPS ≥ 70, and adequate organ function were eligible. Pts were enrolled in cohorts of 3, expanding to 6 if dose-limiting toxicity (DLT) was observed during the first 4 cycles. Pts received P at 300 (cohort 1) or 400 (cohort 2) or 500 (cohort 3) or 600 (cohort 4) mg/m2 followed by G 1500 mg/m2 q 14 d without GCSF. B12 and folic acid were given 1 week prior and continued throughout. DLT was defined as grade (gr) 4 neutropenia (ANC) lasting >7d or neutropenic fever (NF); gr 4 thrombocytopenia or gr 3 with bleeding; ≥gr 3 nonhematologic toxicity, except ALT, AST, alopecia, fatigue; treatment delay ≥1 week due to any unresolved toxicity. Response assessed by RECIST. Results: 16 pts (median age 55, range 43–75; median number prior cytotoxic regimens 2, range 1–4) have enrolled in 4 cohorts. 15 are evaluable for response (1 treated after resection of recurrence); 13 of these15 had a platinum-free interval <6 months. 1 pt in cohort 1 had global deterioration during cycle 1 and was replaced, with best response counted as progressive disease (PD). 1 pt in cohort 3 had dose delay ≥1 week, meeting DLT criteria. Cohort 3 was expanded to 6 pts with no further DLT. 3 pts enrolled in cohort 4 with no DLTs observed. Toxicities per cycle (n = 108): gr 3 ANC 31%; gr 4 ANC 27%; gr 3 dehydration 0.9%; gr 3 platelets 0.9%; 0 pts had NF. Median # cycles/pt was 6, range 1–16, median cycle length 14 d. Objective response was observed in 27% (4/15 pts: 4 PR; 7 SD; 4 PD). All 4 responses were among pts with platinum resistant disease. >50% decrease in CA125 for more than two measurements was observed in 9/15 (60%) pts with evaluable CA125s. Median time to progression is 15 wks (95% confidence interval 10–32 wks). Conclusions: MTD is not yet reached. P 500 mg/m2 + G 1500 mg/m2 with vitamin supplementation is safe in pts with previously treated OC. 27% of patients with platinum-resistant disease had objective responses.

[Table: see text]
Combination therapy with pegylated liposomal doxorubicin and carboplatin in malignant gynecologic tumors. A prospective multicenter phase II trial of the AGO-OVAR and the AGO Kommission Uterus (AGO-K-Ut)
Authors: Hilpert F. , Loibl S. , Huober J. , Wimberger P. , Staehle A. , Jackisch C. , Wollschlaeger K. , Koelbl H. , Beckmann M. , Du Bois A.
Published: March 2020

5095

Background: To determine the toxicity and efficacy of combination therapy with pegylated liposomal doxorubicin (PLD) and carboplatin in patients with malignant gynecologic tumors. Methods: Patients with recurrent or advanced uterine sarcomas, endometrial, cervical or vaginal cancer or with recurrent platinum-sensitive ovarian cancer were treated with PLD 40mg/m2 and carboplatin AUC 6, q28 over 6 cycles (up to 10 cycles allowed). Primary and secondary endpoints were tolerability and efficacy. Efficacy was measured according to RECIST and/or CA-125 GCIG criteria. Results: 67 pts with recurrent ovarian cancer, 11 pts with uterine sarcomas, 31 pts with endometrial cancer and 31 pts with cervical or vaginal cancer have been recruited (total 140 pts, 87 pts evaluable for response). Grade 3/4 hematologic toxicities occured in 8% for anemia, 14% for thrombocytopenia, 23% for leukopenia, and 25% for neutropenia of whom 2% developed febrile neutropenia. Non-hematologic Grade 3/4 toxicities have been observed in more than 5% of all patients for the following items: asthenia (14%), pain (10%), dyspnea (9%), palmo-plantar-erythema (7%), nausea and vomiting (7%), diarrhea (5%). The median dose intensity was 94% for PLD and 97% for carboplatin. 76% of all non-progressing patients received at least 5 cycles. The overall response rate was 56% in ovarian cancer, 43% in uterine sarcomas, 44% in endometrial cancer, and 14% in cervical and vaginal cancer. Conclusions: PLD/carboplatin was well tolerated, even in pretreated patients. The combination showed remarkable efficacy in patients with uterine sarcomas, endometrial cancer, and ovarian cancer which merits further evaluation. CA 125 response criteria in ovarian cancer are under evaluation and will be presented on ASCO. However, the regimen had limited efficacy in cervical and vaginal cancer. A prospective randomized trial in recurrent ovarian cancer patients comparing carboplatin/PLD with paclitaxel/carboplatin has already been started within the international study group network (AGO-OVAR 2.9; CALYPSO-trial).

