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

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.

Effect of Delay in Initiation of Adjuvant Trastuzumab and Dose Interruptions on Overall Treatment Outcome in Breast Cancer Patients, a Retrospective Study

Background HER2 amplification or protein over-expression is found in 20% of invasive breast cancers. It’s clearly associated with accelerated cell growth and proliferation and poor clinical outcome. The amplification of HER2 was historically an adverse prognostic factor associated with a higher risk of recurrence, lack of or lower levels of ER expression, and relative resistance to endocrine therapy and CMF based chemotherapy. Objectives We aimed in this study to assess the impact of delaying the initiation of adjuvant Trastuzumab for more than three months after the diagnosis of breast cancer and the effect of irregular and interrupted doses of adjuvant Trastuzumab, on progression free Survival, relapse, and overall survival (OS) among patients with breast cancer. Patients and Methods A Retrospective cohort study was conducted in Ain Shams University Hospitals. The study included one hundred patients with HER2 positive breast cancer. from January 2011 till December 2016 at the" Department of Clinical Oncology and Nuclear Medicine, Ain Shams University Hospitals". Results The median time to progression in group I was 19 months compared to 30 months in group II. There was statistically significant decrease median of group I compared to group II according to PFS. Conclusion We concluded that delays in the initiation of adjuvant treatment may be particularly harmful in patients with more aggressive tumor types.

The addition of neoadjuvant pertuzumab for the treatment of HER2+ breast cancer: a cost estimate with real-world data

Background Breast cancer (BC) is largely prevalent worldwide. HER2-positive BC account for roughly 20–25% of all BC cases and has an overall survival lower than other BC. Innovation on BC therapeutics is a constant, but novel therapies have higher costs. Therefore, cost-effectiveness research is essential to provide healthcare decision-makers with solid foundations for a resource allocation. This study aims to estimate the average direct medical costs/patient and cost-effectiveness of adding pertuzumab in neoadjuvant treatment (NeoT) for HER2-positive breast cancer (BC). Methods Two retrospective real-world consecutive cohorts of ≥18yo female patients diagnosed with HER2-positive BC treated with NeoT at the Breast Clinic of IPO-Porto were studied. The AC-DH regimen (2012–2015) comprised 8 cycles of neoadjuvant therapy (4 cycles of doxorubicin + cyclosphosphamide followed by 4 cycles ofdocetaxel + trastuzumab), while the AC-DHP regimen (2015–2017) included also pertuzumab as NeoT. NeoT was followed by surgery and adjuvant trastuzumab. Micro-costing technique and a bottom-up approach was used comprising all medical direct costs from the hospital perspective. Unit costs were obtained from government official prices or from IPO-Porto costing system. Costs were adjusted to 2017 and are expressed in euros. Multivariable logistic regression models were used for effectiveness assessment, while generalized linear models with gamma distribution were used for costs. ICER was calculated using the pathological complete response (pCR) as the preferential measure of effectiveness. Sensitivity analysis was also performed. Results AC-DHP (n = 40) and AC-DH (n = 54) cohorts had heterogenous patient profiles (median age 43y/53y; 67.5%/59.3% positive HR; 60.0%/27.8% operable; 25.0%/24.1% inflammatory, respectively). The AC-DHP average total cost/patient was 56,375€, with pertuzumab accounting for 13,978€ (24.79%) and increasing in 15,982€ the average cost/patient (p < 0.001). Clinical staging and hormone receptors (HR) were significantly associated with pCR. ICER was 1.370€ per percentage point of pCR. Conclusions ICER was more favourable in stage III HR negative BC patients compared to other patient profiles. Innovative treatments access is critical to deliver high-quality healthcare, but sustainability must be considered. These results suggest the importance of establishing a cost-effectiveness profile of Pertuzumab in NeoT for HER2-positive BC.

P14.42 Neratinib for treatment of leptomeningeal metastases from HER2-positive breast cancer in extended access program: preliminary results

