Neoadjuvant anti-HER2 Therapy Research Articles

HER2 equivocal breast cancer and neoadjuvant therapy: Is response similar to HER2-positive or HER2-negative tumors?

612Background: While HER2+breast cancers demonstrate high rates of pathologic complete response (pCR) to neoadjuvant HER2-targeted therapy, there is a need to assess objective response in HER2 equivocal tumors. Methods: Retrospective chart review was conducted of patients diagnosed with invasive breast cancer who received neoadjuvant therapy (NAT) between 2010 and 2014 at our institution. Case inclusion required at least ER and HER2 status and pCR information. HER2 was measured by immunohistochemistry (IHC) with IHC 3+ and IHC 0/1+ cases considered positive and negative respectively. IHC 2+ cases were tested by FISH and classified using the 2013 ASCO HER2 guidelines ISH criteria for dual color probe. Cases were also classified by average HER2 copies/cell criteria. Results: 595 cases met criteria for inclusion. pCR rates according to HER2 status are reported below. Conclusions: Of the 46 patients with HER2 equivocal results, 31 (67%) received anti-HER2 NAT. 5 of 31 (16%) achieved pCR: 2 of 8 ER- (25%) and ...

Abstract P4-14-08: Efficacy of trastuzumab re-therapy in the clinical routine of HER2-positive breast cancer patients who relapsed after completed anti-HER2 (neo)adjuvant therapy – 5th interim analysis of the national non-interventional study (NIS) ML21589

Abstract Background HER2 overexpression occurs in approx. 20% of breast tumors and is associated with increased aggressiveness and mortality. Anti-HER2 re-therapy with trastuzumab (Herceptin®, T) is an established therapeutic option for the treatment of recurrent/metastatic HER2-positive breast cancer (MBC). Patients (pts) receiving T re-therapy appear to benefit from the retreatment after a relapse-free (neo)adjuvant anti-HER2 therapy. Methods This NIS is conducted in Germany to gain additional knowledge about efficacy of 1st-line T retreatment in the clinical routine. 122 sites enrolled a total of 239 pts with locally recurrent and/or MBC who relapsed after (neo)adjuvant treatment with T in their medical history. 230 pts met the eligibility criteria. The current analysis presents data collected between 10/2008-04/2015. Tumor progression was clinically assessed by the investigator. Results Median observation period for the total population (n=230) was 41.7 months (m) (range 0.4-94.5). At start of T retreatment, 20.0% (n=46) of the pts presented with local recurrence only, 79.6% (n=183) presented with distant metastases ± local recurrence and one patient (0.4%) presented with elevated tumor markers. 27.4% (n=63) of the pts developed exclusively non-visceral metastases and 52.2% (n=120) were diagnosed with visceral (± non-visceral) metastases. Median duration of T re-therapy in the first line setting was 9.0 m (95% confidence interval (CI): 7.6-10.1). In 69.6% (n=160) of the cases, T was added to chemotherapy (CT). 15.2% of the pts (n=35) were treated with T+CT + endocrine therapy (ET). A median progression free survival (PFS) of 10.1 m was observed among all eligible patients (n = 230) (95% CI: 8.5-12.0). The evaluation by risk groups revealed a PFS of 23.7 m (95% CI: 13.3-NE*) for patients with local recurrence only, 11.8 m (95% CI: 8.3-20.1) for patients with non-visceral metastases and 7.6 m (95% CI: 6.2-9.9) for patients with visceral metastases. *Not evaluable Median PFS according to treatment regimen was 8.3 m for pts who were treated with T+CT (n=125, 54.3%), 17.7 m in pts who received T+CT+ET (n=35, 15.2%) and 11.2 m in pts treated with T+ET (n=38, 16.5%). Pts who received T monotherapy (n=32, 13.9%) had a median PFS of 13.4 m. Of 230 pts, 121 deaths were documented (52.6%) within the observation period. The median overall survival (OS) was 29.6 m for all pts (95% CI: 27.3-36.8). Median OS was statistically reliable for pts with visceral metastases only: 19.4 m (95% CI: 16.9-27.3). The 2-year survival rate was 62.2% for all pts, 81.9% for pts with local recurrence only, 80.7% for pts with non-visceral metastases and 45.6% for pts with visceral metastases. Conclusions The survival observed for pts with HER2-positive MBC receiving T re-therapy in the clinical routine is in line with the results of recently published data. In terms of the 2-year survival rate, 81.9% of the pts with local recurrence were still alive and thus show the most favourable prognosis. T re-therapy provides an efficient treatment option regardless of given as combination-therapy together with CT and/or ET or as monotherapy. Citation Format: Hanker L, Hitschold T, Grafe A, Förster F, Schröder J, Janssen J, Reichert D, Hielscher C, Keitel S, Hesse T. Efficacy of trastuzumab re-therapy in the clinical routine of HER2-positive breast cancer patients who relapsed after completed anti-HER2 (neo)adjuvant therapy – 5th interim analysis of the national non-interventional study (NIS) ML21589. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-08.

