Ariadna Tibau

Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas

Background:Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed.Methods:We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation.Results:We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α-IGF1R (25%), p110α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P⩽0.043). Also, p110α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P⩽0.041). In patients with metastatic disease, decreased PFS correlated with p110α expression (P=0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P⩽0.019; Cox analysis).Conclusion:Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas.

Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma.

Background:Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas.Methods:We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients’ outcome.Results:Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab.Conclusions:Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients.

Author Financial Conflicts of Interest, Industry Funding, and Clinical Practice Guidelines for Anticancer Drugs

PURPOSE Clinical practice guidelines (CPGs) and consensus statements (CSs) are used to apply evidence-based medicine or expert recommendations to clinical practice. Here we explore author financial conflicts of interest (FCOIs), sources of guideline funding, and their relationship with endorsement of specific drugs. METHODS An electronic search of MEDLINE was conducted to identify CPGs and CSs for common solid cancers published between January 2003 and October 2013. The search was restricted to articles evaluating systemic therapy. We extracted data on self-reported author FCOIs, funding sources, use of manuscript writers, and endorsement of specific drugs in the abstract of the article. RESULTS Of 142 articles evaluated, 64% were CPGs, and 36% were CSs. The proportion of articles reporting FCOIs improved from 11% in 2003 to 93% in 2013 (P for trend < .001). Only 45% of articles explicitly reported funding sources. Of these, 65% disclosed partial or full industry sponsorship. Use of manuscript writers was declared in 13%, but many articles did not explicitly report the role of authors in the writing of the manuscript. Endorsement of specific drugs was significantly associated with author FCOIs (odds ratio [OR], 7.29; P = .001), but not with industry funding (OR, 0.95; P = .37). CONCLUSION Reporting of FCOIs in CPGs and CSs has improved over time. Despite prevalent funding of guideline development by industry, such funding is not associated with endorsement of specific drugs. Author FCOIs are prevalent, and endorsement of a specific drug seems to be more common when authors have FCOIs with the pharmaceutical company marketing that drug.

Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration

Background It is uncertain whether drugs approved by the US Food and Drug Administration (FDA) have clinically meaningful benefit as determined by validated scales such as the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods We searched the Drugs@FDA website for applications of anticancer drugs from January 2006 to December 2016. Study characteristics, outcomes, and regulatory pathways were collected from drug labels and reports of registration trials. For randomized controlled trials (RCTs), ESMO-MCBS grades were applied. Meaningful benefit was defined as a grade of A or B for (neo)adjuvant intent and 4 or 5 for palliative intent. All statistical tests were two-sided. Results We identified 63 individual drugs for 118 indications. These were supported by 135 studies, among which were 105 RCTs for which ESMO-MCBS could be applied. Only 46 (43.8%) met the ESMO-MCBS meaningful benefit threshold (100% of (neo)adjuvant trials and 38.8% of palliative trials). In palliative therapy trials, meaningful ESMO-MCBS grades were associated with phase III trials (compared with phase II; odds ratio [OR] = 38.45, 95% confidence interval [CI] = 3.27 to 452.00, P = .004), those with overall survival as their primary end point (compared with intermediate end points; OR = 8.28, 95% CI = 2.49 to 27.50, P = .001) and trials of targeted drugs with companion diagnostics (OR = 11.62, 95% CI = 2.95 to 45.78, P < .001). Over time, there has been an increase in the number of trials meeting the ESMO-MCBS threshold (Ptrend = .04). There were insufficient (neo)adjuvant studies to perform statistical analysis. Conclusions The number of trials meeting the ESMO-MCBS threshold for clinical benefit has improved over time. However, fewer than half of RCTs supporting FDA approval meet the threshold for clinically meaningful benefit.

