bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized comparison of weekly or every-3-week (q3w) nab-paclitaxel compared to q3w docetaxel as first-line therapy in patients (pts) with metastatic breast cancer (MBC)
Authors: Gradishar W. , Krasnojon D. , Cheporov S. , Makhson A. , Manikhas G. , Clawson A. , Hawkins M. J.
Published: March 2020

1032

Background: 130-nM albumin-bound (nab™) paclitaxel combines paclitaxel with albumin without solvents or altering either component. A cross analysis of 2 clinical trials comparing solvent-based (SB) paclitaxel 175 mg/m2 q3w to nab- paclitaxel (Gradishar et al, JCO, 2005) and SB docetaxel (Jones et al, JCO, 2005) suggested comparable antitumor activity between nab-paclitaxel and SB docetaxel and better tolerability with nab-paclitaxel in pts with MBC. The aim of this study was to compare the toxicity and antitumor activity of 3 regimens of nab-paclitaxel (q3w and 2 weekly) with each other and that of SB docetaxel in MBC. Methods: In this open-label study, first-line pts with MBC were randomly assigned to nab-paclitaxel 300 mg/m2 q3w (A); nab-paclitaxel 100 mg/m2 (B) or 150 mg/m2 (C) days 1, 8, and 15, q28 days (q 3/4 w); or SB docetaxel 100 mg/m2 q3w (D). The primary endpoints were overall response rate (complete response + partial response, evaluated q8w) and toxicity. Progression-free survival (PFS) was also determined. Results: 302 pts (median age, 54 years; 99% Caucasian; 75% postmenopausal; ECOG PS =2 [94% =1]) either had at least 2 response assessments (94%) or had discontinued due to PD (6%). The efficacy results are shown in the Table . Neutropenia (N) was greater with D than with A, B, or C (p < 0.001). Grade 4 N was: A) 4%, B) 3%, C) 7%, and D) 74%. Febrile neutropenia (FN) was: A) 1%, B) 1%, C) 1%, and D) 7%. Gr 3 peripheral neuropathy was: A) 14%, B) 7%, C) 12%, and D) 5%. Conclusions: The response rates of q3w nab-paclitaxel and solvent-based docetaxel were comparable. Q 3/4 W nab-paclitaxel resulted in higher response rates than solvent-based docetaxel. Grade 4 N and FN were less frequent with nab-paclitaxel as compared with solvent-based docetaxel. To date, all 3 nab-paclitaxel regimens have a longer PFS than SB docetaxel although the data are not yet mature (33% of events). Final data for a radiological review of response data, PFS, and toxicity will be presented.

[Table: see text]

No significant financial relationships to disclose.
Phase II study of eribulin mesylate (E7389) halichondrin b analog in patients with refractory breast cancer
Authors: Blum J. L. , Pruitt B. , Fabian C. J. , Rivera R. R. , Shuster D. E. , Meneses N. L. , Chandrawansa K. , Fang F. , Fields S. Z. , Vahdat L.
Published: March 2020

1034

Background: Eribulin is a structurally simplified analog of halichondrin B, which inhibits microtubule dynamics via a novel mechanism characterized by suppression of microtubule growth, lack of effect on microtubule depolymerization, and sequestration of tubulin into nonfunctional aggregates. This study was designed to assess the activity and tolerance of eribulin in chemotherapy refractory patients with advanced breast cancer. Methods: Eribulin was evaluated in a single-arm Phase II trial in female patients with refractory breast cancer, ECOG performance status of 0–1, measurable disease, and neuropathy ≤ Grade 2. Patients received ≥ 1 prior chemotherapy regimen, including an anthracycline and a taxane. Eribulin was administered as a 2–5 min IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-Day cycle (Group 1). The schedule was modified to Days 1 and 8 of a 21-Day cycle (Group 2), because of dose delays. The primary efficacy endpoint was ORR according to RECIST criteria based upon independent review (IR) of tumor assessment. Results: Of 104 patients enrolled, 103 received eribulin treatment: 70 in Group 1, 33 in Group 2. Median age was 55 yrs (range 32–84). Patients had received a median of 4 prior chemotherapy regimens (range 1–11). Sixty-one percent of tumors were ER+, 14% Her2/neu 3+, and 29% were triple (ER, PR, Her-2) negative. The incidence of dose interruption, delay, or omission during Cycle 1 was 63% (Group 1) and 18% (Group 2). The most common drug related toxicities were neutropenia (75%, Grades 3: 31%, Grade 4: 30%, febrile neutropenia: 3.9%), fatigue (52%, Grade 3: 2.9%, no Grade 4), alopecia (Grade 1/2: 41%), nausea (37%, Grade 3: 1%, no Grade 4), and anemia (36%, Grade 3: 1%, no Grade 4). Peripheral neuropathy occurred in 34% of patients (Grade 3: 3.9%, no Grade 4). Best overall response rate (all PR) by IR was 14.5% and 15.2% in Groups 1 and 2, respectively; the combined ORR was 14.7% (95 % CI: 9–23%). Median PFS was 85 days, and the 6 mo PFS rate was 31%. Conclusions: Eribulin given as a 2–5 min IV infusion on Days 1, 8 of a 21-Day cycle or Days 1, 8, 15 of a 28-Day cycle exhibited a 15% PR rate by IR and a low incidence of Grade 3 neuropathy in this heavily chemotherapy pretreated population. The most common toxicity was neutropenia. The 21-Day schedule had an acceptable toxicity profile.

