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ExteNET showed that neratinib, an irreversible pan-HER tyrosine ki- nase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved inva- sive disease-free survival in women with early-stage HER2-positive breast cancer. We report the final analysis of overall survival in ExteNET.

Background: Non-adherence or early discontinuation from systemic adjuvant therapy is associated with an increased risk of disease recurrence and mortality. In the phase 3 ExteNET trial, neratinib (NERLYNX®), an oral irreversible pan-HER tyrosine kinase inhibitor, significantly improved invasive disease-free survival (iDFS) when given for 12 months in patients with early-stage HER2-positive (HER2+) breast cancer after trastuzumab-based therapy. Anti-diarrheal prophylaxis was not mandated by protocol and 17% of patients discontinued neratinib early because of diarrhea. Improved iDFS, distant disease-free survival, and overall survival (OS) have since been reported in patients who completed the planned duration of neratinib therapy compared with all randomized patients [ASCO 2021]. Here we assess central nervous system disease-free survival (CNS-DFS) in 3 discrete groups of patients who completed planned therapy with neratinib in ExteNET: intent-to-treat (ITT) population; patients with hormone receptor-positive disease who initiated neratinib within 1 year after prior trastuzumab (HR+/≤1 year, the population for which neratinib is approved in the EU); and HR+/≤1 year with residual disease post-neoadjuvant therapy (i.e. no pathologic complete response [pCR]). Methods: Patients with early-stage HER2+ breast cancer received oral neratinib 240 mg/day or placebo after trastuzumab-based (neo)adjuvant therapy for 12 months. Patients who completed neratinib therapy (defined as treatment duration ≥11 months or cessation of neratinib if recurrence occurred prior to 11 months) were compared with placebo (all randomized patients). CNS-DFS was defined as time from randomization to any CNS recurrence or death from any cause (exploratory endpoint). Kaplan-Meier methods were used to estimate CNS-DFS and OS rates. Hazard ratios (HR) with 95% confidence intervals (CI) for neratinib versus placebo were estimated using a Cox proportional hazards model. Data cutoffs: March 2017 (CNS-DFS); July 2019 (OS); median follow-up 8.0 (range 0-9.8) years. Results: 2840 patients were included in the ITT population (1420 per group). Among patients who completed neratinib therapy, CNS-DFS was improved versus placebo in each of the 3 patient groups (see Table). For CNS-DFS, the magnitude of effect of neratinib versus placebo was consistently greater in patients who completed neratinib therapy than in the corresponding overall randomized patient group: ITT HR, 0.70 vs 0.73; HR+/≤1 year HR, 0.27 vs 0.41; HR+/≤ 1 year no pCR HR: 0.16 vs 0.24, respectively. Conclusions: These descriptive findings suggest that, in addition to improved OS, patients who receive the recommended 12-month course of neratinib may have improved CNS outcomes. A dose-escalation strategy, which was shown to improve the tolerability of neratinib, decrease the proportion of patients who discontinue treatment due to diarrhea (3.3%), and allow more patients to stay on treatment for 11 months or longer in the CONTROL trial (NCT02400476) compared with ExteNET, may help to realize these benefits in the real-world setting. Table: CNS-DFS and OS in patients who completed planned therapy with neratinib (ITT, HR+/≤1 year and HR+/≤1 year no pCR)NCNS-DFS rate (5 years)OS rateaPopulation/group NeratinibPlaceboDifference, %bHR (95% CI)Difference, %bHR (95% CI)ITT14201420+1.10.73 (0.45-1.17)-0.10.95 (0.75-1.21)cCompleted therapyd8721420+1.20.70 (0.40-1.19)+2.00.78 (0.58-1.04)HR+/≤1 yeare670664+2.70.41 (0.18-0.85)+2.10.79 (0.55-1.13)Completed therapyd402664+3.20.27 (0.08-0.69)+5.80.49 (0.29-0.78)HR+/≤1 yearb no pCRf131164+6.40.24 (0.04-0.92)+9.10.47 (0.23-0.92)Completed therapyd92164+6.90.16 (0.01-0.81)+13.20.29 (0.10-0.68)aOS analysis after a median follow-up of 8.0 (range 0-9.8) years; bDifference (neratinib vs placebo); cStratified by randomization stratification factors; dDefined as ≥11 months of therapy or ended treatment due to disease recurrence (neratinib arm), and all randomized subjects (placebo arm); eHR+ and ≤1 year after prior trastuzumab; fResidual disease post-neoadjuvant therapy. Abbreviations: CI, confidence interval; CNS-DFS, central nervous system disease-free survival; HR, hazard ratio; HR+, hormone receptor-positive; OS, overall survival; pCR, pathologic complete response. Citation Format: Frankie Ann Holmes, Debra Patt, Yvonne Manalo, Julie C Smith, Steven W Papish, Noa Efrat, Ana Arance, Bo Zhang, Deepa Lalla, Alvin Wong, Miguel Martin. Improved central nervous system outcomes in patients with early-stage HER2-positive breast cancer who receive neratinib for the recommended duration: Findings from the phase 3 ExteNET trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-21.

