Adjuvant Trastuzumab In Patients Research Articles

The Role of Trastuzumab in Patients with HER2 Positive Small (pT1mi/a) Breast Cancers, a Multicenter Retrospective Study

Simple SummaryTreatment of small HER2+ breast cancers with adjuvant Trastuzumab is still controversial. This study aims to measure the effect of Trastuzumab in early stages of breast cancer (pT1mic/a pN0/1mi) in terms of disease recurrence and to identify which factors most affect the prognosis of small HER2+ tumors. We retrospectively selected and reviewed 100 HER2+ pT1mic-pT1a breast cancer patients with a median follow-up of 86 months. In our study the primary outcome was the disease recurrence rate, which appeared to be significantly lower among patients who received adjuvant Trastuzumab. Among the patients who did not receive adjuvant Trastuzumab, HR− HER2+ tumors showed a risk seven times higher of relapse. The results of our study indicate that adjuvant Trastuzumab reduces the risk of developing a disease recurrence even in small HER2+ tumors. Adjuvant targeted therapy should be considered in patients with HR− HER2+ tumors, the category with the highest risk of recurrence.The treatment with adjuvant Trastuzumab in patients diagnosed with HER2+ small breast cancers is controversial: limited prospective data from randomized trials is available. This study aims to measure the effect of Trastuzumab in the early stages of breast cancer (pT1mic/a pN0/1mi) in terms of disease recurrence and to identify which are the factors that most affect the prognosis of small HER2+ tumors. One hundred HER2+ pT1mic-pT1a breast cancer patients who were treated in three Turin Breast Units between January 1998 and December 2018 were retrospectively selected and reviewed. Trastuzumab was administered to 23 patients. Clinicopathological features and disease-free survival (DFS) were compared between different subgroups. The primary outcome was the disease recurrence rate. Median follow-up time was 86 months. Compared to pT1a tumors, pT1mic lesions had a higher tumor grade (84% of pT1mic vs. 55% of pT1a; p = 0.003), a higher Ki-67 index (81% vs. 46%; p = 0.007) and were more frequently hormone receptor (HR) negative (69% vs. 36%, p = 0.001). Disease recurrence rate was significantly lower among patients who received adjuvant Trastuzumab (p = 0.02), with this therapy conferring an 85% reduction in the risk of relapse (HR 0.15; p = 0.02). Among the patients who did not receive adjuvant Trastuzumab, the only factor significantly associated with an increased risk of developing a recurrence was the immunohistochemical (IHC) subtype: in fact, HR− HER2+ tumors showed a risk seven times higher of relapsing (HR 7.29; p = 0.003). Adjuvant Trastuzumab appears to reduce the risk of disease recurrence even in small HER2+ tumors. The adjuvant targeted therapy should be considered in patients with HR− HER2+ tumors since they have the highest risk of recurrence, independently from size and grade.

Abstract PD10-05: Cost-effectiveness of different neoadjuvant followed by adjuvant treatment combination strategies for women with HER2-positive breast cancer