Low-density lipoprotein receptor–related protein 1 is associated with proliferation and invasiveness in Her-2/neu and triple-negative breast carcinomas

Low-density lipoprotein receptor-related protein 1, a member of the low-density lipoprotein cholesterol receptor family, has been implicated in the progression of certain tumors; but it remains unclear whether it plays a role in infiltrating ductal breast carcinomas. We studied a series of 81 ductal breast tumors to determine the correlation of low-density lipoprotein receptor-related protein 1 overexpression with clinicopathologic and immunohistochemical characteristics associated with prognosis. Low-density lipoprotein receptor-related protein 1 overexpression was identified in 14% (11/81) of tumors and was correlated with a high nuclear grade (P = .043), high mitotic index (P = .006), and Ki-67 greater than 20% (P = .047). Furthermore, low-density lipoprotein receptor-related protein 1 expression was associated with aggressive carcinomas (triple-negative tumors [21%, 7/33] and Her-2/neu tumors [17%, 4/24]) but not with hormone-dependent carcinomas (0%, 0/24) (P = .040). There was no correlation between low-density lipoprotein receptor-related protein 1 expression and survival, but a trend was found between low-density lipoprotein receptor-related protein 1 overexpression and tumor recurrence. Low-density lipoprotein receptor-related protein 1 overexpression was related to proliferation and invasiveness in Her-2/neu and triple-negative breast carcinoma. Moreover, patients with low-density lipoprotein receptor-related protein 1-positive tumors had higher cholesterol levels (62.5%, 5/8) than those with low-density lipoprotein receptor-related protein 1-negative tumors (40%, 19/47). Nevertheless, the correlation between low-density lipoprotein receptor-related protein 1 and hypercholesterolemia was not statistically significant; but cholesterol levels were higher in patients with triple-negative breast carcinoma (60%, 15/25) and Her-2/neu carcinomas (40%, 6/15) than in luminal-A carcinomas (20%, 3/15) (P = .046). These findings suggest a relationship between hypercholesterolemia and aggressiveness of ductal breast carcinomas.

Interaction between Hormonal Receptor Status, Age and Survival in Patients with BRCA1/2 Germline Mutations: A Systematic Review and Meta-Regression

Background Germline mutations in the BRCA1 and BRCA2 genes are the most frequent known hereditary causes of familial breast cancer. Little is known about the interaction of age at diagnosis, estrogen receptor (ER) and progesterone receptor (PgR) expression and outcomes in patients with BRCA1 or BRCA2 mutations. Methods A PubMed search identified publications exploring the association between BRCA mutations and clinical outcome. Hazard ratios (HR) for overall survival were extracted from multivariable analyses. Hazard ratios were weighted and pooled using generic inverse-variance and random-effect modeling. Meta-regression weighted by total study sample size was conducted to explore the influence of age, ER and PgR expression on the association between BRCA mutations and overall survival. Results A total of 16 studies comprising 10,180 patients were included in the analyses. BRCA mutations were not associated with worse overall survival (HR 1.06, 95% CI 0.84–1.34, p = 0.61). A similar finding was observed when evaluating the influence of BRCA1 and BRCA2 mutations on overall survival independently (BRCA1: HR 1.20, 95% CI 0.89–1.61, p = 0.24; BRCA2: HR 1.01, 95% CI 0.80–1.27, p = 0.95). Meta-regression identified an inverse association between ER expression and overall survival (β = -0.75, p = 0.02) in BRCA1 mutation carriers but no association with age or PgR expression (β = -0.45, p = 0.23 and β = 0.02, p = 0.97, respectively). No association was found for BRCA2 mutation status and age, ER, or PgR expression. Conclusion ER-expression appears to be an effect modifier in patients with BRCA1 mutations, but not among those with BRCA2 mutations.

Chromosome 17 centromere duplication and responsiveness to anthracycline-based neoadjuvant chemotherapy in breast cancer.