Background: Among patients (pts) with HER2+ early breast cancer (EBC), the CNS continues to serve as a sanctuary for distant metastases following trastuzumab-based adjuvant treatment (von Minckwitz 2017, Piccart 2020, von Minckwitz 2019). Since the initial trastuzumab adjuvant trials, several other HER2-directed agents, including pertuzumab, lapatinib, ado-trastuzumab emtansine, and neratinib have been evaluated in EBC. We sought to describe the incidence of CNS metastases as a site of first recurrence in pts with HER2+ EBC who have received a HER2 directed agent, in order to evaluate whether there is any evidence of CNS prevention. Methods: A literature analysis was performed to identify controlled pivotal trials of HER2-directed adjuvant therapy in pts with HER2+ EBC and with or without prior neoadjuvant therapy. Data regarding CNS metastases as the first site of recurrence was extracted along with data from a meta-analysis of trastuzumab adjuvant trials. Due to differences in trial design, populations studied and differences in the use of neoadjuvant therapy, a descriptive summary of data is presented in lieu of statistical cross-trial comparisons. Results: Results from adjuvant trials of trastuzumab, lapatinib, neratinib, pertuzumab, and ado-trastuzumab emtansine in pts with HER2+ EBC (meta-analysis of trastuzumab trials, ALLTO, ExteNET, APHINITY and KATHERINE, respectively) are summarized (Table). In the trastuzumab adjuvant trials the incidence of CNS metastases was ~2.5% (Olson 2013). No pts had prior neoadjuvant therapy in APHINITY and neoadjuvant use was limited in ALLTO (8%). The addition of lapatinib, a reversible TKI, or pertuzumab, a HER2 monoclonal antibody, to trastuzumab had no impact on the incidence of CNS metastases. In the lapatinib and pertuzumab studies, the incidence of CNS metastases in all study groups was ~2%. The proportion of pts with CNS recurrence as a first site of metastasis among placebo pts in the ExteNET trial was similar to that reported in the other 3 trials (Table). Numerical improvements in the incidence of CNS as a site of first recurrence were seen in the intention-to-treat (ITT) population as well as in pts with hormone receptor positive (HR+) disease. The 5-year cumulative incidence of CNS metastases as a site of first recurrence in the ExteNET ITT population was 1.3% and in pts with HR+ disease who initiated neratinib ≤1 year post trastuzumab (HR+/≤1yr) was 0.7% (Table). The KATHERINE study, which enrolled higher risk patients, reported a higher incidence of CNS metastases as site of first recurrence, but without a reduction in the intervention arm (5.9% ado-trastuzumab emtansine and 4.3% trastuzumab). In a descriptive analysis of the subgroup of pts in ExteNET who were HR+/≤1yr and had residual disease after neoadjuvant therapy (n=295), the incidence of CNS metastases was 0.8% in the neratinib arm vs 3.6% in the placebo arm. Conclusions: The risk of developing a CNS metastasis as the site of first recurrence is generally low; however, it is higher in those with residual disease after neoadjuvant therapy. The ExteNET trial of neratinib is the only study to show a signal decrease in the incidence of CNS recurrence as the first site of relapse among HER2+ EBC pts. These data are consistent with other trials showing CNS activity with neratinib in the metastatic setting. CNS Recurrence as the First Site of Metastasis in Studies of Adjuvant Therapy in HER2+ EBCTrial and PopulationAnalysis TimepointNNeoadjuvant Population CNS Recurrence, %ComparatorTreatmentAdjuvant trast Meta-analysis1-9020N/A1.942.56ALLTO23 yr5190~822ExteNET3ITT5 yr284026%1.81.3HR+/≤1yr post trast.5 yr133427%2.10.7APHINITY4 node (+) or high-risk node ()3 yr480501.91.9No pCR Post Neoadjuvant TxKATHERINE5 high-risk3 yr1486N/A4.35.9ExteNET3 HR+/≤1yr post trast5 yr295N/A3.60.8HR+/≤1yr, hormone receptor positive with start of neratinib ≤1 year following trastuzumab adjuvant therapy; ITT, intent-to-treat; PLB, placebo; T-DM1, ado trastuzumab emtansine; trast, trastuzumab; pCR, pathologic complete responsea.Using all patients in the trials as a denominator1.Olson 2013; 2. Piccart-Gebhart 2015; 3. Chan 2021; 4. Von Minckwitz 2017; 5. Mamounas 2020 Citation Format: Nancy U Lin, Diana Lueftner, Adam M Brufsky, Sara M Tolaney, Michelle E Melisko, Frankie Ann Holmes, Ahmad Awada. Central nervous system metastases as a site of first recurrence in adjuvant therapy trials of HER2+ early breast cancer (EBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-05.

All ADCC ratios from Figure 3 and trastuzumab/pertuzumab ADCC comparison

Densitometry analysis for Figure 6B

Figure S1: Forest plot of hazard ratios by subgroup in the ITT population (planned analysis) for (A) DFS and (B) OS

Figure S2: Distribution of central Ki-67 scores in (A) ER-positive/HER2-negative breast cancer (n=824) and (B) TNBC (n=454)

Purpose:Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2+) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC.Experimental Design:Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2+ (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array–determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry–based protocols.Results:Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy (P = 0.03) and associated with trastuzumab response (P = 0.01). TKI treatment altered mAb-induced NK cell–mediated ADCC in vitro, but it did not consistently correlate with HER2 expression in HER2+ or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone.Conclusions:TKIs differentially alter tumor cell phenotype which can impact NK cell–mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.

Densitometry for Figure 1D

Figure S3: Forest plots for DFS comparing patients with central Ki-67 high versus low based on quartile cutoffs (exploratory analysis) in (A) ER-positive/HER2-negative breast cancer (n=824) and (B) TNBC (n=454)

Densitometry analysis for Figure 6D/E

Flow cytometry MFI and % positive cells data for fluorescently labelled trastuzumab and pertuzumab in SKBR3, HCC1954, T47D and MCF-7 treated with TKIs

Rituximab ADCC negative control

Flow cytometry control scatter plots for trastuzumab-488 and pertuzumab-550

MFI comparison at T0 and T6 for T47D/MCF-7

Supplementary Tables S1-5. Table S1. Baseline demographic and disease characteristics of patients with central Ki-67 data available. Table S2. Concordance between central and local Ki-67 scores. Table S3. Percentage of patients with a DFS event or death in lobular versus ductal early breast cancer (exploratory analysis). Table S4. 7-year DFS and OS by central Ki-67 scores (exploratory analysis). Table S5. 5-year DFS and OS by local Ki-67 scores (exploratory analysis).