No significant financial relationships to disclose.
Randomized study comparing nab-paclitaxel with solvent-based paclitaxel in Chinese patients (pts) with metastatic breast cancer (MBC)
Authors: Guan Z. , Feng F. , Li Q. L. , Jiang Z. , Shen Z. , Yu S. , Feng J. , Huang J. , Yao Z. , Hawkins M. J.
Published: March 2020

1038

Background: The results of a large clinical study comparing solvent-based paclitaxel 175 mg/m2 with 130-nM albumin-bound paclitaxel (nab-paclitaxel) 260 mg/m2 demonstrated that nab-paclitaxel had greater efficacy and a favorable safety profile in pts with MBC (Gradishar et al., JCO, 2005; 23:7794). The maximum tolerated dose of nab-paclitaxel was 300 mg/m2 infused over 30 minutes without premedication in Chinese pts with solid tumors (Teng et al., Ai Zheng, 2004;23:1431). The aim of this randomized study is to compare the response rates and to evaluate the safety of nab-paclitaxel with those of solvent-based paclitaxel in Chinese pts with MBC. Methods: In this open-label, multicenter study, 210 pts with MBC were assigned to either solvent-based paclitaxel 175 mg/m2 intravenously (IV) over 3 hours every 3 weeks (q3w) with standard premedication (steroids and antihistamines) or nab-paclitaxel 260 mg/m2 IV over 30 minutes q3w with no premedication for 1–6 cycles. The primary endpoints were the overall response rate (ORR, complete or partial response) and toxicity. Stable disease (SD) at =16 weeks was measured. All pts who received at least 1 dose of study drug were evaluable for study endpoints. Results: 210 pts (median age, 50 years; 70% postmenopausal) were enrolled from 29 June 2005 - 1 August 2006. Efficacy results are summarized in the Table . The common toxicities occurring at =20% were alopecia (78%), peripheral neuropathy (75%, 7% gr 3), neutropenia (65%), leucopenia (60%), myalgia (39%), arthralgia (23%), and nausea (21%) and were similar between groups (P = NS). Gr 3/4 neutropenia, measured on days 1 and 8, were similar between groups (p = 0.202). Conclusions: Compared to solvent- based paclitaxel, treatment with nab-paclitaxel was associated with a higher response rate and longer time to progression without increased toxicity. These comparative data in Chinese pts are almost identical to results previously reported in Caucasian pts (Gradishar et al, JCO, 2005).

[Table: see text]

[Table: see text]
Anti-leukemia activity of histone deacetylase (HDAC) inhibitor LBH589 involves depletion of EZH2 and DNA methyltransferase (DNMT) 1 through disruption of their chaperone association with heat shock protein (hsp) 90
Authors: Bhalla K. N. , Fiskus W. , Herger B. , Rao R. , Ustun C. , Jillella A. , Atadja P.
Published: March 2020

10501

Background: LBH589 is a hydroxamate pan-HDAC inhibitor (HA-HDI) that also inhibits HDAC6, which induces acetylation of hsp90 and hsp70. This inhibits the ATP binding and chaperone function of hsp90. We recently reported that treatment with LBH589 depletes the levels of the polycomb repressive complex (PRC) 2 proteins EZH (enhancer of zeste homolog) 2, Suz12 and EED in AML cells. Since EZH2 has been shown to interact with and modulate the DNA methyltransferase activity of DNMT1, which affects its binding to the EZH2-targeted gene promoters, we determined the effects of LBH589 on the levels and interaction between EZH2 and DNMT1 in the CML blast crisis (CML-BC) K562 and LAMA-84 cells as well as in primary AML samples. Methods: Following exposure to 20 to 100 nM of LBH589 for 8 and 24 hours. immunoprecipitation and/or immunoblot analyses were performed to determine hsp90 binding and levels of DNMT1 and EZH2, as well as induction of JunB and loss of clonogenic survival of leukemia cells. Results: Treatment with LBH589 disrupted the chaperone association of DNMT1 and EZH2 with hsp90, resulting in polyubiquitylation and proteasomal degradation of DNMT1. Similar findings were also noted following treatment of leukemia cells with the hsp90 inhibitor, 17-DMAG. DNMT1 depletion by LBH589 was associated with induction of JunB in cultured and primary leukemia cells, which was further enhanced by co-treatment with decitabine. Consistent with this, methylation specific PCR analysis demonstrated increased demethylation of the JunB promoter. Co-treatment with decitabine and LBH589 or DMAG inhibited colony growth of the leukemia cells significantly more than treatment with either agent alone (p<0.05). Conclusions: These findings indicate that in addition to mediating histone acetylation and demethylation, LBH589 treatment induces epigenetic DNA demethylation by targeted depletion of EZH2 and DNMT1 in human leukemia cells. These results support the rationale for testing novel anti- leukemia combinations for epigenetic targeting that include LBH589, decitabine and/or histone methyltransferase inhibitors.

No significant financial relationships to disclose.
The clinical relevance of p53 isoforms modifying the effects of p53 mutation on survival from breast cancer
Authors: Thompson A. , Patten N. , Diot A. , Truong S. C. , Bray S. , Ashfield A. , Baker L. , Quinlan P. , Wu L. , Bourdon J.
Published: March 2020

10505

Background: p53 is a key gene in the development of breast cancer and response to therapy. Nine splice variants of p53 in breast cancer have been identified, with full length p53, p53beta and p53gamma (both 46kD, C terminal truncated proteins) commonly expressed. This study examined the clinical relevance of splice variants in breast cancer. Methods: Tumors from 248 patients with primary breast cancer were examined for mutation with the Roche p53 mutation chip and p53 isoform expression detected by RT-PCR followed by nested PCR; full clinical and pathological data included median follow up of 6.4 years. Results: p53 mutation, identified in 65/248 (26%) cancers, was significantly associated by Chi square test with shorter survival (p=0.001), histological grade 3 (p<0.001) and estrogen receptor (ER) negative cancers (p<0.001), as expected. Expression of p53 beta or p53 gamma mRNA was associated with p53 mutation (p=0.002, Fisher's exact test). Intriguingly, the patient groups with a mutant p53 cancer but expressing p53 gamma or p53 beta or both isoforms had survival curves comparable to patients with cancer containing wild type p53. Similarly, p53 gamma or p53 beta was associated with ER negative cancers (Chi square; p<0.001), but the group of ER negative tumors expressing p53 gamma or p53 beta had improved survival similar to ER positive cancers. Patients with p53 mutant, p53 beta negative and ER negative cancers comprised half of those who died within 3 years of diagnosis. Conclusions: p53 beta or p53 gamma isoform expression in breast cancer is associated with better prognosis and may moderate disease behaviour even in mutant p53 and ER negative cancers. Manipulation of p53 isoforms in breast cancer may thus offer therapeutic potential.

