bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of heterozygosity at the BRCA2 locus is a common finding in prostate cancer in men with a germline BRCA2 mutation
Authors: Dawson S. , Willems A. , Thorne H. , Samaratunga H. , Antill Y. C.
Published: March 2020

10539

Background: The prevalence of prostate cancer (PC) is higher in men with a germline mutation in BRCA2 and to a lesser extent BRCA1. It is unclear as to whether a causal relationship exists between these mutations and PC tumorigenesis. The primary aim of this pilot study was to examine for loss of heterozygosity (LOH) in PC samples from men with a known BRCA1/2 mutation. Secondary aims included assessment of the clinical and pathological features of PC in these individuals. Methods: Subjects were male carriers of a germline BRCA1/2 mutation enrolled in kConFab with a diagnosis of PC. LOH analysis was performed using multiplex ligation-dependent probe amplification and confirmed using PCR and sequencing. Clinical data was obtained on all individuals together with histopathology review. Results: In total, 134 pedigrees from BRCA1/2 mutation positive families known to include = 1men with PC were reviewed; 192 men were identified as having PC, however, only 26 were found to carry a pathogenic family specific mutation. Of these, 14 were ineligible as prostate tissue was unavailable. LOH was therefore assessed in 12 subjects (3 BRCA1 and 9 BRCA2). LOH at the BRCA2 locus was seen in 8/9 (89%) subjects with a BRCA2 mutation whilst the ninth showed no LOH. None of the samples from BRCA1 carriers were found to have LOH at the BRCA1 locus. For samples showing LOH, sequencing confirmed loss of the wild-type allele. No unique clinical or histopathological subtype was identified. Conclusions: LOH appears to occur very frequently at the BRCA2 locus in PC arising in men known to carry a germline BRCA2 mutation with LOH heavily biased towards loss of the wild-type allele. Whilst the cohort studied is small, these two results strongly indicate that BRCA2 is a tumour suppressor of PC and is the first gene shown to have this property. In contrast, failure to identify LOH in the BRCA1 samples suggests that BRCA1 is unlikely to be integral in the development of PC. These results should be confirmed in a larger cohort and further research into the mechanisms of BRCA2 induced prostate tumorigenesis is warranted.

No significant financial relationships to disclose.
An international phase II study of an all-oral combination of oral vinorelbine (NVBo) and capecitabine (X) in HER2-negative metastatic breast cancer (MBC)
Authors: Tubiana-Mathieu N. , Bougnoux P. , Becquart D. , Chan A. , Majois F. , Espie M. , Aubert D. , Villanova G. , Conte P. F.
Published: March 2020

1056

Background: Oral chemotherapy (CT) is attractive for patients (pts) with MBC. The all-oral regimen of NVBo and X is active with good tolerability in MBC. We report efficacy and safety data from an international phase II study of NVBo plus X. Methods: Main eligibility criteria included: measurable HER2-negative, CT-naive MBC, relapse ≥6 months after completing (neo)adjuvant CT, Karnofsky PS ≥70%, age ≥18 years. Study treatment: 3-weekly cycles of NVBo 60 mg/m2 (cycle 1) or 80 mg/m2 (from cycle 2) d1 and d8, plus X 1,000 (750 if ≥ 65 years) mg/m2 twice-daily d1–14. Treatment was continued until progression or unacceptable toxicity. Results: 55 pts were enrolled: median age: 58.5 years (41% ≥65); prior (neo)adjuvant CT in 63%; type of CT: anthracycline 67%, anthracycline + taxane 18%, CMF 15%; visceral involvement in 78%; >2 metastatic sites in 46%. Median 6 cycles; median relative dose intensity: NVBo 88%, X 87%; NVBo dose escalated to 80 mg/m2 in 94% of pts. G3/4 NCI CTC v2 adverse events (n=54): neutropenia 44% of pts, vomiting 9%, febrile neutropenia 7%, stomatitis 7%, asthenia 7%, infection with G3/4 neutropenia 4%, nausea 4%, diarrhea 4%, hand-foot syndrome 4%, thrombosis/embolism 4%. Efficacy (n=48 evaluable pts): objective response rate (RECIST) 44% (95% CI [29–59]), CR 2%, PR 42%, SD 35%, PD 21%, disease control (CR+PR+SD ≥6 months) 56%. Median time to objective response was 2.9 months. Because of short follow-up, progression-free survival, overall survival and duration of response data are not yet available. Conclusion: The all-oral combination of NVBo and X is an effective and well-tolerated first-line therapy for MBC. Based on these results and the high convenience of oral CT, evaluation of this regimen vs i.v. combinations in a randomized trial is ongoing.

[Table: see text]
Gene expression profiling can predict pathological complete response (pCR) to anthracycline-based therapy in estrogen- receptor (ER) negative breast cancer (BC) patients
Authors: Desmedt C. , André F. , Azambuja E. , Haibe-Kains B. , Larsimont D. , D'Hondt V. , Di Leo A. , Piccart M. , Pusztai L. , Sotiriou C.
Published: March 2020