Purpose: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T).Experimental Design: Treatment comprised eight cycles of AC→T (T dose: 100 mg/m2 on day 1) or AC→XT (X dose: 825 mg/m2 twice daily, days 1–14; T dose: 75 mg/m2 on day 1). The primary endpoint was 5-year disease-free survival (DFS).Results: Of 2,611 women, 1,304 were randomly assigned to receive AC→T and 1,307 to receive AC→XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67–1.05; P = 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC→XT versus AC→T (HR, 0.68; 95% CI, 0.51–0.92; P = 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)–positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of Conclusions: The very low event rate in patients with ER-positive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients. Clin Cancer Res; 21(19); 4305–11. ©2015 AACR.

Densitometry for Figure 2B

Background: Neratinib, an oral, irreversible tyrosine kinase inhibitor of multiple human epidermal growth factor receptors (HERs), is indicated for the extended adjuvant treatment of adult patients with, HER2-positive early-stage breast cancer (eBC) to follow adjuvant trastuzumab-based therapy in the United States (US). However, greater efficacy has been seen in patients with hormone receptor-positive (HR+) breast cancer and who initiated neratinib within 1 year of completing trastuzumab. Objective: This study explores the cost-effectiveness of neratinib versus placebo from a US third-party payer perspective in adult patients with HR+ HER2-overexpressed/amplified eBC and who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy. Methods: A Markov model was constructed to model costs and health outcomes of neratinib and placebo over a lifetime horizon. The model consisted of five health states representing the primary stages of disease in eBC—disease-free, local recurrence, remission, distant recurrence, and dead—and corresponds to the primary and secondary endpoints in the neratinib ExteNET trial. Overall survival was modeled based on a combination of post-distant recurrence survival and general population mortality, assuming all cancer-related mortality would occur through the distant recurrence health state. Statistical extrapolation of invasive disease-free survival and post-distant recurrence survival were derived from the ExteNET clinical trial data as well as the proportion of local and distant recurrence and number of adverse events. Non-breast cancer-related mortality was derived from US life tables. Costs per treatment arm were calculated based on drug acquisition, administration, and monitoring costs as well as treatment costs for adverse events and health state-related medical resource use. Quality-adjusted life-years (QALYs) were estimated per health state, and disutilities were applied per adverse event independent of treatment. Utility values for the invasive disease-free survival health state and diarrhoea were estimated using the EQ-5D-3L data collected in ExteNET. Additional health state utilities and adverse events disutilities were identified from the literature. Costs were adjusted to 2020 US dollars. One-way (OWSA) and probabilistic sensitivity analyses (PSA) and scenario analyses were performed to investigate the robustness of the results. Further, analyses were performed to investigate the cost-effectiveness for the subgroup of patients who did not achieve a pathologic complete response (pCR) after neoadjuvant therapy. Results: The results of the base case analysis showed that, compared with placebo, neratinib treatment generated an additional 0.88 incremental QALYs, 0.99 incremental life-years, and a resulting cost per QALY gained of $56,367. The results were robust across multiple scenario analyses with incremental cost-effectiveness ratios (ICERs) below $70,000. OWSA showed that the parameters that most influenced the results were variations in treatment-related costs, efficacy, and health state utility values. The PSA indicated that the probability of neratinib being cost-effective at a $100,000 per QALY threshold was above 75%. The analysis for the subgroup of patients who did not achieve a pCR after neoadjuvant therapy resulted in an improved ICER. Conclusions: The current cost-effectiveness analysis shows that neratinib is a cost-effective therapy for treating adult patients with HR+ HER2-overexpressed/amplified eBC and who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy in the US and in patients who did not achieve a pCR after neoadjuvant treatment. Citation Format: Thor-Henrik Brodtkorb, Cheryl McDade, Deepa Lalla, Frankie Ann Holmes. Cost-effectiveness of neratinib for the extended adjuvant treatment of adult patients with early-stage, HR+, HER2-overexpressed/amplified breast cancer who initiated neratinib within 1 year of completing trastuzumab in the US [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-33.

Purpose: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2+) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC. Experimental Design: Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2+ (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array–determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry–based protocols. Results: Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy (P = 0.03) and associated with trastuzumab response (P = 0.01). TKI treatment altered mAb-induced NK cell–mediated ADCC in vitro, but it did not consistently correlate with HER2 expression in HER2+ or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone. Conclusions: TKIs differentially alter tumor cell phenotype which can impact NK cell–mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.

Purpose: To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor–positive (HR+) breast cancer. Patients and Methods: In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. Results: Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54–1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66–1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10–0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Conclusions: Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.