BACKGROUND Leptomeningeal metastases (LM) occur in 5% of human epidermal growth factor receptor 2 (HER2) breast cancer (BC) with a poor overall survival (OS) of 3 months. Neratinib is an oral, irreversible tyrosine kinase pan-inhibitor that was approved by FDA for the treatment of HER2-enriched BC, who completed a prior adjuvant trastuzumab-based therapy. The aim of the study was to evaluate the activity of neratinib in LM from HER2-positive BC after the failure of multiple lines of treatment, including trastuzumab. PATIENTS AND METHODS Inclusion criteria were as follows: age ≥ 18 years; histological diagnosis of primary HER2-positive BC; newly-diagnosed LM according to LANO criteria; KPS ≥60 at the time of diagnosis of LM; coexistence of BM that have or not received WBRT or radiosurgery; systemic disease with a life expectancy of at least 3 months; concomitant drugs, including capecitabine, trastuzumab, TDM-1, pertuzumab, and hormone therapy were allowed, with the exclusion of lapatinib or other investigational agents. Neratinib was administered 240 mg daily continuously. The primary endpoint was the OS after the diagnosis of LM. Secondary endpoints were progression-free survival (PFS) following the diagnosis of LM, neurological benefit, radiological response rate, and tolerability. RESULTS From January 2018 to April 2021, 9 patients with LM have been enrolled. Median age at the time of diagnosis of LM was 44 years (95%CI 36–59) with a median KPS of 80 (95%CI 60–90). Median time since LM onset from the diagnosis of primary BC was 42 months (95%CI 11–166), and patients underwent a median number of adjuvant treatments before LM of 3 (95%CI 2–5). Three patients developed LM alone, and other 6 had LM associated with multiple brain metastases. Six-months and 1-year OS were 66.7% and 22.3%, respectively, with a median OS of 8 months (95%CI 3–13*). Median PFS was 3.5 months (95%CI 2–6) after the start of treatment. A neurological improvement was reported in 2/9 patients (22.2%), while in other 4/9 patients (44.5%) was achieved a neurological stabilization lasting for a median time of 5 months (95%CI 2–19). The best radiological response was a stable disease in 5/9 patients (55.6%), while no complete or partial response were achieved according to LANO and RANO criteria, respectively. A CSF clearance was observed in 1 patient only (11.1%) following two months of neratinib. Grade III-IV adverse events were not reported, and 2 patients only (22.2%) had mild diarrhea correlated with neratinib. CONCLUSION This is the first study that shows that neratinib might be a safe and effective treatment in LM from heavily pretreated HER2-positive BC.

Adjuvant Trastuzumab with or without Chemotherapy in Stage 1 pT1N0 HER2+ Breast Cancer: A National Cancer Database Analysis

Purpose: Approximately 20% of all breast cancers (BC) are HER2 amplified. In the APT trial, weekly paclitaxel/ trastuzumab in node negative HER2+ BC with tumors <3 cm was associated with a 7-year invasive disease-free survival of 93%. However, this was in the context of a non-randomized trial, and for pT1N0 HER2+ BC it remains unclear whether HER2 monotherapy would provide similar clinical outcomes to chemo-HER2 therapy. We hypothesized that adjuvant chemo-HER2 therapy would be associated with a modestly improved overall survival compared to HER2 monotherapy in patients with tumors <2cm. Methods: In the National Cancer Database (2004-2017), patients with a primary diagnosis of pT1N0M0 HER2+ BC, were separated into two groups: (i) HER2 monotherapy, i.e. trastuzumab, and (ii) chemo-HER2 therapy. A 3:1 propensity match was performed to balance patient selection bias between the two different cohorts. Long-term overall survival (OS) was compared between both groups. Results: A total of 23, 281 patients met the criteria. 22,268 (96.7%) received chemo-HER2 therapy and 1,013 (4.4%) received HER2 monotherapy. Propensity match identified 1,995 patients who received chemo-HER2 therapy, and 666 who received HER2 monotherapy. After match, adjuvant chemo-HER2 therapy was associated with a modest survival advantage over HER2 monotherapy (5-year OS 94.1% vs. 90.6%, P=0.041). Conclusions: Even though there is a modest OS advantage favoring adjuvant chemo-HER2 therapy in pT1N0 HER2+ BC, HER2 monotherapy was associated with 5-year OS >90%. Therefore, in select patients who have contraindications for cytotoxic chemotherapy, or decline adjuvant chemotherapy, adjuvant trastuzumab monotherapy appears to be a reasonable alternative.

Adjuvant Trastuzumab Without Chemotherapy For Treating Early HER2-Positive Breast Cancer In Older Patients: A Cohort Study Accompanying With The RESPECT Trial

Purpose To gauge the effects of treatment practices on prognosis for all older patients with HER2-positive breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This report accompanies the RESPECT study, a randomized-controlled trial (RCT) comparing trastuzumab monotherapy with trastuzumab-plus-chemotherapy for early HER2-positive breast cancer.Patients and methods Patients who declined the RCT were treated based on the physician’s discretion. We studied the (1) trastuzumab-plus-chemotherapy group, (2) trastuzumab-monotherapy group, and (3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method.Results We enrolled 398 eligible patients, aged over 70 years, with HER2-positive invasive breast cancer, of whom 275 (69%) were in the RCT, and 123 (31%) were in this cohort group. The median age was 74.5 years. Among cohort group treatment categories were as follows: (1) trastuzumab-plus-chemotherapy group (n = 36, 30%), (2) trastuzumab-monotherapy group (n = 52, 43%), and (3) non-trastuzumab group (n = 32, 27%). A total of 73% of patients received trastuzumab-containing regimens, with or without chemotherapy. The 3-year DFS was 92.3% in the trastuzumab-plus-chemotherapy group, 89.2% in the trastuzumab-monotherapy group, and 82.5% in the non-trastuzumab group. DFS in the non-trastuzumab group was lower than in the trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR: 3.29; 95% CI: 1.15–9.39; P = 0.026). The relapse-free survival in the non-trastuzumab group was lower than in the trastuzumab-plus-chemotherapy and trastuzumab monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, P < 0.0001). Chemotherapy with trastuzumab or trastuzumab monotherapy did not affect health-related quality of life (HRQoL) at 36 months.Conclusions Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Thus, trastuzumab monotherapy can be considered for patients who reject chemotherapy.Trial registration number The protocol was registered on the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN 000028476).