Eliminating Breast Cancer Surgery with Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy (NCT) and anti-HER2 therapy have been shown to eradicate invasive breast cancer and sometimes in situ carcinoma in up to 60% of patients with triple-negative and HER2-positive breast cancer. This finding begs the question of whether surgery is necessary for all patients, particularly when they receive adjuvant radiotherapy, an approach used for some stages of cervical, prostate, and lung cancers. However, current best breast imaging is neither …

Abstract OT1-3-02: Will chest wall and regional nodal radiotherapy post mastectomy or the addition of regional nodal radiotherapy to breast radiotherapy post lumpectomy reduce the rate of invasive cancer events in patients with positive axillary nodes who convert to ypN0 af

Abstract Background This phase III randomized post-neoadjuvant chemotherapy trial will evaluate if chest wall and regional nodal XRT (CWRNRT) after mastectomy or whole breast irradiation (WBI) with RNRT after breast-conserving surgery significantly reduces the rate of events for invasive breast cancer recurrence-free interval (IBCR-FI) in patients who present with histologically positive axillary nodes but become histologically negative axillary nodes after neoadjuvant chemotherapy. Secondary aims are OS, LRR-FI, DRFI, DFS-DCIS, and second primary cancer. HYPOTHESIS: Can We Use Tumor and Nodal Response to Neoadjuvant Chemotherapy in Order to Individualize the Use of L-R XRT? Correlative science will examine the effect of RT by tumor subtype, molecular predictors of outcome for patients with residual disease, and the development of predictors of degree of reduction in loco-regional recurrence. Methods Eligible patients with clinical T1-3, N1 breast cancer with pathologic axillary nodal involvement (positive FNA or core needle biopsy) must complete ≥12 weeks of neoadjuvant chemotherapy (anthracycline and/or taxane-based regimen). HER2-positive patients must receive neoadjuvant trastuzumab or other anti-HER2 therapy. After neoadjuvant chemotherapy either breast-conserving surgery or mastectomy will be performed. At the time of surgery, all removed axillary nodes must be histologically free from cancer. 3 or more histologically negative sentinel nodes are acceptable to determine axillary nodal involvement. ER/PR and HER-2 neu status before neoadjuvant chemotherapy is required. All patients will receive additional required systemic therapy. Site radiation credentialing with a facility questionnaire and case benchmarking is required. Randomization for mastectomy patients will be to no CWRNRT or CWRNRT and for breast-conserving surgery patients to WBI or WBI RNRT. Statistical Considerations 1636 patients will be enrolled over 5 years with definitive analysis at 7.5 years. The study is powered at 80% to test the main hypothesis that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction in the 5-year cumulative rate of 4.6%. Analysis will be on intent-to-treat with 3 formal interim analyses at 43, 86, and 129 events, with a 4th/final analysis at 172 events. Current accrual is 37. (as of 6-10-14) 736 enrolled patients will be evaluated with targeted patient-reported outcome instruments focusing on the effect of RT. Patient assessments will be prior to randomization and then at 3, 6, 12, and 24 months. Contact Information Study protocol information can be found under the protocol-specific web page on the CTSU member web site https://www.ctsu.org. For protocol-specific questions contact – NRG Oncology Pittsburgh Clinical Coordinating Department. Phone: 1-800-477-7227. Email: ccd@nsabp.org. All investigators will enroll patients by accessing OPEN at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the web site. Support: NCI PHS U10-CA-12027, -69651, -37377, -69974, and -2166. Citation Format: Eleftherios P Mamounas, Hanna Bandos, Julia R White, Thomas B Julian, Atif J Khan, Simona F Shaitelman, Mylin A Torres, Susan A McCloskey, Frank A Vicini, Patricia A Ganz, Soonmyung Paik, Nilendu Gupta, Joseph P Costantino, Walter J Curran Jr, Norman Wolmark. Will chest wall and regional nodal radiotherapy post mastectomy or the addition of regional nodal radiotherapy to breast radiotherapy post lumpectomy reduce the rate of invasive cancer events in patients with positive axillary nodes who convert to ypN0 af [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-3-02.