Expression of human epidermal growth factor receptor 2 (HER2) in breast cancer defines a subset of patients (∼15%-20%) who are candidates for anti-HER2 therapies, most notably, trastuzumab, pertuzumab, antibody drug conjugates (eg, T-DM1), and tyrosine kinase inhibitor (TKI) drugs (eg, lapatinib and neratinib), all of which have dramatically changed the prognosis for this aggressive subtype of breast cancer. A roundtable meeting of the Breast Cancer Therapy Expert Group (BCTEG) was convened in March 2018 in an effort to discuss and clarify, from the perspective of the practicing community oncologist, recent developments in the diagnosis and treatment of HER2-positive (HER2+) breast cancer. Members of the group selected 4 key topics for discussion prior to the meeting, including diagnosis of HER2+ disease, and its treatment in the neoadjuvant, adjuvant, and metastatic settings. Approved testing methods, such as immunohistochemistry and fluorescence in situ hybridization, are used to demonstrate overexpression and/or amplification of HER2 in breast tumors, and established clinical guidelines are used to appropriately define treatment plans for patients with HER2+ disease. The panel acknowledges a range of treatment options now available for treatment of HER2+ breast cancer in the neoadjuvant, adjuvant, and advanced/metastatic settings, although it is noted that many controversies remain, including the optimal sequence of therapies, the most appropriate treatment(s) for subsets of patients with HER2+ disease (eg, hormone receptor-negative or -positive/HER2+), and uncertainties surrounding the diagnosis and definition of HER2+ disease. The current report summarizes the discussion of the BCTEG panel on this topic.

To identify proteomic and genomic alterations in residual disease (RD) for human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC) after preoperative trastuzumab (H), lapatinib (L), or both (H+L) in combination with chemotherapy.Patients with stage II/III HER2+ BC (n = 100) were randomly assigned to preoperative treatment with H versus L 1,250mg versus H+L (L: 750 to 1,000 mg) plus 5-fluorouracil, epirubicin, and cyclophosphamide, followed by weekly paclitaxel. After receiving institutional review board-approved informed consent, targeted next-generation sequencing was performed on 20 patients' formalin-fixed paraffin embedded tumors to characterize genomic alterations across 287 cancer-related genes. Reverse phase protein array (RPPA) analysis was performed on both the baseline biopsy and RD specimens, when available.Two of 20 RD tissues were HER2 negative per next-generation sequencing; one sample had insufficient tissue. Of six pretreatment biopsy specimens, four were comutated withHER2-amplified RD tissue after preoperative H, L, or H+L plus chemotherapy was enriched for

PURPOSE To identify proteomic and genomic alterations in residual disease (RD) for human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC) after preoperative trastuzumab (H), lapatinib (L), or both (H+L) in combination with chemotherapy. PATIENTS AND METHODS Patients with stage II/III HER2+ BC (n = 100) were randomly assigned to preoperative treatment with H versus L 1,250mg versus H+L (L: 750 to 1,000 mg) plus 5-fluorouracil, epirubicin, and cyclophosphamide, followed by weekly paclitaxel. After receiving institutional review board–approved informed consent, targeted next-generation sequencing was performed on 20 patients’ formalin-fixed paraffin embedded tumors to characterize genomic alterations across 287 cancer-related genes. Reverse phase protein array (RPPA) analysis was performed on both the baseline biopsy and RD specimens, when available. RESULTS Two of 20 RD tissues were HER2 negative per next-generation sequencing; one sample had insufficient tissue. Of six pretreatment biopsy specimens, four were comutated with TP53 and PIK3CA. Of 17 HER2+ RD, seven specimens (41%) had PIK3CA mutations always comutated with TP53, and four (24%) also had concurrent CDK12 amplification. Overall, CDK12 amplification was observed in eight of the 17 (47%) HER2+ RD specimens. A total of 12 RD specimens (71%) had TP53 mutations. Although prevalence of individual TP53 and PIK3CA mutations was only modestly higher than published estimates for those in HER2+ primary BCs (55% and 32% for TP53 and PIK3CA, respectively), prevalence of these as comutations appeared higher (41%), compared with less than 10% in several series. On RPPA analysis of the RD tissue with comutations, the strongest Spearman ρ correlations were limited to EGFR and phospho-AKT (ρ, 0.999; P = .019) and phospho-mTOR and phospho-S6 ribosomal protein (ρ, 0.994; P = .048). CONCLUSION HER2-amplified RD tissue after preoperative H, L, or H+L plus chemotherapy was enriched for PIK3CA and TP53 comutations, and the RD tissue demonstrated activation of EGFR/AKT/mTOR signaling on RPPA.

The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Methods: Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Results: Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Conclusions: Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. Trial registration: ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