Abstract Background: Several neoadjuvant and adjuvant treatment options exist for patients with HER2-positive (HER2+) stage II-III breast cancer. Recent results of the KATHERINE trial (NCT01772472) showed that adjuvant T-DM1 can reduce distant recurrence risk in patients without pathologic complete response (pCR) after neoadjuvant chemotherapy. However, pCR rates can range between 20-80% depending on treatment regimen and subtype. Given the high cost of T-DM1 and other HER2-targeted agents, understanding the relationship between the costs and health consequences of various neoadjuvant-adjuvant treatment combinations is needed. Our goal is to identify the treatment strategy that leads to the highest health benefit (i.e., lowest distant recurrence risk) at the least costs. Methods: We developed a decision-analytic Markov model to simulate clinical practice in a cohort of women aged ≥49 with HER2+ breast cancer similar to the KATHERINE trial population. We considered 4 neoadjuvant regimens: HP: trastuzumab (H) and pertuzumab (P) doublet; THP: paclitaxel (T), H and P triplet; ddAC/THP: dose dense anthracycline/cyclophosphamide (ddAC) followed by T, H, P; TCHP: docetaxel (T), carboplatin (C), H, and P, and 4 adjuvant treatments for patients with residual disease including: H; T-DM1; ddAC/THP followed by T-DM1; and ddAC followed by T-DM1. We combined these neoadjuvant and adjuvant treatment options to mimic four clinically plausible treatment de-escalation strategies and examined their cost effectiveness. All patients with pCR after any neoadjuvant treatment received adjuvant H. Strategies for residual disease: 1: neoadjuvant-ddAC/THP+adjuvant-H; 2: neoadjuvant-ddAC/THP+adjuvant-T-DM1; 3: neoadjuvant-THP+adjuvant-ddAC followed by T-DM1; 4: neoadjuvant-HP+adjuvant-ddAC/THP followed by T-DM1; 5: neoadjuvant-TCHP+adjuvant-T-DM1. We informed the effectiveness, cost and utility parameters from the KATHERINE trial, McKesson data, and published literature. We estimated costs and quality-adjusted life years (QALYs) over a lifetime for each strategy, and an incremental cost-effectiveness ratio (ICER), from a healthcare payer perspective and addressed the uncertainty with a probabilistic sensitivity analysis (PSA). Results: The mean per-patient costs varied between $274,550 (Strategy 3) and $354,652 (Strategy 4) and the mean per-patient QALYs varied between 9.44 (Strategy 1) and 10.56 (Strategy 3). When considering the five treatment strategies, Strategy 3 yielded a substantial gain in QALYs at decreased costs, representing the dominating strategy. The decision-analytic model identified Strategies 1, 2, 4 and 5 to be cost-ineffective due to their lower health effects and higher costs (i.e., dominated strategies). PSA indicated Strategy 3 to have the highest probability of cost-effectiveness and expected net benefit across a wide range of willingness-to-pay thresholds ($0-250,000). These findings persisted when changing a number of assumptions, including increasing starting age and varying pCR rates and distant recurrence probability after an initial local recurrence. Conclusions: Our study indicates that neoadjuvant trastuzumab+paclitaxel+pertuzumab followed by adjuvant trastuzumab for patients with pCR (around 46% of patients) and by adjuvant ddAC and T-DM1 for those with residual disease is the most cost-effective treatment strategy for women with HER2+, stage II-III breast cancer. StrategyCostsQALYsICERStrategy 3 Neoadjuvant T, H, P Adjuvant ddAC+T-DM1 for RD; H for pCR$274,55010.56-Strategy 1 Neoadjuvant T, H, P, ddAC Adjuvant H for RD; H for pCR$278,8829.44DominatedStrategy 2 Neoadjuvant T, H, P, ddAC Adjuvant T-DM1 for RD; H for pCR$293,98210.04DominatedStrategy 5 Neoadjuvant T, C, H, P Adjuvant T-DM1 for RD; H for pCR$316,26610.46DominatedStrategy 4 Neoadjuvant H, P Adjuvant T, H, P, ddAC+T-DM1 for RD; H for pCR$354,65210.15Dominated* “Dominated” strategy leads to fewer QALYs at higher costs than the next least costly treatment alternative. Citation Format: Natalia R. Kunst, Shi-Yi Wang, Annette Hood, Sarah Mougalian, Michael P. DiGiovanna, Kerin Adelson, Lajos Pusztai. Cost-effectiveness of different neoadjuvant followed by adjuvant treatment combination strategies for women with HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD10-05.

Mamma-Ca: Trastuzumab adjuvant nur noch 6 Monate

Earl HM, Hiller L, Vallier AL et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+ ) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol 2018; 36 (Suppl) Abstr. LBA1

Abstract P6-17-16: Efficacy and safety of shorter duration of adjuvant trastuzumab for patients with HER2 positive early breast cancer: A meta-analysis of randomized controlled trials