[Table: see text]
Randomized, active-controlled study of denosumab (AMG 162) in breast cancer patients with bone metastases not previously treated with intravenous (IV) bisphosphonates (BP)
Authors: Lipton A. , Alvarado C. , De Boer R. , Steger G. G. , Tonkin K. S. , Kinsey A. , Fan M. , Jun S.
Published: March 2020

512

Background: Receptor activator of NF-κB ligand (RANKL) is a key mediator of osteoclast formation, function, and survival. Denosumab, a fully human monoclonal antibody, binds and inhibits RANKL, thus suppressing excess osteoclastic activity associated with bone metastases. We report interim efficacy and safety results of an ongoing, phase 2 study of denosumab in IV BP treatment-naïve women with advanced breast cancer and bone metastases (BM). Methods: Eligible patients (pts; age ≥ 18 yrs with breast cancer; confirmed BM; naive to IV BP therapy) were stratified by chemo- or hormonal therapy and randomized to 1 of 6 cohorts (5 denosumab [double blind]; 1 IV BP [open label]; see table ). The primary endpoint was the % change from baseline (BL) to week 13 in the resorption marker, urinary N-telopeptide (uNTx), corrected for creatinine. Also evaluated were % of pts with ≥ 65% decrease in uNTX from BL, time to a 65% reduction in uNTx, % of pts with ≥ 1 skeletal-related event (SRE), and safety. Results: In total, 255 pts (∼40/cohort) were enrolled. Mean age was 57 to 59 yrs (denosumab cohorts) vs 52 yrs (BP). Most pts had > 2 sites of BM (denosumab, 74%; BP, 81%); 51% and 49% received concurrent chemo- or hormonal therapy, respectively. As shown in the efficacy table , the 120 mg Q4W dose resulted in the greatest % decrease from BL in uNTx. At data cutoff, the % of all denosumab pts with ≥ 1 SRE was 9% (20/212) vs 16% (7/43) of BP pts. Commonly reported adverse events (AE) among all pts included nausea, vomiting, asthenia, diarrhea, and bone pain. Of 198 denosumab pts tested, none developed anti-denosumab antibodies. Conclusion: In this interim analysis, denosumab resulted in rapid and sustained suppression of bone turnover and was at least as effective as IV BP at reducing the risk of SREs, with a safety profile similar to that seen in advanced breast cancer pts receiving cancer treatment.

[Table: see text]

[Table: see text]
EGFR expression in breast cancer: Association with biologic phenotype, prognosis, and resistance to adjuvant therapy
Authors: Rimawi M. F. , Weiss H. L. , Bhatia P. , Chamness G. , Elledge R. M.
Published: March 2020

513

Background: Expression of the epidermal growth factor receptor (EGFR) in preclinical models of breast cancer is associated with increased proliferation and resistance to apoptosis. In clinical studies, EGFR has been inconsistently linked to poor outcome. We hypothesized that EGFR expression, when objectively and uniformly assessed, is associated with an aggressive biologic phenotype and resistance to systemic adjuvant therapy. Methods: In a database of 54,865 patients with breast cancer, EGFR status was known on 2,567. EGFR levels were measured centrally by ligand binding assay performed on frozen tissue. Tumors with ≥10 fmol/mg of cytosol protein were prospectively deemed positive. Clinical and biological features of EGFR positive and negative tumors were compared. Disease-free survival (DFS) and overall survival (OS) were assessed in systemically untreated patients (untreated patients, n=1068) and those who received hormonal and/or chemotherapy (treated patients, n=1256). Results: 475 out of 2,567 tumors (18.5%) were EGFR positive. Compared to EGFR negative tumors, EGFR positive tumors were more common in younger (<50 years, 40% vs 24% p<0.0001), premenopausal (20% vs 10%, p<0.0001), and black women (10% vs 6% p=0.005). EGFR expression was associated with larger tumors (64% vs 46%, p<0.0001), aneuploidy (68% vs 46%, p<0.0001), high S-phase fraction (53% vs 22%, p<0.0001), and nodal involvement (43% vs 37%, p=0.009). Co-expression of other biomarkers was also studied. EGFR positive tumors were more likely to be HER2 positive (26% vs 16%, p<0.0001), but less likely to be ER positive (60% vs 88%, p<0.0001), and PR positive (26% vs 65%, p<0.0001). In a multivariate analysis, EGFR expression independently correlated with worse DFS (HR=1.6, 95%CI=1.2–2.2, p=0.001) and OS (HR=1.7, 95% CI=1.2–2.4, p=0.001) in treated patients, but not in untreated patients. Conclusions: EGFR expression is more common in breast tumors in young and black women. It is associated with lower hormone receptor levels, higher proliferation, genomic instability, nodal involvement, and HER2 over-expression. It is correlated with significant resistance to adjuvant hormonal and chemotherapy. Blocking EGFR activity may help overcome this resistance in selected patients.