10564

Background: Breast cancers show variable sensitivity to anthracycline (A)-based therapy. Here we aimed to identify gene expression profiles associated with pCR to this treatment. As it has repeatedly and consistently been shown that ER is the most dominant factor influencing the molecular composition of breast cancer, defining different types of BC disease and because we wanted to eliminate the confounding effect of indirect ovarian suppression in ER+ BC, we focused in this study on ER-negative patients only. Methods: We analyzed Affymetrix gene expression profiles generated from 132 ER- pre-treatment samples, constituting the largest series of ER- preoperatively A-treated BC (n=132/35 pCR). Sixty-two samples derived from the prospective multicentric TOP trial (epirubicin single-agent), 41 from Institut G. Roussy (retrospective selection/ FEC) and 27 from MD Anderson (prospective study/ FAC). Results: A student t- test analysis on the combined population of A-treated pts was performed identifying 102 genes that were significantly associated with pCR (p<.01). These genes were mainly involved in cell death, DNA replication and recombination, molecular transport, cell cycle and morphology. Interestingly, 14 of these genes were located on the topoIIa amplicon. Of interest, none of these 14 genes seem to carry any prognostic value in untreated ER- pts (N=161). When we considered gene expression indices for specific A-targets such as topoIIa and helicase, we found that both were associated with pCR. However, subgroup analysis revealed that topoIIa index was predictive in ERBB2+ but not in ERBB2- subgroup. None of the genes from the adriamycin predictor (Potti et al.) or the p53 signature (Miller et al.) were significantly associated with pCR. Conclusions: This study suggests that a group of genes associated with topoIIa can identify ER-negative BC pts likely to respond to A-based therapy. These promising results are currently being validated in a larger series.

No significant financial relationships to disclose.
Prospective phase II study of neo-adjuvant doxorubicin followed by cisplatin /docetaxel in locally advanced breast cancer—5 years of follow up
Authors: Ajarim D. S. , Rahal M. , Al-Sayed A. , Alshabana M. , Tulbah A. , AlMalik O. , El-Husseiny G. , Ezzat A. , Al-Tweigeri T.
Published: March 2020

10574

Background: Neoadjuvant (primary) chemotherapy as part of multimodality treatment is increasingly used as standard of care for patients (pts) with locally advanced breast cancer and firmly established. We conducted a prospective study using doxorubicin 75 mg/m2 q 3 weeks × 3 cycles followed sequentially by docetaxel 75 mg /m2 and cisplatin 75 mg/m2 q 3 weeks × 3cycles. All pts had definitive surgery followed by radiation therapy, ± tamoxifen. Primary end points were pathologic complete response (pCR), secondary endpoints were, safety, rate of conservative surgery and overall survival. Material: Eligible pts included biopsy proven invasive breast cancer, T2-T4 (primary = 4–10 cm) N0-N2, M0. 59 of 60 enrolled pts completed treatment one patient refused surgery after the completion of 6 cycles of chemotherapy were excluded from the analysis, median age:41yrs (24- 60), Premenopausal: 68%, median tumor size: 6.0cm (4 - 10), Stage IIB:32% and IIIA / IIIB: 68%, both ER / PR positive: 53%, Her2/neu (3+) by IHC staining and /or Fish positive: 29%. All patients had negative metastatic workup. Results: 59 pts are evaluable for analysis: clinical complete response was seen in: 44%, clinical partial response in: 56 %. Breast conserving surgery was performed in: 44 %, and MRM in: 56%. Pathological complete response (pCR) in the breast was: 31 %, in axilla were: 37 %. Grade3–4 Toxicities: Febrile Neutropenia: (13%), Nausea vomiting: (12%), Mucositis: (10%), weakness/asthenia/weight loss: 12%. Overall at follow up of 60 months the DFS & OS (67% and 74%).Patients who achieved complete pathologic response in breast and/or axilla the DFS and OS were (91%), 13 patients relapsed 46% were Her2 positive. Conclusion: Sequential combination of doxorubicin followed by docetaxel/cisplatin is a safe, feasible and active combination, that offer the possibility of conservative surgery and associated with high clinical and pathologic response, further investigation of this combinations are warranted.

No significant financial relationships to disclose.
Breast cancer growth rates in BRCA1/2 mutation carriers
Authors: Bosse K. , Goβmann A. , Rhiem K. , Warm M. , Schmutzler R. K.
Published: March 2020

10575

Background: 1. Recent investigations suggest an accelerated growth rate in BRCA1/2-associated breast cancer. 2. This characteristic may have influence on screening policy. Patients and Methods: BRCA1/2 mutation carriers are regularly observed in a structured surveillance program that comprises annual mammography and MRI-scan in addition to sonography undertaken every six months. We performed a prospective study in approx. 2035 women participating in a breast cancer screening program from 01/1997 until 12/2006. In 9 carriers 10 BRCA-associated breast cancer cases were diagnosed of whom at least one previous examination was available. A calculation of the tumor volume doubling time was performed according to the following algorithm: VDT= log2 × (t2-t1)/logm2 - logm1 (VDT= Volume doubling time; t1 and t2 at the beginning and at the end of the observation period; m1 and m2 size of the tumor at point in time t1 and t2). Results: The 10 cases shown in table 1 prove both high growth rates with VDTs measuring on average 48 days and benign morphologic criteria in early stage disease by all 3 imaging procedures. The VDT for BRCA1-associated tumors was in average 42 days, while the single BRCA2 associated case had a VDT of 102 days. Conclusions: Our data demonstrate a short VDT of 48 days in BRCA1/2 mutation carriers. This is in line with another observational study which identified a tumor doubling time of 45 days for familial tumors in comparison to sporadic tumors with 82 days (Tilanus-Linthorst et al., 2005). These data underline the necessity for a closely meshed screening interval of 6 months. Lit: Tilanus- Linthorst et al., Eur J Cancer. 2005. Jul.41(11):1610–17

[Table: see text]

No significant financial relationships to disclose.
High prognostic potential of glioblastoma stem cell analysis
Authors: Banna G. L. , Pallini R. , Ricci-Vitiani L. , Signore M. , Lombardi D. , Martini M. , Maira G. , Giuffrida D. , Larocca L. M. , De Maria R.
Published: March 2020