No significant financial relationships to disclose.
Multicentric phase II trial of gemcitabine plus capecitabine combination in the treatment of previously anthracycline(An)-treated metastatic breast cancer (MBC): SOLTI 0301 study
Authors: Ciruelos E. M. , Baselga J. , Cortes-Funes H. , Lluch A. , Mayordomo J. I. , Ojeda B. , Gonzalez E. , Muñoz M. , Rodriguez C. , Cortes J.
Published: March 2020

1051

Background: Based on clinical activity of capecitabine(C) and gemcitabine (G) on the treatment of MBC, we performed a multicentric phase II trial of the combination to test its efficacy and safety profile. Methods: Sample size of 72 evaluable MBC patients (pts) previously An-treated (neoadjuvant 8%, adjuvant 69%, advanced 30%). Median age: 59 years (35–76 years). Estrogen Receptor positive: 47 (65%). HER2 overexpression: 16 (22%). Prior hormonal/trastuzumab allowed. Soft tissue/ganglionar/pleural/bone disease: 19 (26%); visceral metastasis: 53(74%). Stratification: previous chemotherapy (CT) for advanced disease (none: group 1; any: group 2). Study treatment: oral bid C 1,660 mg/m2/day (d) (d1–14) + iv G 1,000 mg/m2/d (d1&8). Cycles repeated every 3 weeks. RECIST/NCI-CTC 2.0 criteria. Primary end point: Objective Response Rate. Results: Response Rates and Clinical Benefit (CB) are detailed in the table . Median follow-up 7.2 months (m) (0.2–18.4). Median time to progression 11.2 m: group 1, 12 m (95%CI: 6.4–14.5); group 2, 8.9 m (95%CI: 6.9–14).Total and median administered cycles/pt: 479 and 8. Delayed cycles: 103(21.5%): 27% due to hematological toxicity, 11% due to non-hematological toxicity, 62% due to other causes. C dose reduced in 27 cycles (5.6%), 12 of them due to non- hematological toxicity. G dose reduced in 169 cycles (35%), mostly on day 8, and due to hematological toxicity (80% of reduced cycles). Grade 3–4 neutropenia: 32 pts (56%), 1 case of febrile neutropenia. Grade 3–4 non-hematological toxicities: asthenia 8 pts (14%), hand- foot syndrome 6 pts (10.5%), mucositis 3 pts (5%), diarrhea 2 pts (3.5%). Conclusions: Combination of C+G in the treatment of previously anthracycline-treated MBC is safe and active, with a manageable toxicity profile and a good clinical activity.

[Table: see text]

No significant financial relationships to disclose.
Breast cancers with stem cell-like features delineate endocrine responsiveness
Authors: Rody A. , Karn T. , Solbach C. , Gaetje R. , Diallo R. , Gehrmann M. , von Minckwitz G. , Loibl S. , Holtrich U. , Kaufmann M.
Published: March 2020

10517

Background: Endocrine responsiveness is one of the most important characteristics of breast cancer. The negative association between expression of the estrogen receptor (ER) and proliferation detected in normal breast is frequently lost in breast cancers leading to receptor independent growth and poor patients’ prognosis. Methods: Microarray analysis of 171 breast cancer samples allowed the discrimination of a KIT+ tumor group by using a set of genes coregulated with the “stem cell factor” receptor KIT. Validation was performed on three independent datasets encompassing 637 samples. Furthermore the response to endocrine treatment only was analyzed in a dataset of 700 patients. Results: KIT+ tumors are transcriptionally related to proposed mammary stem cells. Two types of KIT+ tumors were identified which are characterized by their positive and negative ER status, respectively. The inverse link of ER expression and proliferation is perfectly conserved within the KIT+ tumor groups, while it is uncoupled among half of the KIT-Low ER positive tumors. Those “uncoupled” ER positive tumors with altered ER response are characterized by a prognosis inferior to the ER negative cancers despite an apparent positive ER status (hazard ratio for disease recurrence, 2.07; 95% CI 1.53–2.81; P<0.001). Moreover, the 5 and 10 year survival rates of lymph node negative “uncoupled” tumors are even worse than those of lymph node positive “normal” ER positive cancers. While all ER positive patients seem to profit from endocrine treatment the relative benefit was reduced in uncoupled tumors (21.2 % vs. 31.7 %). Conclusions: The classification of breast cancers according to this biologically based model identified clinical relevant tumor groups whose further characterization will have important implications. Moreover, since the ability to recognize malfunctions in ER pathways largely depends on an appropriate reference system, the KIT+ tumors could allow a dissection of estrogen responsiveness giving crucial insights for prediction of response to endocrine therapy.