Treatment (tx) choices for HER2+ early stage breast cancer (EBC) have become increasingly complex. Clinicians and patients must decide 1) which chemotherapy and HER2-targeted agents to use, 2) the sequence of surgery and chemotherapy: either neoadjuvant (neoadj) or adjuvant (adj) tx, and 3) whether to shorten or extend maintenance HER2-targeted tx. As tx options expand, so does the need for online decision aids. One online decision support tool was developed in 2015 to provide specific tx recommendations for pts with EBC and showed that community healthcare providers (HCPs) did not consistently align with experts for neoadj or adj tx of many pts with EBC (SABCS 2015 Abs P5-09-04). This study includes analysis of neoadj and adj tx practice patterns of 5 breast cancer experts based on their tx recommendations for 270 unique HER2+ EBC case scenarios made for development of a 2018 online decision tool. We aim to compare these recommendations with the intended treatment of clinicians using the tool. Results Experts agree on neoadj tx approaches: initial surgery, no neoadj tx for pts with cT1a/b N0 tumors; neoadj tx before surgery for pts with ≥cT2 or N+ tumors. There was disparity among experts for pts with cT1c N0 disease: 3 experts recommend neoadj TCH±P and 2 recommend proceeding directly to surgery. Experts generally recommend adj TCHP for pts with stage II N+ or higher HER2+ EBC who did not receive neoadj tx. In addition, 5/5 experts would consider extended adj tx with neratinib for these pts if HR+ and 2/5 experts would also consider neratinib if HR–. In pts who received neoadj chemo+HER2 tx, post-surgery management depends on response to neoadj tx. For pts with pCR, 5/5 experts generally agree on continuing H+P if both were given as neoadj tx or H alone if only H given as neoadj tx for a total of 1 yr of anti-HER2 Ab tx and 2/5 experts would consider extended adj tx with neratinib for HR+ disease. For pts with residual disease, experts would recommend continuing H+P if both were given as neoadj tx and most would add P for subsequent adj tx if H alone was given to complete a total of 1 yr of anti-HER2 Ab tx (Table1). All experts would consider extended adj tx with neratinib for HR+ disease and 3/5 experts would also consider neratinib for HR– disease. None of the experts recommended less than 12 mos of adj HER2-targeted tx. We will present analyses of cases entered into our online tool and detailed comparisons of expert and the intended treatment of clinicians using the tool. Conclusions Practice patterns are changing rapidly and are more complex in response to the evolving treatment landscape for HER2+ EBC. This analysis highlights several areas of expert consensus; however, disparities remain for select cases. The current tool addresses an unmet medical need for expert-led evaluation of HER2+ EBC tx choices and warrants further investigation. Expert Recommendations: Initial Adj HER2 Ab Tx After Neodj Tx With H Alone ExpertsResponse12345pCR (HR-)HHHHHpCR (HR+)HHHHHypT1a-c N0 (HR-)H + PHH + PH + PH + PypT1a-c N0 (HR+)H + PHHH + PHypT2 N0 (HR-)H + PH + PH + PH + PH + PypT2 N0 (HR+)H + PH + PHH + PH + PypTany N+ (HR+ or HR-)H + PH + PH + PH + PH + P Citation Format: Holmes FA, Rosenthal KM, Hurvitz S, Pegram MD, Yardley DA, Obholz KL, O'Shaughnessy J. Consensus and disagreement among experts for treatment of patients with HER2+ early-stage breast cancer suggests unmet need for online decision support tool [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 P6-17-36.

Background Lapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells. Methods We examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer. Results In this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL-2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells. Conclusions Our findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies. Electronic supplementary material The online version of this article (10.1186/s12885-018-4852-1) contains supplementary material, which is available to authorized users.

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5‐fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2‐positive disease) and to evaluate 5‐year disease‐free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5‐fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21‐day cycles of docetaxel (35 mg/m2 days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2‐positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75‐H →wTX‐H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2‐negative breast cancer and of 67% in patients with HER2‐positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent‐to‐treat analysis, the pCR rate was 31% (37/118, 95% CI: 24–40%) in the HER2‐negative patients, 24% (15/62, 95% CI: 14–37%) in ER‐positive/HER2‐negative patients, 39% (22/56, 95% CI: 27–53%) in the ER‐negative/HER2‐negative patients, and 46% (29/63, 95% CI: 34–48%) in the HER2‐positive patients. The pCR rate in the 40 trastuzumab‐treated patients was 53% (21/40, 95% CI: 38–67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand‐foot skin reactions. One trastuzumab‐treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1–2 decrements in left ventricular function; all five patients’ cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease‐free survival was 70% in the HER2‐negative population (78% in ER‐positive/HER2‐negative and 62% in the ER‐negative/HER2‐negative patients) and 80% in the HER2‐positive patients (87% in the trastuzumab‐treated HER2‐positive patients). At 5 years, overall survival was 80% in the HER2‐negative population (88% in ER‐positive/HER2‐negative and 71% in the ER‐negative/HER2‐negative patients) and 86% in the HER2‐positive patients (94.5% in the trastuzumab‐treated HER2‐positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5‐year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.

Background: The international, randomized, placebo-controlled phase III ExteNET trial showed that a 1-year course of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in patients with early-stage HER2+ breast cancer (BC) (hazard ratio 0.67; 95% CI 0.50–0.91; p=0.009) [Chan et al. Lancet Oncol 2016]. The significant iDFS benefit with neratinib was maintained after a median 5 years' follow-up (hazard ratio 0.73; 95% CI 0.57-0.92; p=0.008) [Martin et al. ESMO 2017]. At both time-points, marked benefit with neratinib was evident in patients with hormone receptor (HR)+ tumors, whereas in patients with HR– disease, initial improvements with neratinib diminished after completing treatment. We report exploratory analyses from the ExteNET trial done to better characterize the effects of neratinib in the HR+ subgroup. Methods: Patients with early-stage HER2+ BC were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year after standard primary therapy and trastuzumab-based adjuvant therapy. Randomization was stratified by HR status (locally assessed), nodal status, and trastuzumab regimen. Adjuvant endocrine therapy was recommended for patients with HR+ disease. Data concerning disease recurrences were collected prospectively during year 1-2 post-randomization, and from medical records during year 3–5 post-randomization. Primary endpoint: iDFS. Secondary endpoints: DFS including ductal carcinoma in situ (DFS-DCIS); time to distant recurrence (TTDR); distant DFS (DDFS); cumulative incidence of central nervous system (CNS) recurrences; overall survival (OS). Hazard ratios (95% CI) were estimated using Cox proportional-hazards models. Data cut-off: March 2017. Clinicaltrials.gov: NCT00878709. Results: 2840 patients were randomized (neratinib, n=1420; placebo, n=1420); 1631 (57%) patients had HR+ tumors (neratinib, n=816; placebo, n=815). 93% and 94% of HR+ patients in the neratinib and placebo groups, respectively, were receiving adjuvant endocrine therapy at baseline. Efficacy outcomes in the HR+ cohort after a median follow-up of 5.2 years are shown in the table. In subgroup analyses of the HR+ cohort, hazard ratios for iDFS were 0.49 in centrally confirmed HER2+ patients (n=951), and 0.58 in patients who had completed prior trastuzumab ≤12 months before randomization (n=1334). CNS recurrence and OS data are not yet mature. Updated 2-year analysis5-year analysis Hazard ratiobP-value Hazard ratiobP-value Δ, %a(95% CI)(2 sided)Δ, %a(95% CI)(2 sided)iDFS4.10.49 (0.31–0.75)0.0014.40.60 (0.43–0.83)0.002DFS-DCIS4.80.45 (0.29–0.69) Conclusions: Neratinib was associated with an absolute iDFS benefit of 4.4% in patients with HR+/HER2+ BC after 5 years' follow-up. HR/HER2 receptor cross-talk may underpin the notable effect of neratinib in patients with HR+ tumors when given in combination with endocrine therapy. Citation Format: Chia SKL, Martin M, Iwata H, Moy B, Lalani AS, Holmes FA, Mansi J, von Minckwitz G, Buyse M, Delaloge S, Ejlertsen B, Yao B, Murias Rosales A, Hellerstedt B, Cold S, Inoue K, Shen Z-Z, Galeano T, Barrios CH, Chan A. Effects of neratinib after trastuzumab-based adjuvant therapy in hormone receptor-positive HER2+ early-stage breast cancer: Exploratory analyses from the phase III ExteNET trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-03.