Abstract Background: Trastuzumab has been shown to be able to improve disease free survival(DFS) and overall survival(OS) in HER2-positive breast cancer patients. Adjuvant trastuzumab is empirically recommended for 1 year as a standard regimen. However, several studies claimed that shorter duration of adjuvant trastuzumab is non-inferior to 12 months treatment with reduced cardiac toxicities and costs. Methods: PubMed, EMBASE, Cochrane Library, Google scholar Web, ISI Web of Science, BIOSIS and CNKI, and major conference abstracts were searched systematically in June 2018 to identify eligible non-inferiority studies comparing the intervention outcomes of adjuvant trastuzumab in chemotherapy for women with HER-2 positive breast cancer between short-term and 1-year treatments. Hazard-Ratios(HR) and corresponding 95% Confidence Intervals(CI) were calculated to compare OS and DFS of trastuzumab between short-term and long-term treatments. Pooled data of Odds-Ratio was analyzed for cardiac toxicities. Results: 5 articles were finally eligible in the study. Totally, there were 11,376 women with HER-2 positive early breast cancer, with 5,684 in short-term group and 5,692 in the 1-year group. We found a distinct difference of DFS (HR=1.19, 95% CI=1.08-1.30) and OS (HR=1.22, 95% CI=1.07-1.39) between short-term and 12 months trastuzumab in the total analysis, which demonstrated short-term treatment exhibited a worsening trend on DFS and OS. Subgroup analysis was performed based on estrogen receptor (ER) and lymph node status, and no statistical interaction could be found(p=0.12, 0.52, respectively). The two groups with different duration of trastuzumab treatment displayed statistically significant difference for cardiotoxicities, which favored shorter duration(OR=0.54, 95% CI=0.38-0.77). Conclusions: 1-year adjuvant trastuzumab remains the standard strategy for HER2 positive early breast cancer, however, a concomitant higher risk of associated cardiac adverse effects should not be ignored. Citation Format: Li J, Wang G, Wu Q, Chen C, Tu Y, Yao F, Wei W, Sun S, Santa-Maria CA, Geng P. Efficacy and safety of shorter duration of adjuvant trastuzumab for patients with HER2 positive early breast cancer: A meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-16.

LBA12_PR - PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Cost effectiveness analysis results

Background: Adjuvant trastuzumab has significantly improved outcomes for HER2+ EBC, using the 12m duration empirically adopted from pivotal registration trials. Given an annual per patient cost of trastuzumab treatment of over £30,000 (Euro35,000), a shorter duration has the potential to improve cost-effectiveness if efficacy is maintained. Methods: The cost-effectiveness analysis was based on data from the PERSEPHONE trial, a phase III non-inferiority RCT comparing 6 to 12m Trastuzumab, the largest reduced-duration non-inferiority trial internationally. A landmark analysis 6 months into treatment was conducted, comparing costs and quality of life throughout follow-up (6m – 24m post treatment start). Multiple imputation was required to impute incomplete quality of life data. Quality Adjusted Life Years (QALYs) were adjusted for differences at baseline. Uncertainty is estimated using the non-parametric bootstrap method. Results: 4009 patients were disease free at 6m (6m: n = 2000, 12m: n = 2009) and therefore eligible for the analysis. Of these, 250 individuals (6m: n = 132, 12m: n = 118) had either no returned PQ forms or no returned treatment forms and therefore were excluded from the analysis. The average costs for an individual in the 6m arm and 12 month arm were £2,538.64 (95% CI: £2,383.38 - £2,700.72) and £12,333.83 (95% CI: £12,098.58 - £12,562.27), respectively, giving an average cost saving of £9,793.25 (95% CI: £9,515.86 - £10,071.64) per individual. Trastuzumab treatment and administration accounted for £9,699.58 (95% CI: £9,436.20 - £9.954.67) of this cost saving, the remaining arising from cardiac assessment and treatment costs and inpatient days. The average QALYs for an individual in the 6m arm and 12 month arm were 1.146 (95% CI: 1.131 – 1.161) and 1.128 (95% CI: 1.113 – 1.144), respectively, giving an average QALY difference of 0.018 (95% CI: -0.003 – 0.039). Thus, the 6m arm dominated with a probability of being cost effective of 100%. Conclusions: 6m of trastuzumab was shown to be cost effective compared to 12m with cost-savings and no evidence of a detriment to quality of life. Clinical trial identification: ISRCTN 52968807. Legal entity responsible for the study: University of Leeds. Funding: National Institute of Health Research Health Technology Assessment (NIHR HTA) Programme UK. Funding reference number - 06/303/98. Disclosure: All authors have declared no conflicts of interest.

PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results.