No significant financial relationships to disclose.
Past use of hormone replacement therapy and risk of invasive breast cancer
Authors: Chen W. Y. , Hankinson S. E. , Rosner B. , Colditz G. A.
Published: March 2020

10518

Background: Although current use of hormone replacement therapy (HRT) is associated with a greater risk of breast cancer than past use, the effects of longer term past use of HRT are not well quantified. Methods: We examined the relationship between past HRT use and invasive breast cancer risk within the Nurses’ Health Study, a prospective cohort of 121,700 registered nurses aged 30–55 in 1976 who update information on cancer risk factors and outcomes through biennial questionnaires. For this analysis, the follow-up period was 1980 through 2004 and only included person-time for postmenopausal women. Status of HRT use (never, past, or current), type of HRT (oral unopposed estrogen (E alone) or combination oral estrogen + progesterone (E+P)), and duration of HRT use were assessed every 2 years and defined prospectively. Proportional hazards models controlled for age, body mass index, parity, age at first birth, family history of breast cancer, benign breast disease, alcohol consumption, type of menopause, and ages at menarche and menopause. Results: During 1,388,368 person-years of follow-up among postmenopausal women, invasive breast cancer was diagnosed among 1,554 women who had never used HRT, 459 past users of E+P and 527 past users of E alone. Regardless of duration of use, past use of E alone was not associated with breast cancer risk. Although past use of E+P for less than 10 years was not associated with breast cancer risk (RR (95% CI) 1.01 (0.88–1.17) for < 5 years and 0.95 (0.74–1.21) for 5–9.9 years), past use of E+P for greater than 10 years was associated with an increased risk of breast cancer (RR 1.53 (1.09–2.16) for 10–14.9 years and 1.48 (0.87–2.51) for 15 or more years). Results were similar regardless of time since last use, although power was limited for this subgroup analysis. Conclusions: Past use of E+P for greater than 10 years was associated with a persistent elevation in breast cancer risk. The relationship between duration of past use and breast cancer risk did not appear linear, but suggested a possible threshold effect.

No significant financial relationships to disclose.
Association of p53 codon 72 polymorphism with resistance to adjuvant therapy in primary breast cancer
Authors: Toyama T. , Zhang Z. , Hamguchi M. , Kondo N. , Iwase H. , Iwata H. , Takahashi S. , Yamashita H. , Fujii Y.
Published: March 2020

10520

Background: Single-nucleotide polymorphisms (SNPs) in codon 72 of the p53 gene and in the promoter region of the MDM2 gene (SNP309) have been suggested to play a role in many cancers. We investigated whether these SNPs were associated with patient outcome and influence of adjuvant systemic therapy. Method: The genotypes of p53 codon 72 and MDM2 SNP309 were defined among 557 primary Japanese breast cancer patients (median follow-up, 61.7 months). The effects of several variables on survival were tested by Cox's proportional hazards regression analysis. Results: We showed that the Pro/Pro genotype of p53 codon 72 was significantly associated with poorer disease-free survival (DFS) than other genotypes by Kaplan-Meier analysis (P = .049) and multivariate Cox's proportional hazards regression analysis (P = .047, risk ratio of recurrence = 1.67), whereas MDM2 SNP309 status was not associated with DFS. The association of the Pro/Pro p53 genotype with poorer DFS was especially significant in patients who received adjuvant chemotherapy (P = .009). In contrast, among the patients who had received adjuvant hormonal therapy or no adjuvant systemic therapy, p53 codon 72 genotype was not associated with DFS. Conclusion: The Pro/Pro genotype of p53 codon 72 appears to be an independent prognostic marker of breast cancer patients that have received adjuvant systemic therapy, particularly chemotherapy, and may be predictive of therapy resistance.

[Table: see text]

No significant financial relationships to disclose.
Use of the novel biomarker (HOXB2) to predict response to pancreatectomy for pancreatic cancer
Authors: Biankin A. V. , Kench J. G. , Segara D. , Skalicky D. A. , Biankin S. A. , Cosman P. H. , Merrett N. D. , Musgrove E. A. , Henshall S. M. , Sutherland R. L.
Published: March 2020

10526

Background: Pancreatectomy is the only therapeutic intervention that offers the chance of long term survival for patients with pancreatic cancer, however, only 10% of patients who undergo pancreatectomy survive > 3 years with prognostic factors only determined after pathological examination of the resected specimen. Identification of a biomarker of response to surgical resection that can be determined preoperatively offers the potential to significantly improve survival and quality of life for patients with PC by improving patient selection for pancreatectomy. Methods: We examined the aberrant expression of over 20 genes identified using transcript profiling or known to be important in carcinogenesis using immunohistochemistry and in-situ hybridisation in a cohort of 124 patients with pancreatic cancer to identify potential biomarkers of prognosis and response to operative resection. Results: Aberrant expression of p53, p21WAF1/CIP1, p27KIP1, p16INK4A, cyclin D1, cyclin E, DPC4/Smad4, EGFR, beta-catenin, sfrp4, LMO4, HOXB2, S100P, S100A6, S100A2, RAI3 and CRBP1 were identified in a significant proportion of PC. Multivariate analysis of clinicopathological variables (tumor size, differentiation, subtype, lymph node metastases, perineural invasion and vascular space invasion), treatment parameters (margin involvement, adjuvant therapy, resection type), and aberrant expression of the above candidate biomarkers identified that HOXB2 expression and resection margin involvement by tumor were the only 2 independent prognostic factors. Patients who had absent HOXB2 expression and had clear margins after pancreaticoduodenectomy (48%) had an actual survival of 40% at 3 years and 21% at 5 years, compared to those with HOXB2 expression and/or positive surgical margins who had all died by 28 months. Conclusion: HOXB2 expression may represent a surrogate marker of advanced disease, can potentially be assessed preoperatively using FNAB, and is currently the best predictor of outcome and response to operative resection to be reported. Preoperative assessment of HOXB2 expression has potential clinical utility in predicting response to operative resection for PC to allow better selection of patients for operative intervention.