Background: Neratinib is a pan-HER tyrosine kinase inhibitor that blocks the PI3K/Akt and MAPK signaling pathways downstream from HER2. The international, randomized, placebo-controlled phase III ExteNET trial showed that a 1-year course of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in early-stage HER2+ breast cancer (HR 0.67; 95% CI 0.50–0.91; p=0.0091) [Chan et al. Lancet Oncol 2016]. Furthermore, the effects of neratinib on iDFS were shown to be durable at 5 years' follow-up (HR 0.73; 95% CI 0.57–0.92; p=0.008) [Martin et al. ESMO 2017]. PIK3CA alterations are common in HER2+ breast cancers, and in general are associated with a worse prognosis. We sought to assess the prognostic and predictive significance of PIK3CA alterations in an exploratory substudy of the ExteNET trial. Methods: ExteNET is an international, multi-center, randomized, double-blind, placebo-controlled phase III trial (Clinicaltrials.gov: NCT00878709). Patients received oral neratinib 240 mg/day or placebo for 1 year. Of the intent-to-treat (ITT) population (n=2840), primary formalin-fixed paraffin-embedded (FFPE) tumor specimens were available from 991 patients for PIK3CA mutation testing by RT-PCR for two hot-spot mutations in exon 9 (E542K, E545K/D) and one hot-spot mutation in exon 20 (H1047R). 702 FFPE tumor slides underwent FISH analysis for PIK3CA amplification with a ratio of ≥2.2 considered as amplified. Primary endpoint: iDFS. iDFS events were tested by 2-sided log-rank tests, and HR (95% CI) were estimated using Cox proportional-hazards models. Data cut-off: March 2017. Results: Baseline demographics and disease characteristics between treatment arms of the correlative cohort (n=1201) were balanced. Overall, 21.2% (n=210) of primary tumors harbored one of the specified PIK3CA mutations, and 8.7% (n=61) were PIK3CA FISH-amplified. Patients with PIK3CA-altered tumors (i.e. PIK3CA mutations or FISH-amplified) had fewer iDFS events with neratinib compared with placebo (HR 0.41; 95% CI 0.17-0.90, p=0.028). The interaction test was not significant (p=0.1842). Results of the various correlative analyses within treatment arms are shown in the table. NeratinibPlacebo iDFS iDFS 2-sidedPopulationnevents, nnevents, nHR (95% CI)P valueaITT142011614201630.73 (0.57–0.92)b0.008bCorrelative cohort59345608700.67 (0.45–0.96)0.0317PIK3CA-mutation positive1047106170.43 (0.17–1.01)0.056PIK3CA-mutation negative38527396420.66 (0.40-1.06)0.089PIK3CA-amplified3312840.20 (0.01-1.33)0.106PIK3CA-non-amplified31629325360.85 (0.52-1.39)0.521PIK3CA-altered1308132200.41 (0.17-0.90)0.028a. Log-rank test; b. Stratified analysis Conclusions: One year of neratinib treatment after trastuzumab-based adjuvant therapy significantly improves iDFS after 5 years in patients with early-stage HER2+ breast cancer. From this modest-sized exploratory cohort, it appears that PIK3CA may be a biomarker for differential sensitivity to neratinib after 1 year of trastuzumab in the adjuvant setting.These exploratory results should be validated in a larger subset. Citation Format: Chia SKL, Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Kim S-B, Hugger Jakobsen E, Harvey V, Robert N, Smith II J, Harker G, Lalani AS, Zhang B, Eli LD, Buyse M, Chan A. PIK3CA alterations and benefit with neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: Correlative analyses of the phase III ExteNET trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-12.