No significant financial relationships to disclose.
Biological and clinical outcomes from a phase II placebo-controlled neoadjuvant study of anastrozole alone or with gefitinib in postmenopausal women with ER/PgR+ breast cancer (Study 223)
Authors: Dowsett M. , Smith I. , Skene A. , Llombart A. , Mayordomo J. , Detre S. , Salter J. , Beresford E. , Magill P.
Published: March 2020

515

Background: Gefitinib, an EGFR-tyrosine kinase inhibitor, reduces breast cancer cell growth and potentiates endocrine therapy in model systems. This double-blind multicentre study compared anastrozole 1 mg/day alone with anastrozole + gefitinib 250 mg/day as neoadjuvant therapy for breast cancer in a novel design aiming to assess additional benefit from gefitinib in individual patients. Methods: Postmenopausal women with stage I-IIIB breast cancer and ER and/or PgR+ tumours received anastrozole for 16 wks and were randomised (2:5:5 ratio) to: combination with gefitinib for 16 wks (AG); placebo for 2 wks then gefitinib for 14 wks (A:AG, to test for additional Ki67 suppression); placebo for 16 wks (A alone). Biopsies were taken at baseline, 2 and 16 wks. Primary comparison was change in Ki67 by 16 wks. Secondary comparison was objective tumour response rate (ORR) using UICC/WHO criteria at 16 wks. Results: 206 patients (pts) were randomised: (31 AG, 90 A:AG, 85 A alone); demography was well balanced between the groups. 109 pts were evaluable for Ki67: 59 AG + A:AG; 50 A alone. Change in Ki67 levels at 16 wks was not significantly different in those pts who received gefitinib + anastrozole versus anastrozole alone (p=0.257). The addition of gefitinib after 2 weeks of anastrozole did not further suppress Ki67 levels (p=0.164). 188 pts were evaluable for ORR (109 AG + A:AG; 79 A alone). The ORR was 48% in pts who received gefitinib + anastrozole and 61% in pts treated with anastrozole alone (p=0.067). Conclusions: Neither the biological nor the clinical activity of anastrozole was enhanced by the addition of gefitinib; although non-significant, both endpoints unexpectedly suggested a trend against the combination in this patient population. Molecular investigations of signal transduction pathways are underway to understand the significance of these findings.

[Table: see text]

[Table: see text]
Adjuvant radiotherapy (RT) and trastuzumab in stage I-IIA breast cancer: Toxicity data from North Central Cancer Treatment Group Phase III trial N9831
Authors: Halyard M. Y. , Pisansky T. M. , Solin L. J. , Marks L. B. , Pierce L. J. , Dueck A. , Perez E. A.
Published: March 2020

523

Background: Adjuvant trastuzumab (Herceptin [H]) with chemotherapy improves outcome in HER2+ breast cancer (BC). Preclinical studies suggest H may enhance RT. We herein assess if H given with adjuvant RT increases adverse events (AE) after breast conserving surgery or mastectomy. Methods: N9831 randomized 3505 women with pT1–3N1–2M0, pT2–3N0M0, or pT1cN0M0 (ER/PR negative) HER2+ BC to doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T), AC→T→H, or AC→TH→H. Post-lumpectomy breast ± nodal RT was recommended, as was post-mastectomy chest wall + nodal RT (>3 nodes +); internal mammary RT was prohibited. RT started within 5 weeks of completion of T and allowed concurrently with H. 2324 eligible patients were enrolled on study prior to April 25, 2004: 1460 patients receiving RT are available for analysis of RT-associated AEs. Also, 1286 patients on +H arms who completed T (908 +RT and 378 -RT) are available for analysis of clinical cardiac events (CE). Rates of RT-associated AEs were compared across treatment arms, and rates of CE were compared for +RT vs -RT patients within +H arms. All reported p-values are for chi-squared statistics. Results: With a median follow-up of 1.5 years, significant differences among arms in RT-associated AEs were not identified. No significant differences across arms in +RT patients existed in the incidence of skin reaction (p=0.78), pneumonitis (p=0.78), dyspnea (p=0.87), cough (p=0.54), esophageal dysphagia (p=0.26), or neutropenia (p=0.16). There was a significant difference in +RT patients in the incidence of leukopenia (p=0.02) with higher incidence rates in the arms receiving H. RT did not increase the frequency of CE. In the AC→T→H arm, the incidence of CE was 2.2% in +RT patients versus 2.9% in -RT patients. In the AC→TH→H arm, the incidence of CE was 1.5% in +RT patients versus 6.3% in -RT patients. No difference in CE was seen between left- and right-sided RT fields in +RT patients in either +H arm. Conclusion: Concurrent administration of adjuvant RT with H in early stage breast cancer patients is not associated with an increased incidence of acute RT AEs. Further follow-up is required to assess late AEs.