No significant financial relationships to disclose.
Stage at breast cancer diagnosis is more advanced in BRCA1 carriers but not in BRCA2 carriers
Authors: Kaufman B. , Lahad A. , Krieger M. , Gal M. , Friedman E. , Renbaum P. , Gabizon A. , Paluch-Shimon S. , Catane R. , Levy-Lahad E.
Published: March 2020

10540

Background: BRCA1-associated tumors are known to have less favorable pathological characteristics, but there is little information on whether this is also reflected in the stage at diagnosis. Methods: Clinical and pathological information was collected on 1,122 consecutive Ashkenazi Jewish breast cancer patients who were tested post-diagnosis for the BRCA1/2 mutations common in this population. Results: Of 1,122 patients, 70 (6.2%) were BRCA1 and 50 (4.5%) were BRCA2 carriers. Mean age at diagnosis was 49.9 yrs. in BRCA1 carriers (p=.0001 vs. non-carriers (NC)) vs. 52.0 yrs. in BRCA2 carriers (p=.02 vs. NC) and 56.0 yrs. in NC. Pure DCIS was less common in BRCA1 carriers (3%) than in BRCA2 carriers (8.2%) and NC (11.8%) (p=.03). Medullary carcinoma was more common in BRCA1 (9.8%) and BRCA2 carriers (6.7%) than in NC (1.5%) (p<.001). Invasive lobular carcinomas were rarer in BRCA1 (1.6%) and BRCA2 (2.2%) compared to NC (8.8%) (p=.012). Hormone receptors (HR) negative was more common in BRCA1 (62%) compared to BRCA2 carriers (21%) (p=.00006) and NC (17%) (p<0.0001). Triple negative tumors (HR and HER2 negative) were more common in BRCA1 carriers (60%) than in BRCA2 carriers (14%) and NC (8.3%) (p=0.001). High grade was more common in BRCA1 (60.4%) and BRCA2 (51.4%) carriers than in NC (36.7%, p=.001). Less favorable pathological features and younger age at diagnosis in BRCA1 carriers were reflected in a more advanced stage at diagnosis. Stage I at diagnosis was found in 34% of BRCA1 carriers (p=.05 vs. NC), 43% of BRCA2 carriers and 46% of NC, stage II in 48% of BRCA1 carriers, 41% of BRCA2 carriers and 37% of NC, and stage III in 17% of BRCA1 carriers, 13.5% of BRCA2 carriers and 13.5% of non-carriers. Conclusions: This consecutive cohort study demonstrates that breast cancers in BRCA1 carriers are characterized by more aggressive pathological features and are diagnosed at more advanced stages than in BRCA2 carriers and non-carriers. This may suggest a differential approach for prevention and surveillance in BRCA1 compared to BRCA2 carriers.

No significant financial relationships to disclose.
The functional MDM2 SNP309 polymorphism is associated with an earlier age of diagnosis in women with lung cancer
Authors: Sun S. , Xie X. , Schiller J. H. , Minna J. D. , Tomlinson G.
Published: March 2020

10550

Background: MDM2 protein is a key negative regulator of p53 protein by targeting its destruction through the ubiquitin pathway. A single nucleotide polymorphism (SNP309 T→G) has been identified in the promoter of the MDM2 gene which results in higher levels of MDM2 protein, attenuation of the p53 pathway, and enhanced tumorigenesis. Estrogen signaling has also been shown to upregulate MDM2 expression. Recent studies have suggested that the MDM2 SNP309 polymorphism is associated with earlier age of onset of certain cancers, particularly in women. The purpose of this study was to determine whether the MDM2 SNP309 polymorphism is associated with lung cancer risk in a gender specific manner. Methods: MDM2 genotype analysis was performed on a cohort of 115 consecutive Caucasian patients with histologically confirmed lung cancer using a PCR-based nucleotide polymorphism discrimination test. Allele status was described as homozygous wild-type (TT), homozygous variant (GG) and heterozygous variant/wild-type (TG). Results: In total, 46 female and 69 male lung cancer patients were screened for the MDM2 SNP309 polymorphism ( Table 1 ). Females with the GG genotype were diagnosed at a significantly earlier age as compared to females with the TT genotype (p=0.038), while a similar comparison for males showed no significant difference. A trend towards an earlier age of onset in females as compared to males with the GG genotype was observed, although the sample size was small and this was not significant (p=0.47). Conclusions: In this study, we found that women, but not men, with the MDM2 SNP309 GG genotype were particularly susceptible to the development of lung cancer at an earlier age, supporting the hypothesis that the expression of this polymorphism is gender-specific and possibly regulated by estrogen. Women with the MDM2 polymorphism represent a potential high-risk group for the focus of lung cancer screening and chemoprevention efforts with anti-estrogen therapy.

[Table: see text]

No significant financial relationships to disclose.
The utility of an investigational real-time RT-PCR assay system for the detection of micrometastases in sentinel lymph nodes of breast cancer confirmed by 0.2 mm histological interval analysis
Authors: Kurozumi M. , Kobayashi Y. , Takei H. , Kitsugi K. , Ueno M. , Nishiguchi R. , Green G. , Vargo J.
Published: March 2020

10560

Background: Comparison between real-time RT-PCR and histological analysis for the detection of lymph node metastasis in breast cancer patients is difficult because of the necessary use of different tissue for the two tests. In order to minimize this challenge this study used histology sections taken every 0.2 mm and all tissue between the sections was analyzed by real-time RT-PCR. Methods: 129 Lymph nodes (LNs) were obtained by Sentinel LN biopsy and/or axillary dissection from 80 breast cancer patients. All LNs were cut in half. One half of each LN was used for the routine intra-operative diagnosis. The other half was used for the 0.2mm histological interval analysis. All 10μm sections cut for histology at 0.2 mm intervals were analyzed using frozen section H&E under a light microscope. All remaining tissue between the sections used for histological analysis was assayed by real-time RT-PCR using the genetic markers mammaglobin and cytokeratin-19 (investigational GeneSearch Breast Lymph Node Assay, Veridex, LLC, Warren, NJ, USA). Cutoffs were pre- set for the real-time RT-PCR to detect only metastasis greater than 0.2 mm. Results: Compared to the histological diagnosis using 0.2 mm interval frozen sections, the real-time RT-PCR results were as follows; sensitivity of 100.0% (34/34), specificity of 93.7% (89/95) and overall accuracy of 95.3% (123/129). Conclusions: These data suggest by utilizing the 0.2 mm histological interval analysis, sampling discrepancies are minimized and a high level of sensitivity and overall accuracy is seen for the real-time RT-PCR assay. Assay specificity calculations may be less than 100% due to interpretation challenges in frozen section histology, especially in the cases of smaller metastases and/or lobular cancer, causing a small percentage of clinically relevant metastasis to be missed.