10580

Background: Cancer stem cells (CSCs) are a rare cell population responsible for tumor development and maintenance. Recent studies have shown that glioblastoma stem cells express the CD133 marker and are resistant to radiotherapy and chemotherapy. However, clinical data based on the study of CSCs in patients with glioblastoma are not available yet. Methods: Glioblastoma samples from 44 patients treated with complete or partial tumorectomy, followed by radiotherapy and temozolomide were prospectively analyzed. Immunohistochemistry was performed to evaluate the prognostic value of the number of CD133+ cells present in tumors. Moreover, the relationship between the ability to generate long-term culture of tumorigenic cells in vitro and the clinical outcome of glioblastoma patients was tested. Results: CD133 expression did not show an overall prognostic value. CSC cultures were obtained from 14 of the 44 tumors (32%). The generation of CSCs emerged as significant independent prognostic factor by the Cox multivariate analyses, with an adjusted hazard ratio of 2.50 (95% CI, 1.04 to 6.06; P=0.004). The median overall survival among patients with tumors generating CSCs was 8.0 months (95% CI, 4.0 to 11.5), as compared with 15 months (95% CI, 11.0 to 19.0) among those without generation of CSCs (P=0.0002). The median progression-free survival was 3.5 months (95% CI, 2.0 to 6.0) for glioblastoma generating CSCs and 9.0 months (95% CI, 7.0 to 12.0) for glioblastoma not generating CSCs (P=0.0001). A higher CD133 expression significantly associated with tumors generating CSCs (P=0.006), and correlated with a higher risk of death in patients with tumors generating CSCs in vitro (hazard ratio of 1.65, 95% CI, 1.05 to 2.60; P=0.0285). Conclusions: Generation of long-term culture of tumorigenic CSCs in vitro from glioblastoma predicts a poor clinical outcome for patients, in terms of both overall and progression-free survival. In tumors generating CSCs, CD133 expression may have a prognostic value.

No significant financial relationships to disclose.
Can we identify a group of breast cancer patients with a good prognosis despite four or more positive (4+) axillary nodes using a tissue microarray (TMA)?
Authors: Crabb S. J. , Bajdik C. D. , Speers C. H. , Huntsman D. G. , Gelmon K. A.
Published: March 2020

10582

Background: Although breast cancer with 4+ axillary lymph nodes generally carries a poor prognosis, we hypothesized that a good prognostic subgroup of such patients would be identifiable by immunohistochemical (IHC) biomarkers. Methods: Patients with primary breast cancer with 4+ axillary nodes and no metastatic disease at diagnosis were identified from a large clinically annotated TMA of formalin-fixed paraffin-embedded archival breast cancers and analyzed for eight IHC based biomarkers: estrogen receptor, HER2, carbonic anhydrase IX, EGFR, CK 5/6, progesterone receptor, p53 and Ki67. Expression of each biomarker was scored 0 or 1 to indicate good or bad prognosis based on univariate analysis of relapse free survival (RFS). Patients were banded as having a total score of 0 (i.e. each biomarker predicted a good outcome), 1–4 or 5–8. Kaplan Meier and Cox regression analysis of RFS outcomes was performed. 10 year RFS for each band was compared to the mean of predicted outcomes based on the prognostic tool Adjuvant! ( www.adjuvantonline.com ). Results: 313 eligible patients were identified and complete data were available for 228. The subset of 228 was similar to the larger group of 313 with respect to RFS and conventional prognostic factors. 10 year RFS for the 228 patients was 39.5% (standard error, SE 3.4%). The subgroup of 37 (16%) scoring zero for all 8 biomarkers had a mean 10 year RFS of 77.6% (SE 7.0). Mean 10 year RFS for the bands scoring 1–4 (154 patients, 68%) and 5–8 (37 patients, 16%) were 34.9% (SE 4.1) and 19.0% (SE 6.9) respectively. Mean 10 year RFS predictions by Adjuvant! were 35.9% (SE 2.6), 34.5% (SE 1.2) and 34.3% (SE 2.3) respectively. In multivariate analysis with conventional prognostic factors, the banded biomarker score retained statistical significance for predicting RFS (p=0.0007) along with estrogen receptor status (p=0.03) and tumour size (p=0.01). Conclusions: This TMA biomarker panel identified a breast cancer subgroup with good prognosis despite extensive axillary node involvement. Long term outcome was markedly better than that predicted by conventional prognostic factors. If validated, treatment decisions and clinical trial stratification might be modified using this new score.

No significant financial relationships to disclose.
A twenty eight-gene signature and survival in completely-resected non-small cell lung cancer (NSCLC)
Authors: Van Zandwijk N.
Published: March 2020

10583

Background: Current staging methods are imprecise for predicting the outcome of treatment of non-small-cell lung cancer (NSCLC). We have developed a 28-gene signature that is closely associated with recurrence-free and overall survival. Methods: We used whole-genome gene expression microarrays to analyze frozen-tumor samples from 174 patients (pT1&2, N0&1, MO), who had undergone complete surgical resection in 5 European institutions. Randomly generated numbers were used to assign 2/3 of the samples to an algorithm training group with the remaining 1/3 set aside for independent validation. Cox proportional hazards models were used to evaluate the association between the level of expression and patient survival. We used risk scores and nearest centroid analysis to develop a gene-expression model for the prediction of treatment outcome. Leave-one-out cross validation was used to prevent model over-training. Results: 28 genes that correlated with survival were identified by analyzing microarray data and risk scores. Based on the expression of these genes, patients in training and validation groups were classified as either high (48%) or low (52%) risk. Analysis of predicted risk groups revealed significantly different survival distributions for patients in both the training set (p<0.001) and independent validation set (p=0.006). Genes in our prognostic signature encode for several membrane-bound proteins with previously demonstrated involvement in cell cycle regulation and cell proliferation processes. Conclusions: Our 28-gene signature is closely associated with time to recurrence and overall survival of completely-resected NSCLC patients.