No significant financial relationships to disclose.
Phase III randomized trial to evaluate the use of gabapentin alone vs with continuing an antidepressant in women failing an antidepressant for the treatment of hot flashes: North Central Cancer Treatment Group Study N00C3
Authors: Loprinzi C. L. , Kugler J. W. , Barton D. L. , Dueck A. C. , Tschetter L. K. , Nelimark R. A. , Balcueva E. P. , Carlson M. D. , Duane S. F. , Corso S. W.
Published: March 2020

526

Background: Antidepressants do not adequately alleviate all HFs. Based on placebo-controlled data demonstrating that GABA is an alternative therapy for HFs, this trial was initiated to test whether the combination of an antidepressant and GABA was better than GABA alone in PTS with inadequate HF control on an antidepressant alone. Methods: Eligible PTS on antidepressants with bothersome HFs were randomized to two groups. PTS kept a daily HF diary during a baseline wk (while continuing their antidepressant). Following the baseline wk, all PTS were given GABA 300 mg at hs for 3 days, then BID for 3 days, and then TID for 22 days. One group continued their antidepressant while the other group was weaned off it over several days. PTS continued a daily HF diary during this 4-wk period. Efficacy was measured using the mean daily HF number and score; the latter measured by assigning points (1–4, for mild to very severe) to each HF and then adding the points for a given time. The study design provided 80% power to detect a difference in the changes from baseline at 4 wks between the two groups of 1.2 HFs/day, or 3 points/day in HF scores. Results: 115 PTS were randomized and given GABA. PTS continuing their antidepressant reported a 48% mean reduction in HF score after 4 wks, vs 49% for PTS stopping it (p=0.97). Mean HF numbers were reduced 50% and 47%, respectively (p=0.54). 16 other symptoms and quality of life items were measured by PT-completed weekly questionnaires, with the only suggestive changes from baseline between the two arms being more mood troubles after 2 wks of treatment (p=0.06) and more nervousness after 4 wks of treatment (p=0.01) in PTS stopping their antidepressant. Also, a mild temporary increase in dizziness after 1 wk of treatment was observed in the same group (p=0.08) suggestive of an antidepressant withdrawal reaction. Conclusion: This trial failed to provide any evidence that the combination of GABA and an antidepressant decreased HFs any more than did GABA alone in PTS who had inadequate HF control with an antidepressant alone. The 50% reduction in HFs in both arms is commensurate with the efficacy of GABA delineated in other published reports.

No significant financial relationships to disclose.
The impact of FDG PET in the staging of breast cancer
Authors: Carr C. E. , Conant E. F. , Rosen M. A. , Schnall M. D. , Davidson R.
Published: March 2020

530

Background: To evaluate the impact of whole-body fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in staging breast cancer beyond the breast and axilla. Methods: 200 women, mean age 51 yrs (range 28–81) with breast cancer were enrolled in an IRB approved multi-modality imaging trial from 3/02 to 5/05. After imaging with film screen mammography ± ultrasound (US), patients underwent digital mammography, whole breast US, magnetic resonance imaging (MRI), and whole body FDG PET. Imaging reports and patient charts were reviewed and distant lesions were classified: 1 = no uptake; 2 = physiologic uptake; 3 = non-suspicious uptake; 4 = suspicious uptake without work-up; 5 = suspicious uptake with work-up. Decisions to forego work-up in class 4 lesions were clinical. Class 5 PET lesions were evaluated by confirmatory studies, including computed tomography (CT), MRI, x-ray (XR), bone scan (BS), or pathology. Patients also underwent standard staging with chest XR and BS per clinical judgment. Results: 189/200 (95%) women received PET scans. PET identified 71 distant areas of increased uptake in 42/189 (22%) women. 59/71 (83%) lesions were considered suspicious in 33/42 (79%) women: 50/59 (85%) lesions were class 5 and 9/59 (15%) class 4. Of the 50 class 5 lesions, 19 (38%) were true positive (TP) for neoplastic disease, 2 (4%) were TP for non-neoplastic disease, and 29 (58%) were false positive (FP). The positive predictive value (PPV) for class 5 lesions was 40%. The 19 TP distant sites of malignancy occurred in 6/189 (3%) patients; 4 of these patients (67%) also had TP distant sites identified by standard staging procedures. PET alone identified TP distant disease in 2/189 (1%) women. PET identified 29 FP findings in 22/189 (12%) patients. FP findings prompted 17 CTs, 8 XRs, 2 MRIs, and 1 BS. MRI revealed 2 additional neoplasms that had been false negatives (FN) by PET in 2/189 (1%) women. Conclusions: Whole-body FDG-PET added little additional information in staging our patients with known primary breast cancer, based on low PPV and equivalent TP and FN rates. Additionally, the high FP rate of PET in these patients may prompt unnecessary, costly, and invasive follow-up studies.