[Table: see text]
Investigation of tumor biomarkers as response predictors in a monotherapy study with lapatinib (L) as a first line treatment in ErbB2 amplified women with breast cancer
Authors: Gomez H. L. , Chavez M. A. , Doval D. C. , Franco S. , Arbushites M. , Berger M. S. , Casey M. A. , Stein S. , Zaks T. , Martin A. M.
Published: March 2020

10562

Background: Lapatinib is a potent inhibitor of both EGFR and HER2 tyrosine kinase activity. Results of the phase II trial EGF20009 in advanced or metastatic breast cancer (MBC) indicated an overall response rate of 24% to monotherapy L as first line (1L) treatment in 138 patients. In an effort to better define predictive biomarkers of response, we evaluated correlations between baseline tumor biomarker expression levels and clinical response to L. Methods: Response rate (RR) was defined as either complete response (CR) or partial response (PR). Tumor blocks were available on 118 patients from the time of most recent biopsy, and mRNA was extracted from 65 individual patient blocks for this preliminary analysis. Using qRT-PCR Taqman analysis, tumors were evaluated for expression of ERBB1- 4, PTEN, c-MYC, as well as two comparator genes for normalization. DecisionTree analysis using SpotFire software was performed to determine the genes most significantly associated with RR. Results: For the initial 65 patient samples analyzed, an elevation of ERBB2 expression was significantly associated with response to treatment with L (p=0.02) and a longer time to progression following treatment with L (p<0.0025). Furthermore, of the 17/65 responders in this preliminary study, SpotFire Decision Tree Analysis demonstrated that 16/17 (94%) who responded to L had a gene expression signature combining ERBB1, 2, and 3, which is currently being confirmed. No association was observed with ERBB4, PTEN and c-MYC in this preliminary analysis. Conclusion: This analysis suggests a correlation between elevated ERBB2 mRNA levels and both RR and TTP in patients treated with L as a 1L treatment. Analysis of the full set of samples (including genome-wide microarray analysis) is ongoing in an effort to determine biomarkers predictive of clinical activity beyond HER2.

No significant financial relationships to disclose.
Insulin-like growth factor-1 receptor expression in invasive ductal breast carcinoma is related to tumor characteristics and prognosis
Authors: Hartog H. , Van der Vegt B. , Van der Graaf W. T. , Boezen H. M. , De Bock G. H. , Wesseling J.
Published: March 2020

10563

Background: The role of the insulin-like growth factor-1 receptor (IGF-1R) in the outcome of breast cancer is poorly understood. Therefore, we analyzed the prognostic value of IGF-1R expression in relation to clinically relevant tumor characteristics. Methods: Expression of IGF-1R, insulin receptor, estrogen receptor (ER), progesterone receptor (PR), HER2 receptor, epidermal growth factor receptor and phosphorylated Akt (pAkt) was determined on tissue microarrays comprising primary invasive ductal breast carcinoma samples of a consecutive series of 221 patients. Patients presented at the University Medical Center Groningen between 1996 and 2001. Patient records were reviewed for clinical and tumor parameters. Cytoplasmic and membranous IGF-1R staining were scored separately, as the relevance of IGF-1R cellular localization is yet unknown. Associations were tested by Chi-square, Log Rank test and Cox regression analysis. Results: Overall, IGF-1R expression was present in 79% of the tumors. Cytoplasmic staining was present in 69%, membranous in 52%, staining was combined cytoplasmic and membranous in 42% of the tumors. Cytoplasmic, but not membranous, IGF-1R staining was associated with expression of ER (p<0.001), PR (p=0.001), pAkt (p=0.04), and increased relapse free and overall survival (RFS, p=0.01; OS, p=0.006). No correlations with other parameters were found. In ER/PR positive, HER2 negative tumors, but not in HER2 positive tumors, cytoplasmic IGF-1R expression correlated with increased RFS (p=0.002) and OS (p=0.001). In contrast, in triple negative tumors cytoplasmic and membranous expression of IGF-1R were both significantly associated with shorter RFS (p=0.02, p=0.04, resp.). In multivariate analysis, cytoplasmic IGF-1R expression was an independent prognostic factor for OS (HR 0.3, 95% CI 0.1–0.9, p=0.035). Conclusions: Cytoplasmic IGF-1R expression in invasive ductal breast carcinoma is associated with hormone receptor expression, phosphorylated Akt and good prognosis. Surprisingly, triple negative tumors expressing IGF-1R have a worse prognosis than those without. These results suggest that IGF-1R targeted therapy may have additional value in the treatment of triple negative tumors.

No significant financial relationships to disclose.
Adrenomedullin and its receptors expression in renal tumors
Authors: Deville J. , Salas S. , Bartoli C. , Dupuis C. , Duffaud F. , Sebahoun G. , Figarella-Branger D. , Ouafik L. , Martin P. , Daniel L.
Published: March 2020