Background: The international, randomized, placebo-controlled phase III ExteNET trial showed that 1 year of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in early-stage HER2+ breast cancer (HR 0.67; 95% CI 0.50–0.91; p=0.009) [Chan et al. Lancet Oncol 2016]. The significant iDFS benefit with neratinib was maintained after a median of 5 years' follow-up (HR 0.73; 95% CI 0.57-0.92; p=0.008) [Martin et al. ESMO 2017]. We present exploratory analyses from the ExteNET trial examining the effects of the interval between completion of trastuzumab and randomization to commence neratinib on iDFS. Methods: Women with early-stage HER2+ breast cancer were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year after standard primary therapy and trastuzumab-based adjuvant therapy. Under the original study protocol, (neo)adjuvant trastuzumab was to be completed ≤24 months before randomization; this was revised to ≤12 months before randomization after the NCCTG-N9831/NSABP B-31 4-year analysis showed that the risk of relapse is greatest during the first 12 months after completing trastuzumab. Disease recurrences were collected prospectively during 1 and 2 years post-randomization, and from medical records during 3–5 years post-randomization. Patients randomized ≤12 months after completion of adjuvant trastuzumab were further separated to look at those who initiated neratinib ≤6 months of completing adjuvant trastuzumab. Primary endpoint: iDFS. HR (95% CI) estimated using Cox proportional-hazards models. Data cut-off: March 1, 2017. Clinicaltrials.gov: NCT00878709. Results:The intention-to-treat population comprised 2840 patients (neratinib, n=1420; placebo, n=1420). Median time from last trastuzumab dose to randomization was 4.4 and 4.6 months in the neratinib and placebo groups, respectively. 81% of patients were randomized ≤12 months of completing trastuzumab. The effects of the interval between the last dose of trastuzumab and randomization/initiation of neratinib on iDFS after a median follow-up of 5.2 years are shown in the table. Estimated 5-year iDFS rate, % P-valueInterval from last dose of trastuzumab to randomizationnNeratinibPlaceboHR (95% CI)a(2-sided)≤6 months164190.085.40.62 (0.46–0.84)0.002≤12 monthsb229789.786.50.70 (0.54–0.90)0.006>12 monthsb54392.392.61.00 (0.51–1.94)0.992a. Neratinib vs placebo; b. Protocol-defined subgroups Conclusions: In ExteNET, patients who initiated neratinib within 12 months of completing trastuzumab-based adjuvant therapy appeared to derive greater benefit from treatment than those who started neratinib later. Further, exploratory analyses suggest that the magnitude of benefit with neratinib is greater if initiated sooner (i.e. within 6 months of completing trastuzumab). Given the benefits of neratinib overall in those initiating treatment ≤12 months from the end of adjuvant trastuzumab, extended adjuvant treatment with neratinib should be initiated early following completion of trastuzumab. Citation Format: Ejlertsen B, Chan A, Gnant M, von Minckwitz G, Delaloge S, Buyse M, O'Shaughnessy J, Mansi J, Moy B, Iwata H, Wong A, Ye Y, Means-Powell J, Hui R, Ruiz-Borrego M, Ruiz Simon A, Shen Z-Z, Holmes FA, Lesniewski-Kmak K, Martin M. Timing of initiation of neratinib after completion of trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: Exploratory analyses from the phase III ExteNET trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-05.

Background: The androgen receptor (AR) is expressed in >75% of hormone receptor (HR)+ tumors. AR signaling has been associated with resistance to endocrine therapy (ET). Aromatase inhibitors (AIs) divert estrogen precursors to androgens; in preclinical models enzalutamide (ENZA) blocked both estrogen- and androgen-mediated growth of HR+ cells. In a phase 1 study of ET+ENZA in breast cancer, doubling the dose of exemestane (EXE) to 50 mg was necessary to restore exposure observed with 25 mg.1 Methods: This placebo (PBO)–controlled phase 2 trial randomized patients (pts) with HR+/HER2-normal advanced/metastatic breast cancer (MBC) to either 25 mg EXE+PBO or 50 mg EXE+160 mg ENZA daily (NCT02007512). Two parallel cohorts enrolled pts who had no prior ET (C1) or who had received 1 prior ET for MBC (C2). Randomization was stratified on resistance to prior ET and prior exposure to AI. Tissue samples for biomarker development were mandatory. Brain metastases or a history of seizure was exclusionary. One prior chemotherapy regimen for MBC was permitted. Response was assessed every 8 weeks for 48 weeks, then every 12 weeks. Crossover to ENZA+EXE was allowed at disease progression. A gene signature–based biomarker (Bmkr) indicating AR signaling predictive of response to ENZA was developed using a training set of RNAseq data from 2/3 of randomized pts and validated using a test set of data from the remaining 1/3 of pts. Progression-free survival (PFS) according to RECIST v1.1 was the primary endpoint in the intent-to-treat (ITT) population and in the Bmkr+ subgroup of each cohort. Secondary endpoints included clinical benefit rate at 24 weeks (CBR24), best overall response, and safety. Results: A total of 247 pts were randomized (C1, n=127; C2, n=120). In C1, 50 pts (39.4%) were Bmkr+; in C2, 35 pts (29.2%) were Bmkr+. Statistically significant improvements in median PFS and CBR24 were observed only in the Bmkr+ population with no prior ET (Table). The most common adverse events (AEs) reported in the ENZA+EXE arms were nausea (39%) in C1 and fatigue (37%) in C2. In C1, 9 pts (15%) and 10 pts (16%) discontinued the study due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. In C2, 11 pts (18%) and 5 pts (8%) discontinued due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. Conclusions: In the first reported randomized trial of ENZA in HR+ MBC, ENZA+EXE was well tolerated with no new safety signals. The study met its primary endpoint in pts with Bmkr+ MBC with no prior ET. 1. Schwartzberg et al. Clin Cancer Res. 2017 Mar 9 [Epub ahead of print]. C1: No Prior ETC2: 1 Prior ET ITTBmkr+ITTBmkr+EXE+ENZA | PBOENZA | PBOENZA | PBOENZA | PBO n=63 | n=64n=24 | n=26n=60 | n=60n=15 | n=20Primary endpointPFS, median, months11.8 | 5.816.5 | 4.33.6 | 3.96.0 | 5.3(95% CI)(7.3, 15.9) | (3.5, 10.9)(11.0, NR) | (1.9, 10.9)(1.9, 5.5) | (2.6, 5.4)(2.3, 26.7) | (1.8, 6.7)Hazard ratio0.820.441.020.55(95% CI)(0.54, 1.26)(0.21, 0.96)(0.66, 1.59)(0.23, 1.36)P value0.36310.03350.92120.1936Secondary endpointCBR24, n (%)39 (62) | 29 (45)20 (83) | 10 (38)12 (20) | 19 (32)6 (40) | 6 (30)(95% CI)(49, 74) | (33, 58)(63, 95) | (20, 59)(11, 32) | (20, 45)(16, 68) | (12, 54)P value0.06090.00120.14430.5374 Citation Format: Krop I, Abramson V, Colleoni M, Traina T, Holmes F, Estevez L, Hart L, Awada A, Zamagni C, Morris P, Schwartzberg L, Chan S, Wheatley D, Gucalp A, Biganzoli L, Steinberg J, Gianni L, Trudeau M, Tudor IC, Markova D, Barry E, Tarazi J, Stewart R, Winer E, Yardley DA. Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-07.