No significant financial relationships to disclose.
Predicting non-sentinel lymph node involvement in breast cancer patients
Authors: Kohrt H. E. , Olshen R. A. , Goodson W. H. , Rouse R. V. , Bailey L. , Philben V. , Dirbas F. M. , Stockdale F. E. , Carlson R. W. , Jeffrey S. S.
Published: March 2020

531

Background: Current convention is to perform a completion axillary lymph node dissection (ALND) for invasive breast cancer (BC) patients (pts) with positive sentinel lymph node(s) (+SLN), even though <50% will have non-sentinel lymph node metastasis (+NSLN). Our goal was to develop and compare predictive models of NSLN status among +SLN pts to identify for whom completion ALND may be omitted. Methods: We constructed 3 models by recursive partitioning with receiver-operating-characteristic curves (RP-ROC), boosted classification and regression trees (CART), and a multivariate logistic regression (MLR) informed by CART. Models were developed using a multi-institutional database of 1,040 BC pts who underwent SLN biopsy and completion ALND at academic or community hospitals as part of a prospective, consented study. Accuracies were compared to the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram). Results: 976 BC pts had evaluable SLNs and 285 had +SLNs; 101(35.4%) +SLN pts had +NSLNs. Tumor size, lymphovascular invasion (LVI), and SLN metastasis size were the best predictors of risk (multivariate P-values<0.001) of +NSLN. 39 of 156 +SLN pts (25%) with T1 tumors had +NSLNs vs. 62 of 129 (48%) with T2/T3 tumors. 73.7% with LVI vs 19.5% without LVI had +NSLNs. 4.7% of pts with isolated tumor cells, 42% with micrometastasis and 71% with macrometastasis in SLN had +NSLNs. MLR informed by CART identified 2 highly predictive variables, the LVI × size of SLN metastasis [OR 4.73(3.11–7.20, 95%CI), P<0.001] and tumor size × size of SLN metastasis [OR 1.18(1.10–1.26, 95%CI), P<0.001]. While RP-ROC and boosted CART stratified pts into low-risk (4.3%-9.9%), moderate-risk (33.3%-42.9%), and high-risk (62.2%-93%) groups, MLR predicted NSLN status with accuracy superior to RP-ROC, boosted CART, and the Nomogram: 83.3%, 76.7%, 67.7%, and 76.7%, respectively, after 10-fold cross validation. The Nomogram’s sensitivity was significantly inferior to those of RP-ROC, boosted CART, and MLR: 53.8%, 78.8%, 78.2%, and 78.0%, respectively. Conclusions: In pts with +SLNs, interactions between clinicopathologic characteristics are highly informative in predicting risk of +NSLN. However, neither our methods nor the Nomogram achieved sufficient accuracy to recommend a change in current clinical practice.

No significant financial relationships to disclose.
Gene expression profiles in formalin-fixed, paraffin-embedded (FFPE) core biopsies predict docetaxel chemosensitivity
Authors: Chang J. C. , Makris A. , Hilsenbeck S. G. , Hackett J. R. , Jeong J. , Liu M. , Baker J. , Sexton K. , Osborne C. K. , Shak S.
Published: March 2020