[Table: see text]
Edi-3, a new independent prognostic factor in ovarian cancer
Authors: Mustea A. , Koensgen D. , Lichtenegger W. , Pirvulescu C. , Sun P. M. , Thomas A. , Lausch E. , Steiner E. , Hengstler J. G. , Sehouli J.
Published: March 2020

10585

Background: Recently, we have identified for the first time a new putative phosphodiesterase named edi-3 that correlates with tumorigenesis in endometrial cancer. In the present study we analyzed the prognostic relevance of edi-3 in ovarian cancer. Methods: Edi-3 mRNA expression was measured by quantitative RT-PCR (TaqMan) in 62 patients with primary ovarian cancer. All patients signed informed consent, approved by the Clinical Review Board and Ethics Committee of the Medical University Berlin, Charité, Germany. The tumor specimens were collected according to the Tumor Bank Ovarian Cancer standard operating procedures. A validated systematic intraoperative documentation tool was used for the detailed documentation of all surgical procedures. Using the multivariate proportional hazard model we analyzed whether edi-3 predicts survival independent from FIGO-stage, grading, postoperative residual disease and histological type. Results: Edi-3 expression is associated with survival in the univariate Cox model (hazards ratio [HR]: 1.488, 95% confidence interval [CI]: 1.131 - 1.959, P=0.005). Interestingly, edi-3 was also predictive in the multivariate proportional hazard model adjusted for the conventional clinical factors (HR: 1.521, CI: 1.107 - 2.090, P=0.010). Conclusions: Edi-3 is a new independent prognostic factor in primary ovarian cancer with HR=1.5 (P=0.010). Its function, a possible role in inositol phosphate metabolism, will be further explored in a multi-instutional setting.

No significant financial relationships to disclose.
A phase II clinical trial of ZD1839 (gefitinib) in combination with docetaxel as first-line treatment in patients with advanced breast cancer
Authors: Dennison S. K. , Jacobs S. A. , Wilson J. , Seeger J. , Cescon T. , Raymond J. M. , Geyer C. E. , Wolmark N. , Swain S. M.
Published: March 2020

1059

Background: We conducted a phase II multi-institutional trial of gefitinib and docetaxel as first-line treatment in patients with metastatic breast cancer. The primary objectives were to determine the clinical benefit rate (defined as the proportion of patients who experienced confirmed complete response or partial response or who had stable disease for at least 24 weeks) and the toxicity profile of the combination treatment. Methods: All patients had histologically confirmed breast cancer with metastatic disease. They may have received adjuvant chemotherapy, but no prior docetaxel or prior chemotherapy for metastatic disease. Patients received gefitinib 250 mg once daily and docetaxel 75 mg/m2 every 3 weeks, until tumor progression, toxicity or other reasons for discontinuation. Results: Between April 2003 and September 2004, 33 patients were enrolled at 11 participating institutions. Patients received a median of 5 cycles of treatment. The clinical benefit rate was 51.5% (95% CI: 33.5% - 69.2%). There was 1 confirmed complete response and 12 confirmed partial responses, and the overall objective response rate was 39.4% (95% CI: 22.9% - 57.9%). Four patients had stable disease for = 24 weeks. The median duration of clinical benefit was 10.9 months (95% CI: 6.0 - 17.6 months). The most common reason for study discontinuation was disease progression (16 patients), followed by toxicity (10 patients). Toxicities were mainly attributable to docetaxel, including = grade 3 neutropenia in 43% of patients. Conclusion: The combination of gefitinib and docetaxel is an active regimen in patients with previously untreated metastatic breast cancer. Further work is needed to determine which subset of patients with breast cancer will benefit from gefitinib.

No significant financial relationships to disclose.
Prognostic impact of angiogenic markers in tumor and stromal cells in non-small cell lung cancer (NSCLC)
Authors: Donnem T. , Al-Saad S. , Al-Shibli K. , Delghandi M. P. , Persson M. , Nilsen M. , Busund L. T. , Bremnes R. M.
Published: March 2020

10596

Background: The vascular endothelial growth factors (VEGFs) -A, -C, -D and the vascular endothelial growth factor Receptors (VEGFRs) -1, -2 and -3 are important molecular markers in angiogenesis and lymphangiogenesis. This study elucidates the prognostic significance of these molecular markers in tumor cells as well as in the tumor stroma of resected NSCLC tumors. Methods: Tumor tissue samples from 335 resected patients with stage I to IIIA were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of each molecular marker. Results: In univariate analyses, high tumor cell expression of VEGF-A (P = .0005), VEGFR-1 (P = .013), VEGFR-2 (P = .006) and VEGFR-3 (P = .0003), were negative prognostic indicators for disease-specific survival (DSS). The most significant correlations between angiogenic marker expression and DSS were observed in patients with T2 stage and/or with sqamous cell carcinomas. In tumor stroma, however, high expression of VEGF-A (P = .017), VEGF-C (P = .003), VEGF-D (P = .009), VEGFR-1 (P = .01) and VEGFR-2 (P = .019), correlated with good prognosis. In multivariate analyses, high expression in tumor cells of VEGFR-3 (P = .007) was an independent negative prognostic factor for DSS, whereas high VEGF-C (P = .004) expression in stromal cells had an independent positive impact on survival. Conclusions: While high tumor cell expression of VEGFR-3 is an independent predictor of reduced survival in primary NSCLC, high VEGF-C expression in stromal cells is, in contrast, a favorable independent prognostic indicator.