506Background: Adjuvant trastuzumab has significantly improved outcomes for HER2+ EBC pts, using the 12m duration empirically adopted from the pivotal registration trials. A shorter duration could reduce toxicities and cost whilst providing similar efficacy. No reduced-duration trial to date has demonstrated non-inferiority. Methods: PERSEPHONE is a randomised phase 3 non-inferiority trial comparing 6 to 12m trastuzumab, the largest reduced-duration non-inferiority trial internationally. Mapping onto standard UK practice, all HER2+ EBC pts were eligible. Stratification is by ER status, chemotherapy (CT) type, and CT and trastuzumab timing. The primary endpoint is DFS from diagnosis (first relapse or death from any cause). Randomising 4000 pts (1:1) enabled the trial to assess the non-inferiority of 6m (5% 1-sided significance, 85% power), defining non-inferiority as ‘no worse than 3%’ below the 12m arm’s assumed 80% 4-yr DFS. The pre-planned definitive DFS analysis required 500 events. Results: 4089 pts w...

Adjuvant trastuzumab duration trials in HER2 positive breast cancer \u2013 what results would be practice-changing? Persephone investigator questionnaire prior to primary endpoint results

BackgroundTwelve months treatment is the current standard of care for adjuvant trastuzumab in patients with HER2 positive early breast cancer however the optimal duration is not known. Persephone is a non-inferiority randomised controlled trial comparing 6- to 12-months of trastuzumab. In this trial there will be a trade-off between a possible small decrease in disease-free survival (DFS) with 6-months and reduced cardiotoxicity and cost.MethodsA structured questionnaire asked clinicians who had recruited patients into the Persephone trial about their prior beliefs with regards to the clinical effectiveness of trastuzumab and cardiotoxicity profile, in the comparison of 6- and 12-month durations.ResultsFifty-one clinicians from 40 of the 152 Persephone sites completed the questionnaire. 30/50 responders (60%) believed that 6-months trastuzumab would give the same 4-year DFS rate as 12-months trastuzumab, with 21/50 (42%) holding this belief across all breast cancer subsets. In addition, 46/49 responders (94%) reported expecting to change their clinical practice to 6-months, with their prior beliefs (most commonly 85% 4-year DFS rate with 6-months) being greater than their lowest acceptable rate (most commonly 83% 4-year DFS rate with 6-months). Low levels of cardiotoxicity were expected with both 6 and 12-months trastuzumab, with the majority expecting lower levels with 6-months. With increasing hypothesised differences of cardiotoxicity rates between the two durations, significantly lower levels of 4-year DFS with 6-months trastuzumab were deemed acceptable (p < 0.0001).ConclusionMost responders believe that 6-months trastuzumab is adequate, both overall and within each subset of breast cancer, and plan to change their clinical practice if the Persephone results support their prior belief. An individual patient meta-analysis of the duration trials would give greater precision to estimates of the differences in efficacy and toxicity, and adequate statistical power to establish a 2% level of non-inferiority for 6-months adjuvant trastuzumab.

1966 Study of the impact of Charlson comorbidity index on the efficacy of adjuvant trastuzumab in patients with HER2-positive early breast cancer

1966 Study of the impact of Charlson comorbidity index on the efficacy of adjuvant trastuzumab in patients with HER2-positive early breast cancer

Comparison of IHC, FISH, ER and PR in Breast Cancer in Western Iran

To evaluate the concordance and discordance between IHC and FISH results for detection of Her2/neu protein, analyses of ER and PR, and also evaluation of the benefit of adjuvant trastuzumab in patients diagnosed with human epidermal growth factor receptor 2 (HER2) –positive invasive ductal carcinoma enrolled onto the Herceptin adjuvant. IHC analysis of ER, PR and HER2 was performed in 133 patients of breast cancer with invasive ductal carcinoma. 90(67.6%) cases were confirmed by FISH. Statistical analysis was performed with IBM SPSS version 19, Kaplan-Meier method and log-rank test. Age mean of patients was 46.39±10.81 years (range, 24-78 years). Concordance rates between IHC and FISH were 32.4% for IHC 2+ and 81.25% for IHC 3+ (P<0.001). There were 17 and 56 patients of IHC 2+ and 3+ with ER positive and also 23 and 59 patients of IHC 2+ and 3+ had PR positive.The 83 patients had age ≤50 years and 50 patients had >50 years. Of 133 the patients, 48(36.1%) patients were treated with trastuzumab and 85(63.9%) were treated without trastuzumab. The overall survival(OS) for patients treating with trastuzumab were mean of 37.8 months and the OS for patients treating without trastuzumab were mean of 20.8 months (P<0.05). The results are that trastuzumab therapy is effective and improves the survival of HER2-positive breast cancer patients and trastuzumab therapy is effective and tolerated for breast cancer with Her-2 positive. There is a statistically significant relationship between ER positive with PR positive and ER negative with PR negative that these results need to more studies with more patients in the world.

Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort

In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy. We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495. Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5.4 years (IQR 3.1-6.8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0.64 (95% CI 0.44-0.93; two-sided log-rank p=0.016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0.29 (95% CI 0.11-0.78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group). These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease.

Nine weeks versus 1 year adjuvant trastuzumab in patients with early breast cancer: an observational study by the Turkish Oncology Group (TOG)

Optimal duration of adjuvant trastuzumab in early breast cancer is an unresolved issue. In this observational study, we compared the outcome of 9weeks and 1year adjuvant trastuzumab in early breast cancer patients in Turkey. Records of 680 patients with HER2-positive early breast cancer who received adjuvant trastuzumab plus chemotherapy were obtained and patients were followed up to compare the disease-free survival (DFS) outcome of 9weeks versus 1year trastuzumab. Nine weeks and 1year trastuzumab was given to 202 (29.7%) and 478 (70.3%) patients, respectively. There was a significantly lower rate of patients with negative lymph nodes in the 9-week trastuzumab group. At median 3years of follow-up from the date of starting trastuzumab, the DFS rates were 88.6 and 85.6%, respectively (p=0.670). When adjusted for all the prognostic factors that were significant on univariate analysis, again there was no significant difference in DFS between the groups (HR 0.675; 95% CI 0.370-1.231; p=0.200). Cardiac toxicity defined as a ≥15% decrease in LVEF was significantly higher in the 1-year trastuzumab group (1.88% versus none for 1-year and 9-week trastuzumab groups, respectively; p=0.050). The results of this observational study suggest that DFS outcome of 9weeks of adjuvant trastuzumab may be comparable to 1year adjuvant trastuzumab: this needs confirmation by randomized trials.

Outcome of patients with HER2-positive breast cancer treated with or without adjuvant trastuzumab in the Finland Capecitabine Trial (FinXX)

Background. Little information is available about survival outcomes of patients with HER2-positive early breast cancer treated with adjuvant capecitabine-containing chemotherapy with or without trastuzumab. Patients and methods. One thousand and five hundred patients with early breast cancer were entered to the Finland Capecitabine trial (FinXX) between January 2004 and May 2007, and were randomly assigned to receive either three cycles of adjuvant TX (docetaxel, capecitabine) followed by three cycles of CEX (cyclophosphamide, epirubicin, capecitabine; TX-CEX) or three cycles of docetaxel followed by three cycles of CEF (cyclophosphamide, epirubicin, fluorouracil; T-CEF). The primary endpoint was recurrence-free survival (RFS). The study protocol was amended in May 2005 while study accrual was ongoing to allow adjuvant trastuzumab for patients with HER2-positive cancer. Of the 284 patients with HER2-positive cancer accrued to FinXX, 176 (62.0%) received trastuzumab after amending the study protocol, 131 for 12 months and 45 for nine weeks. The median follow-up time was 6.7 years. Results. Patients with HER2-positive cancer who received trastuzumab had better RFS than those who did not (five-year RFS 89.2% vs. 75.9%; HR 0.41, 95% CI 0.23–0.72; p = 0.001). Patients treated with trastuzumab for 12 months or nine weeks had similar RFS. There was no significant interaction between trastuzumab administration and the type of chemotherapy. Four (2.3%) patients treated with trastuzumab had heart failure or left ventricular dysfunction, three of these received capecitabine. Conclusion. Adjuvant trastuzumab improves RFS of patients treated with TX-CEX or T-CEF. Few patients had cardiac failure.

