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• W2089209210 abstract "Four large adjuvant trastuzumab trials involving well over 10,000 patients have consistently shown that the addition of adjuvant trastuzumab given for 1 year to adjuvant chemotherapy, either sequentially or concurrently, significantly improves disease-free survival in high-risk patients with HER2 positive breast cancer with hazard ratios ranging from 0.48 to 0.76 and with an absolute gain at 4 years ranging from 5% to 12.8%.1Perez EA, Romond EH, Suman VJ, et al. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. Presented at Proc Am Soc Clin Oncol 2007; Abstract 512.Google Scholar, 2Smith I Procter M Gelber RD et al.2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.Lancet. 2007; 369: 29-36Abstract Full Text Full Text PDF PubMed Scopus (1334) Google Scholar, 3Slamon D, Eiermann W, Robert N, et al. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC → T) with doxorubicin and cylophosphamide followed by docetaxel and trastuzumab (AC → TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. San Antonio Breast Cancer Conference 2006; Abstract 52.Google Scholar A much smaller trial from Finland (FinHER) has shown that a mere 9 weeks Herceptin given with chemotherapy achieves similar results (hazard ratio 0.42, absolute gain at 4 years 11.7%).4Joensuu H Kellokumpu-Lehtinen PL Bono P et al.Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.N Engl J Med. 2006; 354: 809-820Crossref PubMed Scopus (1280) Google Scholar These trials have also shown significant early overall survival benefits with a median of 2–3 years of follow-up. Only one relatively small French trial (PACS 004) involving 540 patients in which trastuzumab was given sequentially after chemotherapy has failed to show a significant disease free survival benefit (see below).5Spielmann M, Roché H, Humblet Y, et al. 3-year follow-up of trastuzumab following adjuvant chemotherapy in node positive HER2-positive breast cancer patients: results of the PACS-04 trial. San Antonio Breast Cancer Conference 2007; Abstract 72.Google Scholar It can therefore be stated with confidence that adjuvant trastuzumab in addition to chemotherapy improves clinical outcome in high risk patients with HER2 positive breast cancer and this has now become standard of breast cancer care worldwide. Important questions however still remain unanswered. These include: whether sequential trastuzumab after chemotherapy is as effective as concurrent; whether anthracycline chemotherapy is optimal; the optimal duration of trastuzumab treatment; whether there is a role for trastuzumab alone without chemotherapy; whether patients with so-called low risk <2cm cancers benefit from trastuzumab; and whether other targeted agents such as lapatinib might achieve further benefit given with or instead of trastuzumab. At the St. Gallen consensus meeting in 2007 the majority of the panel considered that sequential trastuzumab given after completion of all chemotherapy (as for example in the HERA trial) was as acceptable as concurrent chemotherapy in which trastuzumab was given concurrently with taxanes following anthracyclines (as in the other trials).6Harbeck N Jakesz R St. Gallen 2007: Breast Cancer Treatment Consensus Report.Breast Care. 2007; 2: 130-134Crossref Scopus (32) Google Scholar Since that meeting data have become available from the French PACS 004 trial in which patients were randomized to trastuzumab for 1 year following completion of chemotherapy or to observation. This design was very similar to HERA. Chemotherapy was itself randomized to 6 courses of an FEC regimen or 6 courses of epirubicin and docetaxel.5Spielmann M, Roché H, Humblet Y, et al. 3-year follow-up of trastuzumab following adjuvant chemotherapy in node positive HER2-positive breast cancer patients: results of the PACS-04 trial. San Antonio Breast Cancer Conference 2007; Abstract 72.Google Scholar In contrast to all the other adjuvant trastuzumab trials, PACS 004 showed no significant improvement in disease free survival (HR 0.86; 95% confidence interval (CI), 0.61–1.22; p=0.41) and no suggestion of an overall survival improvement (HR 1.27; 95% CI 0.68–2.38).5Spielmann M, Roché H, Humblet Y, et al. 3-year follow-up of trastuzumab following adjuvant chemotherapy in node positive HER2-positive breast cancer patients: results of the PACS-04 trial. San Antonio Breast Cancer Conference 2007; Abstract 72.Google Scholar Although the much larger HERA trial showed a significant benefit for sequential trastuzumab after chemotherapy, the PACS 004 trial has inevitably raised questions as to whether the sequential approach might be inferior. The only trial to address this question directly is NCCTG N9831, a 3 arm trial in which all patients are given AC anthracycline chemotherapy followed by paclitaxel and randomized to trastuzumab starting concurrently with paclitaxel and continuing for a year (concurrent) versus trastuzumab for a year starting after completion of paclitaxel (sequential) versus no trastuzumab. Mature data are not yet available on the comparison