No significant financial relationships to disclose.
Haploinsufficiency of CDK4 prevents hepatocarcinogenesis in mice deficient in ELF, a mediator of TGF-beta signaling
Authors: Pishvaian M. J. , Blake T. M. , Kitisin K. , Kim S. S. , Kang A. , Rashid A. , Tang Y. , Mishra B. , Reddy E. P. , Mishra L.
Published: March 2020

10608

Background: The transforming growth factor-β (TGF-β) has a dual role in cancer, but in the prevention of tumorigenesis, TGF-β signaling inhibits cell cycle progression through an increase in cell cycle inhibitors and decrease in cell cycle activators. The adaptor protein embryonic liver fodrin (ELF) is crucial for normal TGF-β signaling. ELF facilitates the association and nuclear translocation of the TGF-β signaling proteins, Smad3 and Smad4. We have demonstrated that elf± mice develop hepatocellular cancers (HCC) spontaneously within 12 months. We have also shown that most human HCCs demonstrate a decreased expression of ELF. Our goal was to assess the interaction between ELF and cyclin dependent kinase 4 (CDK4), which is overexpressed in most human cancers. Methods: We compared the expression of CDK4 and ELF by immunohistochemistry and analyzed the interaction between CDK4 and ELF, in vitro by immunoprecitpitation and western blot. Finally, we assessed the development of HCC in intercrossed elf± and CDK4+/neo mice. Results: CDK4 and ELF expression are inversely correlated in HCCs from elf± mice. Furthermore, ELF interacts with CDK4 by forming a complex that includes Smad3 in COS-7 and HepG2 cells. ELF is phosphorylated upon overexpression of CDK4, revealing a possible mechanism by which CDK4 may inhibit ELF-dependent TGF-β signaling. To further assess whether the development of HCC in elf± mice is dependent upon CDK4 expression, we have intercrossed elf± and CDK4+/neo mice. At 12 months, only 17% of the elf±/CDK4+/neo mice developed HCC, compared to 40% of our historical control elf± mice. This initial data strongly suggests that haploinsufficiency of CDK4 can prevent the HCCs seen in elf± mice, and provides the genetic foundation for further exploring the benefits of specific inhibitors of CDK4 in the treatment of HCC. Conclusions: These results demonstrate the molecular interactions between ELF and CDK4, and suggest a mechanism by which CDK4 may render cells unresponsive to the growth inhibitory effects of TGF-β signaling. Furthermore, haploinsufficiency of CDK4 prevents the formation of HCC, and thus targeted-inhibition of CDK4 activity may be a logical treatment for HCC in humans.

No significant financial relationships to disclose.
Improvement in survival of breast cancer patients with synchronous metastases
Authors: Salmon A. Y. , Uziely B. , Meirowitz A. , Sharon N. , Peretz T.
Published: March 2020

1063

Background: Less than 10% of breast cancer patients are diagnosed with metastatic disease upon initial diagnosis. Once metastases are detected, median survival ranges between 18 and 24 months. Many new chemotherapy agents, hormonal therapy, monoclonal antibodies and supportive care options were presented during the last decade. Although a few randomized trials have demonstrated improvement in survival for various agents, it has not been clear whether the overall survival of these patients has improved. In this study, we analyzed the survival of patients diagnosed with metastatic breast cancer in during the 1990’s Methods: We have analyzed 874 patients diagnosed with breast cancer at our Institute in the years 1991–1994 and 1102 patients in 1996–1999. Tumor characteristics, treatments, and the outcomes of these patients were compared. We used Kaplan-Meier, Wilcoxon test and Cox proportional hazard in order to investigate variants between the 2 groups. Results: After excluding all women with no evidence of metastatic disease at diagnosis, we analyzed 96 patients. No major difference in tumor characteristics was found between the group of patients diagnosed in the early 1990’s and the group diagnosed in the late 1990’s. We found a significant relationship between the period of diagnosis of metastatic breast cancer and survival: median survival was 19 months for the first group and 35 months for the second group (p=0.0398, 95% C.I), with 5-year overall survival rates 8% for patients diagnosed in the early 1990’s and 25% for patients diagnosed in the late 1990’s, p=0.0497. Two years survival was 25% and 60% respectively, although insignificant, p = 0.0941. Although there was no significant difference in number of chemotherapy courses given in the 2 groups, many more new generation treatments were used for the late 90th group. The Hazard of death within 5 years for patients treated with at least one new generation protocol was 0.53, p= 0.004. Conclusions: This study suggests that there has been significant survival improvement in breast cancer patients diagnosed with synchronous metastasis during the second half of the 1990’s. This improvement can be explained by the introduction of new treatments agents and strategies during the last decade

No significant financial relationships to disclose.
Capecitabine (X) in elderly patients (pts) with hormone-refractory metastatic breast cancer (MBC)
Authors: Messina C. G. , Longo F. , Seri M. Di , Restuccia M. , Zivi A. , Proietti E. , Russillo M. , Cerbone L. , Bianco V. , Speranza I. , Basile G. M. L. , De Filippis L.
Published: March 2020