Cost-effectiveness analysis of neoadjuvant pertuzumab and trastuzumab therapy for locally advanced, inflammatory, or early HER2-positive breast cancer in Canada

Objective:The NeoSphere trial demonstrated that the addition of pertuzumab to trastuzumab and docetaxel for the neoadjuvant treatment of HER2-positive locally advanced, inflammatory, or early breast cancer (eBC) resulted in a significant improvement in pathological complete response (pCR). Furthermore, the TRYPHAENA trial supported the benefit of neoadjuvant dual anti-HER2 therapy. Survival data from these trials is not yet available; however, other studies have demonstrated a correlation between pCR and improved event-free survival (EFS) and overall survival (OS) in this patient population. This study represents the first Canadian cost-effectiveness analysis of pertuzumab in the neoadjuvant treatment of HER2-positive eBC.Methods:A cost-utility analysis (CUA) was conducted using a three health state Markov model (‘event-free’, ‘relapsed’, and ‘dead’). Two separate analyses were conducted; the first considering total pCR (ypT0/is ypN0) data from NeoSphere, and the second from TRYPHAENA. Published EFS and OS data partitioned for patients achieving/not achieving pCR were used in combination with the percentage achieving pCR in the pertuzumab trials to estimate survival. This CUA included published utility values and direct medical costs including drugs, treatment administration, management of adverse events, supportive care, and subsequent therapy. To address uncertainty, a probabilistic sensitivity analysis (PSA) and alternative scenarios were explored.Results:Both analyses suggested that the addition of pertuzumab resulted in increased life-years and quality-adjusted life-years (QALYs). The incremental cost per QALY ranged from $25,388 (CAD; NeoSphere analysis) to $46,196 (TRYPHAENA analysis). Sensitivity analyses further support the use of pertuzumab, with cost-effectiveness ratios ranging from $9230–$64,421. At a threshold of $100,000, the addition of pertuzumab was cost-effective in nearly all scenarios (93% NeoSphere; 79% TRYPHAENA).Conclusion:Given the improvement in clinical efficacy and a favorable cost per QALY, the addition of pertuzumab in the neoadjuvant setting represents an attractive treatment option for HER2-positive eBC patients.

400P - Efficacy of Anti-Her2 Retherapy with Trastuzumab at First Relapse and/or First Occurrence of Metastases of Her2-Positive Breast Cancer in Clinical Routine – 4Th Interim Analysis of the Non-Interventional Study (Nis) Ml21589