538

Background: Docetaxel has one of the highest response rates as a single agent in breast cancer, but de novo resistance is frequent. Previously, we had identified a 92-gene expression pattern that predicted response to neoadjuvant docetaxel. Other studies have validated that a high Recurrence Score (RS) by the 21-gene RT-PCR assay is predictive of worse prognosis (Paik, NEJM 2004) but better response to chemotherapy (Gianni, JCO 2005). We investigated whether tumor gene expression of these 21 genes and other candidate genes can predict response to docetaxel. Methods: Core biopsies from 97 patients were obtained before treatment with neoadjuvant docetaxel (4 cycles, 100 mg/m2 q3 weeks). Baseline and post-treatment measurements of the primary breast cancers were recorded. Three 10-micron FFPE sections were submitted for quantitative RT-PCR assays of 192 genes that were selected from our previous work and the literature. Results: Of the 97 patients, 81 (84%) had sufficient invasive breast cancer, 80 (82%) had sufficient RNA for assay of 192 genes, and 72 (74%) had clinical response data. Mean age was 48.5 years, and the median tumor size was 6 cm. Clinical complete responses (CR) by RECIST were observed in 12 (17%), partial responses in 41 (57%), stable disease in 17 (24%), and progressive disease in 2 patients (3%). The concordance of IHC and RT-PCR results was >80% for ER, PgR, and HER2. By univariate logistic regression, a significant correlation (p<0.05) between gene expression and CR was observed for 14 genes. Notably, CYBA-1 involved in mitochondrial metabolism, identified by gene expression profiling, significantly predicted CR (p=0.006). CR was associated with lower expression of the ER gene group and higher expression of the proliferation gene group. Multivariate analysis indicated that panels of genes better predictors of docetaxel response. Of note, CR was more likely with high RS and less likely with a low RS (p=0.008). Conclusion: We have established molecular profiles for breast cancers either responding or not responding to neoadjuvant docetaxel. This technology is a potential predictive test for docetaxel sensitivity by using small amounts of FFPE material, and may reduce unnecessary treatment, toxicity, and cost for breast cancer patients.

[Table: see text]
Distinct PIK3CA mutation profiles in estrogen receptor (ER) negative breast cancer (BC) subsets
Authors: Doane A. S. , Danso M. , Lal P. , Donaton M. , Wheler J. , Moynahan M. , Zhang L. , Hudis C. , Gerald W.
Published: March 2020

540

Background: ER negative, progesterone receptor (PR) negative BC is clinically heterogeneous and underlying biology may be complex. We have identified two primary subtypes of ER(-)/PR(-) BC based on genome-wide molecular analysis (Doane et al., 2005, Oncogene, In Press), however the biological mechanisms underlying these molecular differences are not known. Methods: We performed genome-wide expression analysis of 99 primary BC samples and 13 BC cell lines. Total RNA was extracted and hybridized to Affymetrix HG-U133 oligonucleotide microarrays. Unsupervised and supervised analyses were used to investigate gene expression profiles. Predictive models were developed using a supervised k-nearest neighbor technique. Samples were further characterized by immunohistochemistry (IHC) for selected gene products, and HER2 status was determined by IHC and FISH. PIK3CA exons 9 and 20 were sequenced by RT-PCR amplification, direct sequencing, and restriction enzyme digest. Results: Genes differentially expressed between ER(-)/PR(-) subsets (designated class A and B) included SPDEF, ALCAM, AR, and FGFR4 (p<0.0001). Further study revealed a significant association with class A and the PIK3CA A3140G:H1047R activating mutation among ER(-)/PR(-) BC (p=0.012). HER2 status (gene amplification or 3+ IHC) was not significantly associated with this subtype (p=0.33). MDA-MB-453 corresponded to class A according to molecular profile and PIK3CA mutation status. This cell line demonstrated a proliferative response to androgen (A) in an androgen receptor (AR) dependent and ER-independent manner. In addition the A-induced transcriptional program of MDA-MB-453 significantly overlapped the molecular signature of ER(-)/PR(-) class A human BC (p<0.0001). Conclusion: Hormonal signaling through the AR may be significantly different in ER(-)/PR(-) molecular subsets. Enhanced AR signaling may be due to cooperation with growth factor signaling through PI3K. The potential molecular crosstalk between activated PI3K and the androgen signaling pathway provides therapeutic opportunities and deserves further study.

No significant financial relationships to disclose.
Pharmacogenomic analysis of HER2 amplified breast cancer treated with preoperative trastuzumab and paclitaxel, 5-fluorouracil, epirubicin, cyclophosphamide (T/FEC) chemotherapy
Authors: Esteva F. J. , Anderson K. , Lin F. , Nahta R. , Mejia J. , Altundag K. , Buzdar A. U. , Hortobagyi G. N. , Symmans W. F. , Pusztai L.
Published: March 2020