1080

Background: X has demonstrated consistently high single-agent activity and good tolerability in pretreated and chemonaive MBC, and extends survival when added to docetaxel. High activity, minimal myelosuppression and no alopecia make X interesting in elderly pts with hormone-refractory disease. Methods: Between Feb 2004 and Oct 2006, 36 elderly (>65 years) MBC pts previously treated with adjuvant therapy and at least one previous hormonal therapy for advanced disease received X 1,000 mg/m2 twice daily, days 1–14 every 3 weeks. Study objectives were to assess efficacy, safety, and impact on quality of life (QoL), assessed by Clinical Benefit Response (CBR) every third cycle. Results: Median age was 70 years (range 68–73), median ECOG PS was 1 (range 0–2). All pts had visceral metastasis and 19 (53%) had ≥2 metastatic sites. A total of 284 cycles were administered (median 6 cycles per pt). After 3 cycles, 10 pts (28%) showed a partial response, 16 (44%) had stable disease (SD), and 2 (6%) had a minor response, resulting in a disease control rate of 78%. Biochemical response (CEA and/or CA 15.3 reduction) was observed in 20 (56%) pts. SD was maintained in 22 pts (61%) after 6 cycles, 10 pts (28%) after 9 cycles and 2 pts (6%) after 12 cycles. Treatment was well tolerated, the most common grade 3 events being mucositis (6%) and hand-foot syndrome (6%). There were no grade 3/4 hematologic toxicities. All adverse events were easily managed with dose adjustments and supportive therapies as required. As a result, all pts (100%) complied with appreciable benefits in terms of QoL (positive CBR in 56% of pts). Conclusions: These preliminary data indicate that this X dose is active and well tolerated in elderly pts with hormone-refractory MBC. This regimen also warrants study as first-line treatment in pts with less aggressive MBC who might not be suitable for combination therapy.

No significant financial relationships to disclose.
Cost-effectiveness of docetaxel compared to paclitaxel in metastatic breast cancer: A UK health economic analysis
Authors: Jones S. E. , Benedict A. , Cameron D. , Jourdan S.
Published: March 2020

1081

Background: Docetaxel was shown to be superior to paclitaxel in OS and TTP (median OS: 1.28 vs 1.06 yr, HR=1.41; median TTP: 0.47 vs 0.30 yr, HR= 1.64) for the treatment of patients with metastatic breast cancer progressing after an anthracycline-based regimen (Jones et al. J Clin Oncol. 2005;23:5542). A cost-effectiveness analysis based on this head-to-head comparison was performed considering clinical effectiveness, quality-adjusted life-years, and direct medical costs in the UK. Methods: A probabilistic Markov model was developed to examine results over a 10-yr long time-horizon. Patient level data were available on PFS and OS, treatment cycles and doses, number of cycles affected by adverse events, G-CSF use and post-failure treatment. Generalized gamma regression, fitting patient-level data best were used to model baseline PFS and OS in the paclitaxel arm. HRs adjusting for all covariates were applied to the baseline hazards to generate the docetaxel arm. Resource use and utility values for health states were obtained from published literature and practicing UK oncologists. Unit costs came from 2005 NHS reference costs; drug costs from the British National Formulary 2006 without hospital discount. Costs and benefits were discounted at 3.5%. A Monte-Carlo simulation and extensive 1-way sensitivity analyses were conducted. Results: Docetaxel is more costly (£13,500 vs £10,600), but yields higher health benefits than paclitaxel (2.01 vs 1.48 LYs and 1.18 vs 0.85 QALYs for docetaxel and paclitaxel, respectively) over a 10-yr time horizon. The discounted Incremental Cost-Effectivness Ratio (ICER) of docetaxel vs paclitaxel 3-weekly was estimated to be £5,532/LY gained (95% CI 2,250–12,700) and £8,741/QALY gained (95% CI 3,400–17,300). The ICER was most sensitive to the HR for PFS, OS and the cost of docetaxel and paclitaxel. However, ICERs remained below £20,000/QALY at extreme values of the parameters. Conclusions: Compared with paclitaxel 3-weekly, over a 10-yr time horizon docetaxel provides survival and quality-adjusted survival benefit to metastatic breast cancer patients failing anthracycline regimens at an acceptable cost in a UK setting. Docetaxel is cost-effective compared to paclitaxel.

No significant financial relationships to disclose.
Trastuzumab with taxanes in HER2-ECD(+), IHC/CISH(-) advanced and heavily pretreated, chemotherapy-refractory breast cancer patients: Findings from a case series
Authors: Ardavanis A. , Kountourakis P. , Malliou S. , Kyriakou F. , Koumna S. , Kardara E. , Garoufalli A. , Yioti I. , Rigatos G.
Published: March 2020

1089

Background: The “invisible” potential of a tumor is responsible for the discrepancy sometimes observed between favourable initial pathological profile and aggressive clinical course. We describe a series of Breast Cancer patients with refractory to standard chemotherapy advanced tumors without HER2-amplification/overexpression treated with trastuzumab (TZB). Methods: Twenty five patients progressing under anthracyclines and taxanes were selected on the basis of increased HER2-ECD levels at entry (>16 ng/ml) and lack of HER2-amplification/overexpression in the primary tumor documentation. In 22/25, TZB 6 mg/m2 with either docetaxel 75 mg/m2 q3w or paclitaxel 90 mg/m2 weekly were administered for six courses or less if toxicicity or progression was documented; TZB alone had to be continued thereafter until progression. Serial HER2-ECD were performed during therapy. Results: No objective response was noted; however, in 5 and 11 pts minor response and stabilization respectively was noted. All minor responders and stabilized patients experienced subjective improvement. Toxicity was acceptable. Median time to progression has not yet been reached, actually 5+mos; in 9 patients the progression-free period is 12 months from start of therapy. Median HER2-ECD declined from 54ng/ml at baseline to 14.3ng/ml at 28 weeks from treatment start. Conclusion: Although the sample size of this case-series is small, our findings suggest that, in HER2 negative patients with clinical aggressive behaviour and refractoriness to standard chemotherapy, HER2 positivity should be assessed by serum ECD levels and the addition of trastuzumab may be a valuable therapeutic option. However, these findings should be confirmed in larger number of patients.