ABSTRACT Aim: Patients receiving trastuzumab (Herceptin®; H) ReTherapy seem to benefit from a repeated treatment. Aim of this NIS is the proof of efficacy of first line treatment with H after relapse-free (neo)adjuvant anti-HER2 therapy. Methods: In total, 122 sites enrolled 239 patients with locally recurrent and/or metastatic HER2-positive breast cancer into this trial. The current interim analysis presents data from 225 patients collected between 10/2008 and 01/2014. Results: At the time of inclusion, 19.2% (n = 43) of patients only suffered from local recurrence only, 80.8% (n = 181) had developed distant metastases ± local recurrence, of which 27.7% (n = 62) had exclusively non-visceral and 53,1% (n = 119) visceral (± non-visceral) metastases. Median duration of H ReTherapy was 10.7 months (m) (range 0-56.9). Median progression-free survival amounted to 10.1 m (95% CI: 8.3-12.0) in the total population, 11.5 m (8.3-20.1) for patients with non-visceral disease, and 8.0 m (6.3-10.2) for patients with visceral disease. H ReTherapy was given either as monotherapy (H: 13.3%) or in combination with hormono- (H + HT: 16.4%) and/or chemotherapy (total: 70.2%; H + CT: 54.7%; H + CT + HT: 15.5%). The most frequently used drugs were paclitaxel (26.6%), vinorelbin (18.4%), and docetaxel (10.8%). Progression-free survival for patients treated with H monotherapy amounted to 13.4 m, with H + HT to 11.2 m, with H + CT to 8.1 m, and with H + CT + HT to 19.5 m. The overall response rate in the total population was 44.3%, for patients with only local recurrence 65.5%, with non-visceral disease 35.8%, and with visceral disease 42.0%. Conclusions: The results of the current interim analysis indicate that Herceptin ReTherapy is an efficacious treatment option in first line therapy for patients with locally recurrent and/or metastatic HER2-positive breast cancer. Over 70% of ReTherapies combined Herceptin with chemotherapy. The combination of Herceptin with both chemo- and hormonotherapy was most efficacious in terms of progression-free survival. The present data are in line with the results of other recent trials. Disclosure: T. Wohlfarth: employee, stock ownership (Roche). All other authors have declared no conflicts of interest.

Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response

Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response. We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m(2)). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m(2) plus epirubicin 100 mg/m(2) plus cyclophosphamide 500 mg/m(2)) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov, number NCT00553358. 455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50-4·22), 3-year event-free survival was 78% (95% CI 70-84) in the lapatinib group, 76% (68-82) in the trastuzumab group, and 84% (77-89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66-1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47-1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60-4·24), and 3-year overall survival was 93% (95% CI 87-96) for lapatinib, 90% (84-94) for trastuzumab, and 95% (90-98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45-1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30-1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22-0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15-0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events. Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response. GlaxoSmithKline.

A retrospective study of inflammatory breast cancer patients from seven hospitals in the United Kingdom.

e11062 Background: Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer characterised by rapidly progressive breast erythema, pain and tenderness, oedema and paeu d’orange. It is estimated that between 1-4 % of all newly diagnosed breast cancer patients in the United Kingdom have IBC. Methods: We retrospectively identified 51 patients who were treated for IBC at 7 hospitals in the West midlands area of the United Kingdom between 1997 and 2011. Data including patients’ demographics, clinical, radiological and histopathological characteristics were collected from electronic clinical records. The test for HER-2 over-expression was not carried out routinely before 2002, therefore HER-2 status of such patients were assessed retrospectively on the archived tissues. A cox regression analysis was used for statistical assessment of survival and prognostic factors. Results: Median age at diagnosis was 55 years (range 34-83 yrs). Median overall (OS) and progression free survival (PFS) were 32 months (range 7-97 months) and 27 months (range 2-53 months) respectively. The 3–year survival rate for the entire cohort was 32%. Majority of patients were ER and HER-2 positive (49% and 52% respectively). The rate of complete pathological response (pCR) after neoadjuvant chemotherapy was 14%. All cases who had achieved pCR were HER-2 positive who had received anti HER-2 treatment during the neoadjuvant chemotherapy. The OS for the HER-2 positive patients with pCR was not statistically different from the whole cohort (49 vs 32 months, p=0.09) or from the patients with residual disease (49 vs 26 months, p=0.13). Although the triple negative IBC patients consisted 20% of the cohort, no patients in this group had achieved pCR. The OS and PFS for the triple negative patients were 20 and 14 months respectively. Although the rate of pCR was higher in patients treated with taxane compared to those treated with anthracycline containing chemotherapy (35% vs 7%), there was no significant difference in OS between either of these regimens (29 vs 27 months). Conclusions: HER-2 positive IBC patients had higher rate of achieving pCR after neo-adjuvant anti HER-2 therapy. However higher rate of pCR did not improve the OS.