545

Background: We performed gene expression analysis to identify molecular predictors of resistance to preoperative concomitant trastuzumab and T/FEC chemotherapy. Methods: Pretreatment fine needle aspirations from 21 patients with HER2 amplified, stages II-III breast cancer were available for transcriptional profiling with Affymetrix U133 A chips. Results: Overall pathologic complete response (pCR) rate was 71%. Age, nuclear grade, tumor size, nodal status or quantitative estrogen and HER2 receptor mRNA expression showed no association with response in univariate and multivariate logistic regression. We tested the accuracy of a 30-gene pCR predictor that was previously developed from patients who received T/FEC only preoperative chemotherapy. This predictor was accurate in validation in T/FEC treated patients (n=51) but showed low sensitivity in patients who also received trastuzumab (sensitivity 53% versus 92%). We could not identify any differentially expressed genes between pCR (n=15) and residual disease (RD, n=6) at a false discovery rate (FDR) <90% in the HER2 amplified trastuzumab-treated cases. Hierarchical clustering using the “Perou intrinsic gene set” also failed to separate pCR from RD. Gene Set Enrichment Analysis with 22 genes from trastuzumab-resistant cell lines showed a modest association with RD (FDR=9%). Conclusions: Clinical variables and pharmacogenomic predictors that predict pCR in the absence of trastuzumab are no longer accurate when trastuzumab is included in the treatment. Trastuzumab-resistance associated genes identified in vitro are also associated with resistance in vivo. Support: Ellence Foundation.

No significant financial relationships to disclose.
Phase II trial of trastuzumab (T), paclitaxel (P) and cisplatin (C) in metastatic (M) or recurrent (R) head and neck squamous cell carcinoma (HNSCC): Response by tumor EGFR and HER2/neu status
Authors: Gillison M. L. , Glisson B. S. , O’Leary E. , Murphy B. A. , Levine M. A. , Kies M. S. , Chan D. , Forastiere A. A.
Published: March 2020

5511

Background: EGFR expression is associated with poor prognosis and resistance of HNSCC to therapy. EGFR/Her2/neu heterodimers may potentiate receptor signaling and therapy resistance. T enhances cytotoxic effects of C and P in Her2/neu+ cell lines. Methods: A phase II trial evaluated the response rate (RR) of HNSCC pts to TPC as a function of Her2/neu and EGFR expression by immunohistochemistry (IHC). Secondary outcomes included toxicity, one-year progression-free (PFS) and overall (OS) survival. Eligible pts had M or R HNSCC, ECOG PS 0–1, CrCl >50 ml/min, and ANC >1500. Chemotherapy regimen consisted of P (175 mg/m2) and C (75 mg/m2) IV on day 1 and T (4 mg/kg day 1, cycle 1, 2 mg/kg subsequent) IV on day 1, 8 and 15 of 21. Paraffin embedded tumor was analyzed for Her2/neu (HercepTest) and EGFR (Zymed Lab) expression by IHC and for Her2/neu amplification by FISH (−/+) at LabCorp. Two-stage Simon design had 80% power for a 15% improvement in RR over 35% and required response in ≥ 14/42 pts by ECOG response criteria. Results: 61 pts (55 R HNSCC) received a median of 4 cycles (range 1–14) of TPC. Membrane staining of ≥ 10% of cells was observed for Her2/neu in 4/58 (6.9%, 95% CI 2–17) and for EGFR in 41/57 (72%, 95% CI 58–83). Her2/neu amplification was absent in 55/55 (0%, one-sided 97.5% CI 0–6.7) tumors. A RR of 36% (95% CI 24–50) was observed in 58 evaluable pts. RR was lower in pts with ≥ 10% staining by EGFR (25% versus 62.5%, p = 0.01). Her2/neu expression had no effect on RR (p = 0.75). Toxicities included two grade 5 dehydration/hypokalemia, and grade 3–4 neutropenia, fatigue, infection, nausea, vomiting, and neuropathy were common. Median follow-up was 4.2 yrs. For all 61 pts: median TTP was 4.3 mos, PFS 19.8% (95% CI 10.6–30.9) and OS 44% (95% CI 31.6–56.2) at 1 yr. Pts with <10% EGFR membrane staining had improved median PFS (6.7 vs 3.1 mos, p = 0.003) and OS (16.1 vs 7.4 mos, p = 0.005) when compared to patients with tumors with ≥ 10% EGFR. Conclusions: T did not improve RR to PC, likely because Her2/neu gene amplification and expression was rare. Tumor EGFR status significantly affected RR, PFS, and OS to the underlying regimen of PC. Sponsored by Bristol-Myers Squibb, Genentech, and Damon Runyon Cancer Research Foundation (MG).