No significant financial relationships to disclose.
EGFR, MAPK, and Akt status by immunohistochemistry (IHC) are not correlated with clinical outcome in HER2-positive (HER2+) metastatic breast cancer (MBC) patients (pts) treated with trastuzumab (T) with or without chemotherapy (CT)
Authors: Gori S. , Sidoni A. , Colozza M. , Ferri I. , Cioccoloni C. , Fenocchio D. , Mosconi A. , Anastasi P. , De Angelis V. , Crinò L.
Published: March 2020

1090

Background: T alone or in combination with CT has been shown to be an active therapy in HER2-positive MBC pts. However, not all pts will benefit and mechanisms of resistance to T are still poorly understood. The aim of this study was to evaluate the IHC expression of EGFR and two downstream effectors of the EGFR family signaling pathway, MAPK and Akt and their correlation with clinical outcome in HER2-positive MBC pts treated with T ± CT. Methods: 133 consecutive HER2+ MBC pts were treated between 04/99 and 03/06 but tumor tissue was available for this analysis only from 45 pts. HER2 evaluated by CB11 was scored according to Herceptest. Tumors were considered EGFR positive if =1% positive tumor cells and MAPK positive and Akt positive if the percentage of positive tumor cells was =10%. Results: At median follow up of 57 months (range 5–229) from the start of T, 45 pts were evaluable for TTP and OS and 42 for response to T. Median age of pts was 53 years (23–77). Twenty seven objective responses (CR+PR) to T ± CT (64.28%) were observed; median TTP was 24 months (3.3–179.8). In 11 of the 27 responsive pts (40.7%), progression was observed in CNS ± other sites. Median OS from the start of T was 74 months. EGFR positive tumors were 10 (22.2%), MAPK positive tumors were 16 (35.5%) and Akt positive tumors were 23 (51.1%). We analyzed the correlation of HER2, EGFR, MAPK and Akt status with response to T, TTP and OS. HER2 was significantly correlated with response to T (p = 0.013): in HER2 3+ tumors we observed 22 (9 CR and 13 PR) out of 27 objective responses but, no significant correlation was found between HER2 status and TTP and OS. EGFR, MAPK and Akt status of tumor were not significantly associated with response to T, TTP and OS in this series of HER2+ MBC pts. Conclusions: We did not found any significant correlation between EGFR, MAPK, Akt status evaluated by IHC and clinical outcome in HER2+ MBC pts treated with T ± CT. Only HER2 status evaluated by IHC significantly correlated with response to T ± CT.

No significant financial relationships to disclose.
Capecitabine (X) monotherapy as first-line chemotherapy (CT) for metastatic breast cancer (MBC): High efficacy regardless of prior therapy
Authors: Mauriac L. , Trainaud A. , Floquet A. , Donamaria C. , Durand M. , Brouste V. , Debled M.
Published: March 2020

1092

Background: X is one of the most active agents in pretreated MBC. Data on X monotherapy as first-line CT are limited, although a recent randomized phase III trial showed a survival benefit vs oral CMF (Stockler et al SABCS 2006). We retrospectively analyzed MBC pts receiving first-line X at our institution. Methods: Between 01/2002 and 09/2006, 167 pts received X (bid, days 1–14 q3w). Response classifications (improvement in disease [ID], stable disease [SD], or progressive disease [PD]) were as described by Hennessy et al (Ann Oncol 2005). Results: Median age was 68 years (range 34–91). Prior adjuvant therapy included CT in 47% and tamoxifen in 49% of pts. Median interval between initial surgery and MBC was 4.4 years (range 0–39). Before X, most pts (79%) had received endocrine therapy (ET) for MBC (median 2 lines, median duration 2.1 years). Median no. of metastatic sites was 2; bone and visceral metastases were each present in 60% of pts. The initial X dose was 1,500–2,500mg/d in 23%, 3,000mg/d in 47%, and 3,150–4,800mg/d in 29% of pts. ID was seen in 57% of pts (median duration 11.7 months [95% CI 3.8–28.6]). A further 20% had SD for =6 weeks. Median time to X failure (TTF) and OS were 9.0 [95% CI 7.1–11.0] and 25.8 months [95% CI 22.1–29.5], respectively. None of the following influenced TTF: age (<70/=70y), prior adjuvant CT (yes/no), prior ET for MBC (no/<12m/=12m), visceral disease (yes/no), initial dose (<3,000/3,000/>3,000mg). Toxicities were typical of X monotherapy. X was continued for =12 months in 46 pts without cumulative toxicity. Conclusions: X appears highly active as first-line CT for MBC pts, including those who had received ET for MBC and/or adjuvant CT. Long-term treatment is well tolerated. The safety profile is consistent with previous reports. High activity, oral administration, lack of alopecia, and low hematologic toxicity make X a very attractive first- line CT for slowly progressing disease and/or after ET failure.

No significant financial relationships to disclose.
Capecitabine/cisplatin doublet in antracycline and taxane pre-treated patients with metastatic breast carcinoma
Authors: Oksuzoglu B. , Abali H. , Ozdemir N. , Budakoglu B. , Hayran M. , Zengin N.
Published: March 2020