Abstract 4065: Regulation of luminal breast cancer stem cells by HER2 does not require gene amplification providing a potential molecular explanation for the efficacy of adjuvant trastuzumab in patients with “clinically HER2-negative” breast cancer.

Abstract Although current breast treatment guidelines limit the use of HER2 blocking agents such as trastuzumab to women whose tumors display HER2 gene amplification, recent retrospective analysis by several groups have suggested that in the adjuvant setting a wider group of patients whose tumors do not display HER2 amplification may also benefit from this therapy. We hypothesized that these unanticipated results might be explained by the cancer stem cell (CSC) hypothesis. We previously demonstrated that HER2 was an important regulator of CSCs in HER2 amplified breast cancers. We now utilize breast cancer cell lines, mouse xenograft and matched human primary and metastatic tumor samples to demonstrate that HER2 is selectively expressed in and regulates the self-renewal of CSC populations in ER-positive luminal breast cancers which do not display HER2 amplification. In luminal MCF7 and ZR-75-1 breast cancer cells, as well as in primary human tumors, we demonstrate an association between cells which express HER2 and the stem cell marker aldehyde dehydrogenase (ALDH1). In vitro trastuzumab reduced the CSC population as assessed by tumorsphere formation or ALDH expression while no such effects were scene in basal/claudin-low MDA-MB-231 and SUM159 cells. In mouse luminal tumor xenografts, the effects of trastuzumab were highly dependent on the timing of administration. While the effects of trastuzumab on established tumors were limited to those with HER2 amplification, trastuzumab administration begun immediately after tumor inoculation blocked the growth of luminal tumors which did not display HER2 amplification. HER2 expression was increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastasis from patients with luminal breast cancer compared to matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification, but rather was mediated by RANK ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC targeting agents are administered in the adjuvant setting. Citation Format: Korkaya Hasan, Fayaz Malik, Kathleen C. Day, Suthinee Ithimakin, April Davis, Ahmed A. Quraishi, Nader Tawakkol, Kathleen Woods Ignatoski, Dafydd Thomas, Shawn G. Clouthier, Max S. Wicha. Regulation of luminal breast cancer stem cells by HER2 does not require gene amplification providing a potential molecular explanation for the efficacy of adjuvant trastuzumab in patients with “clinically HER2-negative” breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4065. doi:10.1158/1538-7445.AM2013-4065

Magnitude of Trastuzumab Benefit in Patients With HER2-Positive, Invasive Lobular Breast Carcinoma: Results From the HERA Trial

To evaluate the benefit of adjuvant trastuzumab in patients diagnosed with human epidermal growth factor receptor 2 (HER2) -positive invasive lobular carcinoma (ILC) enrolled onto the Herceptin Adjuvant (HERA) trial. Patients randomly assigned to receive one year of trastuzumab and one year of observation in the HERA trial were included (n = 3,401). Centrally reviewed estrogen receptor (ER), progesterone receptor (PgR), and HER2 copy numbers were used. First site-specific relapse pattern was evaluated for ILC and invasive ductal carcinoma (IDC). The magnitude of trastuzumab benefit was assessed using the Cox proportional hazards model for disease-free survival (DFS) and overall survival (OS). Median follow-up time was 4 years. A total of 187 ILC and 3,213 IDC patients were included. High Allred scores (6 to 8) were more common in patients with ILC than IDC for both ER (36.9% v 22.7%) and PgR (44.1% v 28.5%). A trend toward decreased HER2 copy number was observed in the ILC group. The ILC and IDC subgroups had similar patterns of first site of disease relapse. DFS hazard ratios (HRs) comparing 1 year of trastuzumab versus observation were 0.63 for ILC (95% CI, 0.34 to 1.15) and 0.77 for IDC (95% CI, 0.67 to 0.89; P for interaction = .49). The OS HRs comparing 1 year of trastuzumab versus observation were 0.60 for ILC (95% CI, 0.27 to 1.31) and 0.86 for IDC (95% CI, 0.71 to 1.06; P for interaction = .29). In this retrospective analysis, there was no suggestion that patients in the ILC cohort experienced a different magnitude of benefit from adjuvant trastuzumab than those in the IDC cohort.

Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial

A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1:1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C(trough)) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0·80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12·5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300. 299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C(trough) was 51·8 μg/mL (coefficient of variation 52·5%) in the intravenous group and 69·0 μg/mL (55·8%) in the subcutaneous group. The geometric mean ratio of C(trough) subcutaneous to C(trough) intravenous was 1·33 (90% CI 1·24-1·44). 107 (40·7%) of 263 patients in the intravenous group and 118 (45·4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4·7% (95% CI -4·0 to 13·4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33·2%] of 298 patients in the intravenous group vs 86 [29·0%] of 297 in the subcutaneous group), leucopenia (17 [5·7%] vs 12 [4·0%]), and febrile neutropenia (10 [3·4%] vs 17 [5·7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8·1%] in the subcutaneous group vs 13 [4·4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two--both in the subcutaneous group--were deemed to be treatment related. Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative. F Hoffmann-La Roche.

Pregnancy occurring during or following adjuvant trastuzumab in patients enrolled in the HERA trial (BIG 01-01)

Only few case reports describe the pregnancy course and outcome of breast cancer patients, who were under treatment with trastuzumab at the time of conception or who have completed trastuzumab therapy before becoming pregnant. The HERA trial is a large phase III randomized clinical trial in which patients with early HER2-positive breast cancer were randomized to receive 1 or 2 years of trastuzumab or observation following completion of primary chemotherapy. To examine the effect of trastuzumab on pregnancy outcome, we report all pregnancy events that occurred until March 2010 in patients enrolled in the study. For the sake of this analysis, patients were assigned to three groups: (1) pregnancy occurring during and up to 3 months after trastuzumab exposure (group 1); (2) pregnancy occurring >3 months of last trastuzumab dose (group 2); and (3) pregnancy occurring in patients without prior exposure to trastuzumab (group 3). Sixteen, 45 and 9 pregnancies took place in groups 1, 2, and 3, respectively. 25 and 16% of patients in groups 1 and 2 experienced spontaneous abortion, the former being higher than figures reported in the general population. However, short-term fetal outcome appeared normal across the three groups. Only 2 congenital anomalies were reported, one in group 2 and one in group 3. No congenital anomalies were reported in those exposed to trastuzumab in utero. This is the first report from a large randomized trial assessing the effect of trastuzumab on pregnancy course and outcome. Based on our results, trastuzumab does not appear to affect fetal outcome in patients who manage to complete their pregnancy. We are currently initiating a collaboration to collect similar data from the other large adjuvant trastuzumab trials to confirm these findings.

P1-12-01: Pregnancy during and Following Adjuvant Trastuzumab in Patients with HER2−Positive Breast Cancer: An Analysis from the HERA Trial (BIG 01-01).

Abstract Background: 1-year of adjuvant trastuzumab (T) is the standard of care in managing patients (pts) with early HER2−positive breast cancer (BC). As T is not known to alter fertility, pts with childbearing potential could become pregnant during or following treatment with T. Cases of oligohydramnios, some associated with fatal pulmonary hypoplasia of the fetus have been reported in women receiving T during pregnancy (preg). Here we report the outcome of preg in all pts enrolled in the HERA trial. Methods: Pregnancies in the HERA trial are reported on a distinct “pregnancy form” for up to 10 years following T completion. The form includes information on approximate date of conception, preg course &amp; outcome, fetal measurements at birth, and congenital anomalies. Any missing data were retrieved from the study site, if available. For this analysis, pts were grouped into 3 groups: 1) preg during and up to 3 months after T, 2) preg &amp;gt; 3 months of last T dose, and 3) preg with no prior exposure to T. Results: By March 2010, 70 preg were reported in 58 out of 5102 pts randomized. Five, 30 and 7 completed preg were reported in groups 1, 2 &amp; 3 respectively. As per protocol, all pts on T were required to use adequate contraceptive measures, yet 16 pts became pregnant during the course of T and up to 3 months thereafter. The percentage of completed preg was lowest in group 1, with 4 spontaneous and 7 induced abortions. In group 2, preg occurred at a mean of 29 months following completion of T, with 6 spontaneous and 4 induced abortions. In group 3, abortion was induced in 3 pts and no spontaneous abortions reported. Across all 3 groups, all but 1 spontaneous abortion occurred during the 1st trimester. Two congenital anomalies were reported; a Down's syndrome in a 43 year old pt &amp;gt;5 years after completing T for which abortion was induced, and one with partial fusion of the 2nd and 3rd toe born to a pt in group 3. Conclusions: Unintentional exposure to T during preg may be associated with spontaneous abortion, yet the numbers remain low to draw firm conclusions (spontaneous abortion rate in general population is up to 20%). No oligohydramnios or anomalies were observed in group 1. While an increased risk of oligohydramnios has been reported when T is administered after the 1st trimester, T administered to Cynomolgus monkeys during organogenesis did not cause fetal harm (Pentsuk et al; 2009). Nevertheless, women of childbearing potential should be advised to use effective contraception during and up to 6 months after treatment with T. On the other hand, prior exposure to T did not appear to affect the preg course or outcome. We are planning to collect information from the other T adjuvant trials to confirm our findings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-01.