P1-12-18: Change in HER2 Status in HER2 Positive Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without Anti-HER2 Therapy: Analysis of Two Consecutive Cohorts.

Abstract Introduction: emerging literature data have shown a change of HER2 expression from primary tumors to metastatic deposits. Tumor heterogeneity, genetic drift as well as selective pressure of adjuvant therapy have been suggested to explain this phenomenon. Aim of the present analysis is to evaluate the change in HER2 expression after neoadjuvant chemotherapy with or without anti-HER2 agents. Methods: two consecutive cohorts of HER2+ breast cancer patients treated with neoadjuvant therapy were identified from a prospectively maintained database including 310 patients. The first cohort (A) includes 38 patients enrolled before 2005, treated with chemotherapy alone. The second cohort (B) includes 48 patients treated with neoadjuvant chemotherapy in combination with antiHER2 agents (trastuzumab or lapatinib). HER2 expression was evaluated by IHC on pre-treatment core biopsy (tru-cut with 14 gauge needle) and on surgical specimen after neoadjuvant therapy. FISH analysis was performed on IHC 2+ samples. Results: The two cohorts were balanced in respect of tumor stage, patient age, and HR expression. In particular, a co-expression of HER2 and HR was observed in 60% of the patients in cohort A and in 70% of the patients in cohort B (p=0.2). Patients in cohort B have a significantly higher rate of pathologic complete response (pCR) in comparison to cohort A (45% vs 11%, p=0.001). A change in HER2 expression from biopsy to post-therapy samples was observed in 39% of the patients in cohort A vs 12% of the patients in cohort B (p=0.02). No patients with pCR have recurred so far vs 25% of the patients with less than pCR (p=0.005). The rate of recurrence was significantly higher for patients experiencing a change in HER2 expression (50% vs 19%, p=0.018). Conclusion: contrary to our expectations, patients not receiving anti-HER2 therapy as part of neoadjuvant therapy were more likely to have a change in HER2 status vs patients receiving anti-HER2 neoadjuvant therapy. The change in HER2 status has a negative prognostic impact. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-18.

Pathologic Complete Response After Neoadjuvant Chemotherapy Plus Trastuzumab Predicts Favorable Survival in Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer: Results From the TECHNO Trial of the AGO and GBG Study Groups

To evaluate efficacy and safety of epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab as neoadjuvant treatment in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Patients with centrally confirmed HER2-overexpressing breast cancer (≥ 2 cm or inflammatory) received four 3-week cycles epirubicin and cyclophosphamide (90/600 mg/m(2)) followed by four 3-week cycles paclitaxel (175 mg/m(2)) and trastuzumab (6 mg/kg) before surgery. Trastuzumab was continued after surgery to complete 1 year of treatment. Primary end point was pathologic complete response (pCR) defined as no residual invasive tumor in breast and lymphatic tissue. Thirty-nine percent of 217 enrolled patients achieved a pCR. Breast conservation was possible in 64% of patients. Three-year disease-free survival (DFS) was 88% in patients with pCR compared to 73% in patients without pCR (P = .01). Three-year overall survival (OS) was 96% in patients with pCR compared to 86% in patients without pCR (P = .025). pCR was the only significant prognostic factor for DFS (hazard ratio [HR] 2.5; 95% CI, 1.2 to 5.1; P = .013) and OS (HR, 4.9; 95% CI, 1.4 to 17.4; P = .012) in multivariable analysis. Cardiac toxicity was reported in eight patients (3.7%) of whom six presented with an asymptomatic left ventricular ejection fraction decrease and two with symptomatic chronic heart failure. Neoadjuvant combination of trastuzumab and chemotherapy resulted in a high pCR rate in HER2-overexpressing primary breast cancer. Patients with a pCR after neoadjuvant anti-HER2 therapy in combination with chemotherapy followed by maintenance trastuzumab have an improved long-term outcome. Patients without a pCR had an increased risk for relapse and death.