1093

Background: Treating heavily pretreated metastatic breast cancer patients is challenging. To evaluate the activity and toxicity of the combination of capecitabine and cisplatin (CapCisp) in antracycline and taxane pretreated metastatic breast carcinoma (MBC) patients was the aim of our study. Methods: Thirty-three female MBC patients, 20 to 61 years of age (median; 41) were included in the study. Patients received Cap 2x1000 mg/m2 on days 1–14, and Cisp 60 mg/m2 on day 1, repeated every 3 weeks. In the case of disease control without intolerable toxicity, single agent Cap was continued. Results: Infiltrative ductal carcinoma was the most common histology (88%). In 23 patients with assigned histological grade, 13% had grade 1, 48% grade 2, and 39% grade 3 disease. Estrogen receptor (ER), Progesteron receptor (PR), and c-ErbB2 were positive in 39%, 63%, and 42%, respectively. All patients were pretreated with antracycline and taxane on an adjuvant or palliative basis before CapCisp chemotherapy. Altogether were given 154 courses of CapCisp chemotherapy (range; 1–8 courses per patient, median; 5 courses). Disease control rate was 82% (complete response, n: 1; partial response, n:16, stable disease, n: 10, progressive disease, n: 6). Eleven patients continued with single agent Cap (median; 4, range; 3–6 cycles). Grade 1 and 2 nausea/vomiting (66.7%) and fatigue (60.6%) were the most frequently observed side effects. Grade 3 neutropenia was observed in 4 patients (12.1%). Median follow-up was 9.5 months or until death. Median duration of response was 5.1 months (3.2–6.9, %95 CI). Median time to disease progression was 6.3 months (3.8–8.8, %95 CI). Fifteen patients died, and median survival was 11.5 months (6.9–16.1, 95% CI). Conclusion: CapCispl doublet has an encouraging antitumor activity with acceptable and manageable toxicity in antracycline and taxane pretreated metastatic breast carcinoma patients.

No significant financial relationships to disclose.
A retrospective review of breast cancer patients with central nervous nystem metastasis treated with capecitabine
Authors: Kurt M. , Aksoy S. , Hayran M. , Guler N.
Published: March 2020

1098

Background: In all of the major studies on the effects of capecitabine in metastatic breast cancer (MBC) patients with central nervous system (CNS) metastasis were categorically excluded, understandably due to the poor outcome associated with such advanced disease, and as a consequence, the data are limited on such cases. The aim of this study was to evaluate the effectiveness and toxicity of capecitabine in breast cancer patients with CNS metastasis. Methods: The records of all patients with MBC presenting to the Department of Medical Oncology at Hacettepe University Hospital, Ankara, Turkey, for treatment between December 2001 and December 2005 were evaluated. Patients who recieved capecitabine as a sole agent for MBC with CNS metastasis were included in the study. All patients recieved capecitabine at a dose of 2,500mg/m2/day for 14 days at 3 weeks intervals. Results: Twenty patients were included in this retrospective analysis. All were female with a median age of 38 years (range, 20–58) at the diagnosis and the median time to brain metastasis was 3.9 years (range, 0.5–19.6). Three patients had undergone surgery for CNS metastasis, and all patients had recieved whole brain radiotherapy before the capecitabine treatment. A total of 159 cycles of chemotherapy were introduced and for each patient median number of chemotherapy cycles were 6.5 (range 1–28 cycles). Nine of them were given capecitabine as first-line chemotherapy after brain metastasis. There were 2 (10%) complete (one patient had metastasectomy for brain metastasis), and 7 (35%) partial responses with 6 (30%) patients having stable disease. Progressive disease was observed in 5 (25%) patients. Overall response rate was 45%. Median progression free survival time was 7.3 months (range 1.8–26.7). Adverse effects were seen in 13 patients, with grade 3 hand food syndrome occuring in 5 patients resulting in dose reduction. Grade II neutropenia was observed in 1 patient. Conclusions: Capecitabine is effective and well tolerated in the treatment of breast cancer patients with CNS metastases.

No significant financial relationships to disclose.
Randomized phase II study of biweekly gemcitabine (gem)-paclitaxel (pac), gem-carboplatin (carb) and gem-cisplatin (cis) as first-line treatments in metastatic breast cancer (MBC) after anthracycline failure
Authors: Xu B. , Jiang Z. , Kim S. , Yu S. , Feng J. , Malzyner A. , Giglio A. Del , Chung H. , Yu M. , Serrano A.
Published: March 2020

1099

Background: Biweekly gem-pac and gem-cis regimens have shown promising activity and safety in different tumor types. In MBC biweekly gem-pac is active and well tolerated. The aim of this multi-country study is to evaluate the efficacy and safety of gem in combination with pac, carb or cis on a biweekly schedule in patients (pts) with MBC. Methods: Major eligibility criteria included: tissue diagnosis of stage IV breast carcinoma; prior anthracycline therapy; ECOG performance status (PS) of 0 or 1; and written informed consent. Pts were randomized to receive gem 2500 mg/m2 in combination with pac 150 mg/m2 (Arm A), carb AUC 2.5 (Arm B) or cis 50 mg/m2 (Arm C) on day 1 of 2-week cycles. The primary endpoint was response rate, with safety a secondary endpoint. Results: This interim analysis was planned to occur when patient enrollment had reached 50% (75/150 pts), at which point there were 26 pts in Arm A, 25 in Arm B and 24 in Arm C, with 12 pts still on treatment. The baseline characteristics were similar in the three arms, including mean age (Arm A 50.2 yr, Arm B 46.1, Arm C 47.3); ECOG PS (PS 0: 50.0%, 64.0%, 54.2%); mean number of sites of tumor involvement (2.9, 2.6, 2.7); dominant type of metastasis (visceral: 73.1%, 80.0%, 79.2%); and disease-free interval (<24 mo: 53.8%, 60.0%, 41.7%). The mean number of cycles was 6.4, 6.0 and 5.8. There was a partial response in 5/26 efficacy qualified pts (19.2%), 5/25 pts (20.0%) and 2/23 pts (8.7%) in Arms A, B and C, respectively, stable disease in 10 pts (38.5%), 9 pts (36.0%) and 9 pts (39.1%), and progressive disease in 5 pts (19.2%), 6 pts (24.0%) and 6 pts (26.1%). There were no treatment-related deaths. Conclusions: The three regimens appear to show activity and have manageable toxicity when given on a biweekly schedule.

[Table: see text]

No significant financial relationships to disclose.