[Table: see text]
Long-term results of Intergroup RTOG 91–11: A phase III trial to preserve the larynx—Induction cisplatin/5-FU and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy
Authors: Forastiere A. A. , Maor M. , Weber R. S. , Pajak T. , Glisson B. , Trotti A. , Ridge J. , Ensley J. , Chao C. , Cooper J.
Published: March 2020

5517

Background: The 2-year results of Intergroup RTOG 91–11 were published in 2003 (NEJM 349:2091–8,2003). We now present the 5-year results (after median follow-up for surviving patients of 6.9 years) of 515 eligible pts with resectable stage III or IV (excluding T1 and high volume T4), cancer of the glottic or supraglottic larynx. Methods: Patients were randomized to induction cisplatin/5-FU (CF) with responders then receiving RT (I+RT) (n = 173); or concurrent cisplatin (100 mg/m2 q 21 days × 3) and RT (CRT) (n = 171); or RT alone (R) (n = 171). Laryngectomy was performed for < partial response to induction CF, for persistent/recurrent disease or for laryngeal dysfunction. Results: At 5 years, laryngectomy-free survival (LFS) was significantly better with either I+RT (44.6%, p = 0.011) or CRT (46.6%, p = 0.011) compared to R (33.9%). There was no difference in LFS between I+RT and CRT (p = 0.98). Laryngeal preservation (LP) was significantly better with CRT (83.6%) compared to I+RT (70.5%, p = 0.0029) or R (65.7%, p = 0.00017). Local-regional control (LRC) was significantly better with CRT (68.8%) compared to I+RT (54.9%, p = 0.0018) or R (51%, p = 0.0005). I+RT compared to R for LP and LRC showed no significant difference (p = 0.37 and 0.62, respectively). The distant metastatic rate was low (I+RT 14.3%, CRT 13.2%, R 22.3%) with a trend (p ∼0.06) for benefit from chemotherapy. Disease-free survival (DFS) was significantly better with either I+RT (38.6%, p = 0.016) or CRT (39%, p = 0.0058) compared to R (27.3%). Overall survival rates were similar for the first 5 years (I+RT 59.2%, CRT 54.6%, R 53.5%); thereafter I+RT had a non-significant lower death rate. Compared to CRT, significantly more pts in the R group died of their cancer (34% vs 58.3%, p = 0.0007); the rate for I+RT was 43.8%. Conclusion: These 5-year results differ from the 2-year analysis by a significant improvement in LFS now seen for both I+RT and CRT treatments compared to R. For the endpoints of LP and LRC, CRT is still the superior treatment with no advantage seen to the addition of induction CF to R. There is no significant difference in overall survival.

[Table: see text]
Locally advanced resectable larynx (L) or oropharynx (OP) cancer: Updated results of organ preservation trial ECOG 2399
Authors: Cmelak A. J. , Li S. , Murphy B. , Burkey B. , Adams G. L. , Cannon M. , Pinto H. , Rosenthal D. I. , Ridge J. A. , Forastiere A. A.
Published: March 2020

5527

Background: Taxane-based concurrent chemoradiation (CCR) for head and neck cancers has proven feasible and has a favorable toxicity profile compared to concurrent cisplatin and radiation. This phase II multi-institutional trial evaluates taxane-based induction chemotherapy followed by CCR for organ preservation in resectable Stage III/IV L and OP patients. Methods: Eligibility: Resectable stage T2N+, or T3-T4N0–3M0 biopsy-proven squamous Ca, age ≥18, PS 0–2, good organ function, and no prior chemotherapy or radiation. Treatment: induction paclitaxel (P) 175 mg/m2 and carboplatin (C) AUC 6 for 2 cycles q21d followed by concurrent P 30 mg/m2 q7d with 70 Gy if no evidence of progression. Weekly epoetin alpha 40kU was used if Hgb ≤15 (male) or ≤14 (female). The primary endpoint is organ preservation (freedom from salvage surgery with preserved speech and swallowing). Results: 105/111 pts (69 OP, 36 larynx) were eligible. Median FU is 33 months. No grade 5 toxicities occurred. 94% received full dose RT and 91% received ≥5 cycles of concurrent paclitaxel. At one year post-treatment, 13 (12%) patients required salvage surgery at the primary site (7-L, 6-OP), and 6 pts (6%) progressed and died (3-L, 3-OP). 1 pt (1%) died without progression and 85 pts (81%) are alive without progression (25-L, 60-OP). 12 pts (10%) have developed distant mets (6-L, 6-OP). 1-yr and 2-yr PFS for all pts is 77% and 64%. 12/69 OP and 9/36 L pts have died of disease. 1-yr event-free survival (EFS = no salvage surgery, recurrence or death) is 72% (77%-OP, 64%-L), and 2-yr EFS is 57% (68%-OP, 34%-L) (p = 0.02). 1-yr OS is 93%, 2-yr OS is 74% (OP vs. L p = 0.11). Conclusions: This regimen is well tolerated and is feasible in a multi-institutional setting. EFS with this regimen is lower than expected in larynx patients. The benefit of induction chemotherapy in this setting remains unproven but does not preclude CCR delivery. Funded, in part, by Bristol-Myers Squibb.

[Table: see text]