10568

Background: Adrenomedullin (AM) is a 52 amino acid peptide that has an important role on tumor cell proliferation and neoangiogenesis through its receptors CRLR/RAMP2 and CRLR/RAMP3. AM gene expression is stimulated by Hypoxia Inductible Factor-1 (HIF- 1) and 60–80% of the human conventional renal carcinomas (cRCC) display mutations in the tumor suppressor protein von Hippel-Lindau, which leads to constitutively elevated HIF-1. Methods: Tumors and non-malignant kidney tissues were obtained from patients who underwent unilateral nephrectomy. We studied VEGFA, AM and its receptors expression by quantitative RT-PCR in 62 frozen renal tumors including: 40 cRCC; 5 cRCC metastasis; 5 chromophobe carcinomas; 5 Papillary carcinomas; 2 oncocytomas; 2 collecting duct carcinomas; 2 normal adjacent renal tissue; 1 unclassified renal tumor. AM and AM-receptors expression was studied in 42 paraffin-embedded renal tumors by immunohistochemistry using rabbit anti-AM, anti-CRLR, anti-RAMP2 and anti-RAMP3 polyclonal antibodies. Effects of these anti AM or anti AM- receptors antibodies on cell proliferation were examined in vitro on BIZ cell line (cRCC cells). Results: VEGFA, AM and AM-receptors genes were overexpressed in cRCC compared to other renal tumors (Except AM gene in chromophobe carcinoma). Their expressions were independent of classical prognostic factors (such as Fuhrman Grade and pT status). In cRCC, there was a strong positive correlation between VEGF-A gene expression and AM (r=0.7; p=0.01) and AM-receptors genes expressions (RAMP2 r=0.61; p= 0.01 and RAMP3 r=0.58; p= 0.01). Immunohistochemistry confirmed a tumor expression of CRLR, RAMP2 and AM in more than 80% cRCC. RAMP3 was expressed by inflammatory cells but not by tumoral cells. The cell proliferation assay showed a significant inhibition of BIZ cell proliferation by AM antibody or AM-receptors antibodies. Conclusion: AM and its receptor CRLR/RAMP2 are overexpressed in cRCC. In vitro cell proliferation assay results support that AM inhibition may suppress cRCC growth, independently of potential antiangiogenic effects. Further studies on animal models are needed but AM pathway may be a potential therapeutic target in cRCC.

No significant financial relationships to disclose.
Outcome prediction to cetuximab in advanced colorectal cancer: Analysis of EGFR and HER2 gene copy number by fluorescence in situ hybridization
Authors: Personeni N. , De Hertogh G. , Störkel S. , Debiec-Rychter M. , Geboes K. , De Roock W. , Humblet Y. , Piessevaux H. , Van Cutsem E. , Tejpar S.
Published: March 2020

10569

Background: Recent studies suggest that increased epidermal growth factor receptor (EGFR) gene copy number assessed by in situ hybridization predicts response to cetuximab in patients (pts) with advanced colorectal cancer (mCRC). Additionally, preclinical data indicate that HER2, a member of the EGFR family, can modulate the efficacy of anti-EGFR monoclonal antibodies. Methods: We assessed EGFR and HER2 gene copies by fluorescent in situ hybridization (FISH) on paraffin-embedded samples from 70 pts with mCRC treated with cetuximab alone or with irinotecan. FISH was assessed either on primary tumors (55 pts) or on metastases (15 pts) according to two parameters: the absolute copy number of genes and chromosome (chr) centromeres, and their frequencies in 100 tumor cells. A sensitivity analysis was performed and fitted to outcome data in an attempt to define relevant cutoffs. EGFR protein expression by immunohistochemistry was deemed positive with =10% tumor cells being stained. Multiple paired samples originating from different tumor sources were analyzed whenever available (27 pts). Results: The overall response rate was 25%. Prevalent FISH patterns were disomy (8%) and balanced polysomy (90%) for EGFR gene and chr 7. EGFR amplification was seen in two pts (2%), of which only one responded. HER2 amplification was seen in two of 54 pts (3%), both experiencing stable disease. Average EGFR copies and frequency of tumor cells with >2 copies respectively ranged from 1.6 to 4.0 and from 10% to 90%, thus reflecting a substantial tumor heterogeneity. Despite assessing multiple centile cutoffs of gene copy numbers and their frequencies in tumor cells, we found no association between EGFR and HER2 copy numbers and objective response, time to progression, and overall survival. Analysis of paired samples did not improve the predictive value of EGFR copies by FISH. Excluding EGFR amplification, associated to a strong (3+) EGFR staining, we found no correlation between EGFR copy number and protein expression. Conclusions: Neither EGFR nor HER2 copies by FISH, nor EGFR expression, are predictors of outcome in mCRC pts treated with cetuximab. FISH might still play a role in screening EGFR and HER2 amplification, but cost-effectiveness is debatable.

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The combination of the HER2 antibody trastuzumab, the EGFR tyrosine kinase inhibitor gefitinib, and docetaxel as first-line therapy in patients with HER2 overexpressing stage IV breast carcinoma
Authors: Somlo G. , Koczywas M. , Luu T. , McNamara M. , Bedell V. , Slovak M. L. , Wilczynski S. , Morgan R. , Russell C. , Frankel P.
Published: March 2020

1057

Background: Interference with both HER2 and epidermal growth factor (EGFR) dependent pathways may improve therapeutic efficacy of docetaxel (doc) in pts with HER2 overexpressing (+) BC. Methods: Patients (pts) without prior chemotherapy (Rx) exposure for stage IV HER-2 + BC were enrolled. Prior hormonal or adjuvant Rx inclusive of taxane or trastuzumab (tras) were allowed. A left ventricular ejection fraction of > 45% and ECOG performance status of ≥ 2 were required. Pts were to receive doc 75 m2, tras every 3 weeks, and gefitinib (gef) 250 mg daily. BC samples from 12 pts were analyzed by FISH for HER2 and EGFR amplification (amp), and topoisomerase II (topo II) amp or loss. IHC was to be performed to examine p-Src, p-STAT3, Ki67 and survivin expression. Results: The median age was 49 (range, 34–67) and ECOG performance status 0.5 (0–1). The first 9 patients received gef 250 mg daily; 2 pts received dox 75 mg/m2 and developed grade 3 febrile neutropenia (neu), hence, additional pts received doc at 60 mg/m2: 3 more episodes of grade 3 neu were seen. Gef was held due to grade 3 dermatitis (2 pts) and diarrhea (2 pts). Pts received a median of 6 cycles (3–10). Gef schedule then was changed, and was prescribed on days 2–14, only. Three of the next 9 pts experienced grades 3 or 4 neu, and we observed 3 cases of grade 3 gastrointestinal toxicities; pts were able to receive 11 + (range; 5–25+) cycles on this schedule (p<0.04). There were 4 complete (CR)and 6 partial R (23 % CR, 59 % overall R), and 3 pts had stable disease (SD; all R and SD confirmed); 3 pts progressed at 4, 4, and 5 mos, 1 pt was inevaluable. The median time to progression is 12 + mos. Samples from 3 pts revealed topo II amplification and one pt sample showed loss of one topo II allele; none were amplified for EGFR. Outcome will be correlated with IHC defined signal trasduction status and proliferation rates. Conclusions: The combination of doc, tras, and short course of gef is feasible, with encouraging R and SD rates and time to progression. Further exploration of simultaneous blockage of multiple signal transduction pathways is indicated in combination with chemoRx. Supported by NCI CA33572 and by a grant from AstraZeneca.