Possible available treatment option for early stage, small, node-negative, and HER2-overexpressing breast cancer

Trastuzumab is known for its clinical activity in women with HER2-overexpressing breast cancer. Randomized clinical trials have shown significant improvement in disease-free and overall survival with trastuzumab administered in conjunction with adjuvant chemotherapy for early-stage HER2-positive breast cancer. However, there is no direct evidence of clinical benefit from adjuvant trastuzumab in patients with node-negative, HER2-overexpressing, small (T1a-b) breast cancers. Previous literature shows that most breast cancers with node-negative small tumors have a good prognosis, but HER2-overexpressing disease might still be worse in this population. Some recent retrospective studies showed that an adjuvant trastuzumab-based regimen has a better prognostic effect, even in patients with node-negative, HER2-overexpressing, small breast cancers, although absolute survival differences were small. On the basis of the available literature, we believe that trastuzumab should be considered for patients with minimal HER2-overexpressing disease, although tools for accurate selection of patients at risk of relapse still need to be developed.

High recurrence risk and use of adjuvant trastuzumab in patients with small, HER2-positive, node-negative breast cancers

Five randomized trials of adjuvant trastuzumab have reported significant improvements in recurrence-free survival (RFS) and overall survival. However, patients with node-negative tumors 1 cm or smaller were excluded from these trials. We assessed the recurrence risk and benefit of adjuvant therapy in such patients with small tumors. We identified patients with node-negative breast tumors 1 cm or smaller between April 2003 and December 2007. Patients were categorized according to HER2 status and pathological tumor size (pT <5 mm vs. 5-10 mm), hormone receptor (HR) status and adjuvant chemotherapy. The primary endpoint was RFS. Of 267 patients included in the analysis, 42 had HER2-positive tumors. The median follow-up was 4.3 years. RFS was worse in patients with HER2-positive tumors than HER2-negative tumors (90.5 vs. 97.7% at 5 years; P = 0.031). In the group with HER2-positive tumors, there were no recurrences in patients with pT<5 mm, but 4 recurrences in those with pT 5-10 mm. RFS was worse in patients with pT 5-10 mm than pT <5 mm (79.0 vs. 100%, P = 0.025). Furthermore 3 recurrences occurred in patients without adjuvant trastuzumab, and 1 recurrence occurred as soon as adjuvant trastuzumab was finished. Our results appear to establish the efficacy of adjuvant trastuzumab therapy. HR status and use of adjuvant chemotherapy were not significantly associated with RFS. Patients with HER2-positive, node-negative breast tumors 1 cm or smaller (especially 0.5-1.0 cm) have a significant recurrence risk and the decision to employ adjuvant trastuzumab therapy should be discussed with patients based on our results and those of other studies.

C-MYC Alterations and Association With Patient Outcome in Early-Stage HER2-Positive Breast Cancer From the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial

Findings from the human epidermal growth factor receptor 2 (HER2) -positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (> 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial-North Central Cancer Treatment Group (NCCTG) N9831. This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8. In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio ≤ 2.2 (n = 618; 77%) and > 2.2 (n = 181; 23%) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus ≤ 5.0 (n = 534; 67%) and > 5.0 (n = 265; 33%) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18%) and ≥ 1.3 or < 1.3 with polysomy 8 (n = 658; 82%) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16%) and ≥ 2.5 (n = 669; 84%) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05). We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.