Human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) genes have been proposed as predictive biomarkers of sensitivity to anthracycline chemotherapy. Recently, chromosome 17 centromere enumeration probe (CEP17) duplication has also been associated with increased responsiveness to anthracyclines. However, reports are conflicting and none of these tumor markers can yet be considered a clinically reliable predictor of response to anthracyclines. We studied the association of TOP2A gene alterations, HER2 gene amplification, and CEP17 duplication with response to anthracycline-based neoadjuvant chemotherapy in 140 patients with operable or locally advanced breast cancer. HER2 was tested by fluorescence in situ hybridization and TOP2A and CEP17 by chromogenic in situ hybridization. Thirteen patients (9.3%) achieved pathologic complete response (pCR). HER2 amplification was present in 24 (17.5%) of the tumors. TOP2A amplification occurred in seven tumors (5.1%). CEP17 duplication was detected in 13 patients (9.5%). CEP17 duplication correlated with a higher rate of pCR [odds ratio (OR) 6.55, 95% confidence interval (95% CI) 1.25-34.29, P = .026], and analysis of TOP2A amplification showed a trend bordering on statistical significance (OR 6.97, 95% CI 0.96-50.12, P = .054). TOP2A amplification and CEP17 duplication combined were strongly associated with pCR (OR 6.71, 95% CI 1.66-27.01, P = .007). HER2 amplification did not correlate with pCR. Our results suggest that CEP17 duplication predicts pCR to primary anthracycline-based chemotherapy. CEP17 duplication, TOP2A amplifications, and HER2 amplifications were not associated with prognosis.

Raising Concern About the American Society of Clinical Oncology Conflict of Interest Policy Amendment

TO THE EDITOR: In April 2013, the American Society of Clinical Oncology (ASCO) updated its policy for relationships with companies withacommitmenttoimprovetransparencyandreflect independencein the development and presentation of scientific and educational content. The two major changes were to (1) define more categories in classifying potential conflictsof interest (COI),and(2)refuseacceptanceofabstracts or papers describing company-funded research if the first, last, or corresponding author had been the company’s employee, investor, or paid speaker during the previous 2 years. Justification for this new policy was based on evidence that cancer researchers working for pharmaceutical companies, or investing in them, are more likely to be influenced by the profit goals of the company; or in the case of a speaker s bureau to share knowledge as a marketing tool rather than to disseminate unbiased information. Implementation of this policy was to become effective immediately with the exception of the author restrictions which were due to become effective after April 22, 2014. On February 10, 2014, ASCO published an article in Journal of Clinical Oncology that delays implementation of these new guidelines for a period of at least 3 years. The argument to support this decision is concern from scientific and medical leaders from both public and private sectors that scientists working for private entities will be restricted from publishing their original research, thus preventing dissemination of knowledge, and critical appreciation and debate from peers. It was also argued that employment or other financial relationships can be reported transparently. With this amendment there are essentially no COI restrictions for authors to submit their work. We welcome one aspect of this latest revision of ASCO s policy on COI and publication, but find no basis to support the others. We agree that researchers working for private companies should be recognized for their work, and deserve to be first, last, or corresponding authors according to their level of contribution. This recognizes that good science is conducted within privately financed laboratories, and the revised policy will improve transparency. Honorary and ghost authors are prevalent in medical journals and restriction of authorship by scientists employed by for-profit companies would likely have increased the use of honorary authors rather than those who designed and conducted the experiments. Restrictions should, however, continue for the reporting of clinical trials, which are generally conducted by academic clinicians. We have demonstrated previously that spin is used to highlight nonrelevant aspects of a clinical trial when the primary end point was negative, and positive conclusions supporting the use of experimental drugs have been shown to be more prevalent in trials sponsored by pharmaceutical companies. We are disappointed that ASCO has modified the proposed regulations to allow first, corresponding or senior authorship for those who own stock or are paid speakers for companies, with the exception that the new rule should have allowed a 2-year period to allow potential authors to rid themselves of this COI. There is no justification in the Journal of Clinical Oncology editorial for revoking this requirement of prominent authors, despite membership in a speakers’ bureau and stock ownership being associated with substantial COI. This requirement would not prevent the publication or presentation of original research, since authors other than company employees can easily rid themselves of such relationships. We look to ASCO, as our professional society, to lead in setting standards to ensure unbiased reporting; here ASCO appears sadly to be responding instead to the self-interest of a minority of its members.