No significant financial relationships to disclose.
Pathological response rates in 710 operable breast cancer (BC) patients treated by neoadjuvant chemotherapy (NCT), according to immunohistochemichal subtypes of tumours
Authors: Chollet P. J. , Abrial C. , Tacca O. , Raoelfils I. , Leheurteur M. , Mouret-Reynier M. , Amat S. , Durando X. , Dauplat J. , Penault-Llorca F.
Published: March 2020

10579

Background: Pathological responses rates were studied in 710 women with stage II-III operable BC treated between 1982 and 2004. A pathological review was conducted to assess the residual disease in breast and nodes according to Chevallier's classification (Am J Clin Oncol 1993) and patients repartited according to 3 tumour phenotypes: Her2+ (Her2+ phenotype), Her2-HR+ (Hormonal Receptor; luminal phenotype) and Her2-HR- (triple negative phenotype). Methods: Median diameter of the invasive tumour was 40 mm [10–130]. 555 (78%) patients had a canalar, 90 (13%) a lobular, 18 (2.5%) a mixed or invasive carcinoma, 36 (5%) neoplasic cells only and 11 (1.5%) another carcinoma. 25.6% of the tumours were grade III SBR. The median number of NCT courses was 6 [1–9] followed by a surgery for 92%, a radiotherapy for 95%, an adjuvant chemotherapy for 17% and/or an hormonotherapy for 52%. A breast evaluation was realized before, during and after NCT. Results: Overall response rate was 68% (16% complete). The complete pathological response (pCR) rate was 14.2% according to Chevallier's classification. On 656 patients operated, 470 (72%) had a conservative surgery. On 520 patients with an axillary dissection, 272 (52.3%) had involved nodes. After a median follow-up of 93 months, Disease-Free Survival (DFS) and Overall Survival (OS) at 120 months were 54.9% and 66.5%, respectively. According to tumour's phenotype, the pCR rate (Chevallier's classes 1+2) was: 24.5% in Her2+ phenotype, 14.8% in triple negative phenotype and 4.4% in luminal phenotype. These results showed that: -the pCR was three-fold more frequent in Her-2+ phenotype than in luminal one (p = 3.5.10-5) -the pCR was two-fold more frequent in triple negative phenotype than in luminal one (p = 3.10-3) -no significant pCR difference was found between Her2+ phenotype and triple negative one Furthermore, a significantly better DFS was found for luminal phenotype; DFS was intermediate for triple negative phenotype, and lower for Her2+ phenotype. Conclusions: The pCR rates were higher in Her2+ phenotype and in triple negative one. It is important to note that, in this series, most Her2+ patients did not receive any Herceptin treatment.

No significant financial relationships to disclose.
The role of BRCA1 in DNA repair and chemosensitivity
Authors: Sharma V. B. , Kurian A. W. , Feldman A. , Ford J. M.
Published: March 2020

10606

Introduction: The BRCA1 tumor suppressor protein has been implicated in many cellular processes, including several different DNA repair pathways. Inherited mutations in the BRCA1 gene result in an increased risk for developing breast and ovarian cancer. BRCA1 associated tumors are frequently estrogen receptor negative thus rendering them ineffective targets of hormonal manipulations. Therefore chemotherapy is the only treatment option available to patients with metastatic disease. Methods: Global genomic repair activity was detected by an immunoslotblot assay. UV-C and chemosensitivity was determined by the MTT assay. The comet assay was used to measure oxidative DNA damage (ODD). Results: Brca1 deficient cells demonstrate decreased global genomic repair independent of p53 expression. These cells are 3-fold more sensitive to UV-C radiation, 5-fold more sensitive to cisplatin, and 25-fold more sensitive to gemcitabine than Brca1 positive cells. The combination of cisplatin and gemcitabine is synergistic. This synergy is independent of Brca1 protein expression. In addition, the cholesterol lowering drug lovastatin is able mitigate the ODD caused by hydrogen peroxide. Reduced ODD is also observed in breast epithelial cells from high risk patients after 6 months of oral lovastatin use. Discussion: These results confirm our earlier findings that BRCA1 is involved in the nucleotide excision repair pathway. In addition, we demonstrate that this effect is independent of p53 expression. We also find that Brca1 deficient MMECs are more sensitive to UV-C, and the cytotoxic drugs cisplatin and gemcitabine. Cisplatin is known to cause DNA intra- and inter-strand crosslinks whereas gemcitabine is a nucleoside analog. The increased sensitivity of Brca1 deficient MMEC's to these agents supports the role of Brca1 in the different molecular pathways involved in their repair. In addition, we demonstrate that lovastatin can overcome ODD in vitro and in vivo and may be an effective agent to modify breast cancer risk for individuals at increased risk.

No significant financial relationships to disclose.