between the concurrent and sequential arms and there is still no solid evidence base for recommending concurrent treatment as superior to sequential. In the ALTTO trial (see below) in which the oral HER1/HER2 signal transduction inhibitor lapatinib is compared with trastuzumab alone, in combination or sequentially, HER2 inhibitor therapy is allowed either concurrently with a taxane or sequentially afterwards. Nevertheless, the data on the concurrent approach (4/4 positive trials) seem more secure than for the sequential approach (1/2 positive trials). The 2007 St. Gallen consensus recommended that the standard duration of trastuzumab therapy is accepted as 1 year.6Harbeck N Jakesz R St. Gallen 2007: Breast Cancer Treatment Consensus Report.Breast Care. 2007; 2: 130-134Crossref Scopus (32) Google Scholar The HERA trial is so far the only trial formally investigating longer follow-up with a 3rd arm comparing 2 years treatment with 1 year with observation only. Data are not yet available on the 2 year versus 1 year comparison. Meanwhile the results from the FinHER trial remain very provocative. In this small trial trastuzumab was given for a mere 9 weeks upfront with single agent docetaxel or vinorelbine, versus the same chemotherapy without trastuzumab. Patients in both arms were then given standard anthracycline chemotherapy. Initial results showed a very significant benefit for the trastuzumab arm with a HR of 0.42 (p<0.01).4Joensuu H Kellokumpu-Lehtinen PL Bono P et al.Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.N Engl J Med. 2006; 354: 809-820Crossref PubMed Scopus (1280) Google Scholar Indeed, the unpublished hazard ratio for patients treated with trastuzumab and docetaxel versus docetaxel alone is 0.26, but numbers here were very small. A further small trial involving only 227 patients has compared short duration trastuzumab for 9–10 weeks given with paclitaxel followed by adriamycin and cyclophosphamide (AC) alone versus the same chemotherapy regimen with trastuzumab given for 1 year. The main aim of this trial was to compare cardiotoxicity. Nevertheless with the proviso of small numbers no significant difference in disease-free survival or overall survival was seen between the two arms, nor was there even the suggestion of a trend in favour of longer treatment.7Sledge GW O'Neill A Thor A et al.Adjuvant trastuzumab: long-term results of E2198.Breast Cancer Res Treat. 2006; 100: S106Google Scholar A much larger international trial involving 3000 patients run by the Finnish Breast Cancer Group, SOLD (Synergism or Long Duration Study) is currently comparing 9 weeks trastuzumab with 1 year's treatment, in combination with docetaxel followed by anthracycline chemotherapy. At the St. Gallen meeting in 2007, a slim majority considered that the use of carboplatin and docetaxel concurrently with trastuzumab without an anthracycline was an acceptable alternative to standard anthracycline-containing chemotherapy followed by trastuzumab and docetaxel. This was based on the results of the BCIRG006 trial in which these treatment options were of similar efficacy and both were superior to the same standard anthracycline-containing chemotherapy followed by docetaxel alone, without trastuzu-mab.3Slamon D, Eiermann W, Robert N, et al. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC → T) with doxorubicin and cylophosphamide followed by docetaxel and trastuzumab (AC → TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. San Antonio Breast Cancer Conference 2006; Abstract 52.Google Scholar The non-anthracycline containing carboplatin/docetaxel/trastuzumab arm had significantly less cardiotoxicity than both the other arms. There have been no updates of these results since 2007 and they remain unpublished. This issue therefore remains uncertain, but an increasing number of centres particularly in the USA are using the carboplatin/docetaxel/trastuzumab combination. On clinical grounds it would at the very least seem reasonable to use this in patients with a pre-existing risk of cardiotoxicity. All of the adjuvant trastuzumab trials so far have excluded patients with T1a–b (≤1 cm) node negative (N0) cancers. There are data however suggesting that these small cancers may also carry an adverse prognosis. In a population based series from British Columbia, 75% of whom had received no adjuvant therapy, patients with pT1N0 cancers (total 1245) had a significantly worse prognosis if the tumours were HER2 positive compared with HER2 negative and this included patients with T1a–b cancers.8Norris B, Chia S, Cheang M, et al. Poor 10yr breast cancer specific survival (BCSS) and relapse free survival (RFS) for HER-2 positive T1pN0 tumors. San Antonio Breast Cancer Conference 2006; Poster 2031.Google Scholar In a Finnish population based study involving 2842 women diagnosed in 1991–1992, 852 women were identified with pT1N0 breast cancer of whom 12% (134) were HER2 positive. Only 5% had adjuvant therapy. Patients with T1a–b N0 tumours (≤1cm) had a significantly and markedly worse prognosis than those who were HER2 negative (6 year disease free survival around 63% versus around 95%; p<0.0001).9Joensuu H Isola J Lundin M et al.Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: a nationwide population-based study.Clin Cancer Res. 2003; 9: 923-930PubMed Google Scholar 965 women with pT1a–bN0 breast cancers were identified from the MD Anderson hospital between 1990 and 2002, and 9% of these had HER2 positive disease (IHC 3+ or FISH+ with a ratio ≥2). Patients with HER2 positive breast cancers had a significantly worse relapse free survival (5 year RFS 78.2% versus 95.6%; HR 5.19; p<0.0001) and distant relapse free survival (5 year DRFS 87.6% versus 97.8%; HR 4.66; p< 0.0001), and this remained true for T1a cancers analysed separately from T1b.10Rakkhit R, Broglio K, Peintinger F, et al. Significant increased recurrence rates among breast cancer patients with HER2-positive, T1abN0M0 tumors. San Antonio Breast Cancer Conference 2008; Abstract 701.Google Scholar These results were confirmed in a separate cohort of 350 women with pT1a–bN0 cancers, 6% of whom had HER2 positive cancers, from cancer centres in Belgium and Austria. The European Institute of Oncology reviewed 2130 patients with pT1a–bN0 cancers treated between 1999 and 2006 of whom 150 were HER2 positive and these were matched against HER2 negative controls. No adjuvant trastuzumab was given. Patients who were HER2 positive and also hormone receptor positive had a worse prognosis with a 5 year disease free survival of 92% versus 99% (HR 5.2; p = 0.013). In contrast no significant disease free survival difference was seen for patients whose tumours were HER2 positive and hormone receptor negative versus HER2 negative/hormone receptor negative with a 5 year disease free survival of 91% versus 92% (HR 1.2). As described above, patients with T1a–b N0 HER2 positive breast cancers have so far been excluded from adjuvant trastuzumab trials. In the HERA trial however 510 out of 3401 patients in the 1 year versus observation arm had T1c (1.1–2 cm) node negative cancers (15%).2Smith I Procter M Gelber RD et al.2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.Lancet. 2007; 369: 29-36Abstract Full Text Full Text PDF PubMed Scopus (1334) Google Scholar In a sub-group analysis these patients had proportionally as much benefit as patients with so-called higher risk cancers (HR 0.53; absolute 3 year survival difference 4.6%). These data suggest that even patients with T1a–b N0 cancers which are also HER2 positive may not have a good prognosis and may benefit from adjuvant trastuzumab with or without chemotherapy. Trials addressing this question are now indicated. In the 2007 St. Gallen guidelines6Harbeck N Jakesz R St. Gallen 2007: Breast Cancer Treatment Consensus Report.Breast Care. 2007; 2: 130-134Crossref Scopus (32) Google Scholar the majority of the panel was prepared for selected women to contemplate trastuzumab with endocrine therapy but without chemotherapy despite the absence of clinical trial evidence to support this approach. Since then no trials data have emerged on this issue and it is unlikely now that such a trial, with a no trastuzumab arm, will ever be done. In metastatic breast cancer, two Phase II studies have shown trastuzumab alone has single agent activity with overall response rates of 35%11Vogel CL Cobleigh MA Tripathy D et al.Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.J Clin Oncol. 2002; 20: 719-726Crossref PubMed Scopus (2770) Google Scholar and 23%.12Baselga J Carbonell X Castaneda-Soto NJ et al.Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule.J Clin Oncol. 2005; 23: 2162-2171Crossref PubMed Scopus (379) Google Scholar The respective clinical benefit rates (overall response plus stable disease for at least 6 months) were at least 48% and 36%. These data suggest that adjuvant single agent trastuzumab is likely to have some benefit. Nevertheless these results appear inferior to response rates quoted for 1st line trastuzumab in combination with chemo-therapy.13Slamon DJ Leyland-Jones B Shak S et al.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N Engl J Med. 2001; 344: 783-792Crossref PubMed Scopus (9491) Google Scholar, 14Marty M Cognetti F Maraninchi D et al.Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.J Clin Oncol. 2005; 23: 4265-4274Crossref PubMed Scopus (1387) Google Scholar In a recent randomized Phase II study (HERTAX) in metastatic breast cancer the overall response rate to combined trastuzumab and docetaxel was 73% compared with 50% for trastuzumab single agent followed by the combination treatment on progression.15Bontenbal M, Seynaeve, J, Stouthard, M, et al. Randomized study comparing efficacy/toxicity of monotherapy trastuzumab followed by monotherapy docetaxel at progression, and combination trastuzumab/docetaxel as first-line chemotherapy in HER2-neu positive, metastatic breast cancer (MBC) (HERTAX study). Presented at Proc Am Soc Clin Oncol 2008; Abstract 1014.Google Scholar No significant difference in disease free survival or overall survival is reported although there was a trend in favour of the upfront combination for overall survival (median 30.5 months versus 20 months for the sequential approach. HR 1.45; 95% CI 0.87–2.41; p=0.15). In the TAnDEM trial, anastrozole with trastuzumab was shown to be superior to anastrozole alone with trastuzumab on progression as 1st line treatment for metastatic breast cancer with an improvement in median progression free survival of 4.8 months compared with 2.4 months (p=0.0016).16Kaufman B. Trastuzumab plus anastrozole prolongs progression-free survival in postmenopausal women with HER2 positive, hormone-dependent metastatic breast cancer (MBC). European Society for Medical Oncology (ESMO) Congress 2006; Abstract LBA2.Google Scholar Likewise a combination of 1st line Letrozole and lapatinib has been shown to be superior to Letrozole alone in women with metastatic HER2 positive breast cancer with a median progression free survival of 8.2 versus 3.0 months (HR 0.71; p=0.019).17Johnston S, Pegram M, Press M, et al. Lapatinib combined with letrozole vs. letrozole alone for front line postmenopausal hormone receptor positive (HR+) metastatic breast cancer (MBC): first results from the EGF30008 Trial. San Antonio Breast Cancer Conference 2008; Abstract 46.Google Scholar All this circumstantial evidence suggests that single agent adjuvant trastuzumab is likely to be of some benefit for women with HER2 positive breast cancer, but less so than in combination with chemotherapy. Recent ASCO/CAP (College of American Pathologists) guideline recommendations for HER2 measurement have been published.18Wolff AC Hammond ME Schwartz JN et al.American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.J Clin Oncol. 2007; 25: 118-145Crossref PubMed Scopus (3062) Google Scholar These recommendations include the following:•HER2 should be determined for all invasive breast cancers.•All testing should be done in a CAP-accredited laboratory or equivalent.•A positive HER2 test is defined on the basis of immunohisto-chemical staining 3+ (uniform intense membrane staining >30% invasive tumour cells) or FISH >6 HER2 gene copies per nucleus or HER2/CEP17 ratio >2.2.•A negative HER2 test is defined on the basis of IHC 0–1 or FISH <4 copies or a ratio of <1.8.•An equivocal HER2 test is defined as IHC 2+ (non-uniform or weak 10% staining) or FISH 4–6 copies or a ratio 1.8–2.2.•An equivalent test based on IHC 3 (about 15% of all testing) should be checked with FISH. An equivocal FISH test (only 3% or so of all patients) should be repeated or checked by IHC. The authors make the following further points:•There is no gold standard assay to define responders accurately at present.•Equivocal FISH results of 2–2.2 were allowed in adjuvant trials but this involved only 3% of patients. Discordant results between IHC 3+ and FISH + are described in around 4% of patients. Currently there are many targeted therapies either directly anti-HER2 or potentially synergistic with anti-HER2 agents that are in clinical trials but so far only 2 are being assessed as adjuvant therapy. Lapatinib is an oral small molecule dual inhibitor of HER1 and HER2 tyrosine kinase with established clinical efficacy in combination with chemotherapy against metastatic breast cancer.19Geyer CE Forster J Lindquist D et al.Lapatinib plus capecitabine for HER2-positive advanced breast cancer.N Engl J Med. 2006; 355: 2733-2743Crossref PubMed Scopus (2854) Google Scholar It is currently being assessed as adjuvant therapy for women with centrally confirmed high risk HER2-positive breast cancer in the worldwide adjuvant ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation Trial) 4 arm trial in which single agent lapatinib for one year is compared with trastuzumab for one year versus the two in combination for a year versus trastuzumab for 3 months followed by lapatinib to complete 1 year's treatment. Bevacuzimab, a monoclonal antibody targeted against vascular endothelial growth factor, has shown clinical efficacy in combination with chemotherapy in metastatic breast cancer.20Miller K Wang M Gralow J et al.Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.N Engl J Med. 2007; 357: 2666-2676Crossref PubMed Scopus (2734) Google Scholar Bevacuzimab has experimental synergy with trastuzumab and the potential clinical efficacy of this is being assessed in a randomized adjuvant trial (BETH) in which women with early high risk HER2 positive breast cancer are treated with chemotherapy plus trastuzumab versus chemotherapy plus trastuzumab plus bevacuzimab. Adjuvant trastuzumab for 1 year with appropriate chemotherapy now has an established role in the treatment of early high risk HER2 positive breast cancer. All patients with early invasive breast cancer should now have HER2 measured following guidelines laid down by ASCO and the College of American Pathologists." @default.
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• W2089209210 date "2009-10-01" @default.
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• W2089209210 title "Targeting HER2 in the adjuvant setting: Dealing with new standards and with open questions" @default.
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