Postmarketing Modifications of Drug Labels for Cancer Drugs Approved by the US Food and Drug Administration Between 2006 and 2016 With and Without Supporting Randomized Controlled Trials

Purpose Modifications in cancer drug indications, dosing, and related toxicities after Food and Drug Administration approval are common. It is unclear whether drug approval without a supporting randomized controlled trial (RCT) influences the probability of such modifications. Methods We searched the Drugs@FDA Web site for new drug indications for solid tumors approved between January 2006 and December 2016. Study characteristics, regulatory pathways, and label modifications from approval to October 2017 were collected from drug labels. Label modifications were considered to be major if defined as such in the drug label. Indications approved with and without supporting RCTs were compared using logistic regression. The Benjamini-Hochberg false discovery rate method was used to adjust for multiplicity. Results We identified 59 individual drugs for 109 solid tumor indications. Of these, 17 indications (15.6%) were not supported by an RCT, with no change over time. Indications not supported by RCTs were more likely to require companion diagnostic tests (odds ratio [OR], 3.90; P = .02), to include surrogate end points as primary outcomes (OR, 7.88; P < .001), and to receive breakthrough therapy designation (OR, 7.62; P = .006) or accelerated approval (OR, 17.67; P < .001). Indications not supported by RCTs were associated with significantly higher odds of postapproval modifications in common adverse events (71% v 29%; OR, 5.78; P = .002). A nonsignificantly higher odds of postapproval major modifications in warnings and precautions was also observed (88% v 62%; OR, 4.61; P = .051). Postapproval major modifications in indication and usage, dosing and administration, boxed warnings, and contraindications were comparable in the two groups. Conclusion Cancer drug indications not supported initially by RCTs are associated with more postmarketing safety-related label modifications. Health care professionals should be vigilant for unrecognized adverse effects when prescribing drugs approved without a supporting RCT.

Role of cooperative groups and funding source in clinical trials supporting guidelines for systemic therapy of breast cancer

Introduction Clinical research is conducted by academia, cooperative groups (CGs) or pharmaceutical industry. Here, we evaluate the role of CGs and funding sources in the development of guidelines for breast cancer therapies. Results We identified 94 studies. CGs were involved in 28 (30%) studies while industry either partially or fully sponsored 64 (68%) studies. The number of industry funded studies increased over time (from 0% in 1976 to 100% in 2014; p for trend = 0.048). Only 10 (11%) government or academic studies were identified. Studies conducted by GCs included a greater number of subjects (median 448 vs. 284; p = 0.015), were more common in the neo/adjuvant setting (p < 0.0001), and were more often randomized (p = 0.018) phase III (p < 0.0001) trials. Phase III trial remained significant predictor for CG-sponsored trials (OR 7.1 p = 0.004) in a multivariable analysis. Industry funding was associated with higher likelihood of positive outcomes favoring the sponsored experimental arm (p = 0.013) but this relationship was not seen for CG-sponsored trials (p = 0.53). Materials and Methods ASCO, ESMO, and NCCN guidelines were searched to identify systemic anti-cancer therapies for early-stage and metastatic breast cancer. Trial characteristics and outcomes were collected. We identified sponsors and/or the funding source(s) and determined whether CGs, industry, or government or academic institutions were involved. Chi-square tests were used for comparison between studies. Conclusions Industry funding is present in the majority of studies providing the basis for which recommendations about treatment of breast cancer are made. Industry funding, but not CG-based funding, was associated with higher likelihood of positive outcomes in clinical studies supporting guidelines for systemic therapy.