Background Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2 − metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial. Patients and Methods In the present prospective analysis of hormone receptor-positive (HR + )/HER2 − and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m 2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity. Results We enrolled 54 HR + and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR + and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane-pretreated patients (ORR, 31.4% and 28.6% for HR + and TN patients, respectively). The median OS was 17.9 months for HR + patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment. Conclusion Ixabepilone plus carboplatin is active even in later-line HR + and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.

// John O’Shea 1 , Mattia Cremona 1 , Clare Morgan 1 , Malgorzata Milewska 1 , Frankie Holmes 2 , Virginia Espina 3 , Lance Liotta 3 , Joyce O’Shaughnessy 4 , Sinead Toomey 1 , Stephen F. Madden 5 , Aoife Carr 1 , Naomi Elster 1 , Bryan T. Hennessy 1, * and Alex J. Eustace 1, * 1 Department of Medical Oncology, Royal College of Surgeons in Ireland, Beaumont Hospital, Beaumont, Ireland 2 Texas Oncology-Memorial Hermann Memorial City, US Oncology Research, Houston, TX, USA 3 George Mason University, Manassas, VA, USA 4 Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX, USA 5 Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland * These authors have contributed equally to this work Correspondence to: Bryan T. Hennessy, email: bryanhennessy74@gmail.com Keywords: MEK inhibitor, HER2-positive breast cancer, acquired resistance to HER2-targeted therapies, reverse phase protein array Received: August 25, 2016 Accepted: June 02, 2017 Published: July 22, 2017 ABSTRACT Purpose: The MEK/MAPK pathway is commonly activated in HER2-positive breast cancer, but little investigation of targeting this pathway has been undertaken. Here we present the results of an in vitro preclinical evaluation of refametinib, an allosteric MEK1/2 inhibitor, in HER2-positive breast cancer cell lines including models of acquired resistance to trastuzumab or lapatinib. Methods: A panel of HER2-positive breast cancer cells were profiled for mutational status and also for anti-proliferative response to refametinib alone and in combination with the PI3K inhibitor (PI3Ki) copanlisib and the HER2-targeted therapies trastuzumab and lapatinib. Reverse phase protein array (RPPA) was used to determine the effect of refametinib alone and in combination with PI3Ki and HER2-inhibitors on expression and phosphorylation of proteins in the PI3K/AKT and MEK/MAPK pathways. We validated our proteomic in vitro findings by utilising RPPA analysis of patients who received either trastuzumab, lapatinib or the combination of both drugs in the NCT00524303/LPT109096 clinical trial. Results: Refametinib has anti-proliferative effects when used alone in 2/3 parental HER2-positive breast cancer cell lines (HCC1954, BT474), along with 3 models of these 2 cell lines with acquired trastuzumab or lapatinib resistance (6 cell lines tested). Refametinib treatment led to complete inhibition of MAPK signalling. In HCC1954, the most refametinib-sensitive cell line (IC 50 = 397 nM), lapatinib treatment inhibits phosphorylation of MEK and MAPK but activates AKT phosphorylation, in contrast to the other 2 parental cell lines tested (BT474-P, SKBR3-P), suggesting that HER2 may directly activate MEK/MAPK and not PI3K/AKT in HCC1954 cells but not in the other 2 cell lines, perhaps explaining the refametinib-sensitivity of this cell line. Using RPPA data from patients who received either trastuzumab, lapatinib or the combination of both drugs together with chemotherapy in the NCT00524303 clinical trial, we found that 18% (n=38) of tumours had decreased MAPK and increased AKT phosphorylation 14 days after treatment with HER2-targeted therapies. The combination of MEK inhibition (MEKi) with refametinib and copanlisib led to synergistic inhibition of growth in 4/6 cell lines tested (CI @ED 75 = 0.39-0.75), whilst the combinations of lapatinib and refametinib led to synergistic inhibition of growth in 3/6 cell lines (CI @ED 75 = 0.39-0.80). Conclusion: Refametinib alone or in combination with copanlisib or lapatinib could represent an improved treatment strategy for some patients with HER2-positive breast cancer, and should be considered for clinical trial evaluation. The direct down-regulation of MEK/MAPK but not AKT signalling by HER2 inhibition (e.g. by lapatinib or trastuzumab), which we demonstrate occurs in 18% of HER2-positive breast cancers may serve as a potential biomarker of responsiveness to the MEK inhibitor refametinib.

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.

Background: Neratinib (NERLYNX®) is an irreversible pan-HER inhibitor that significantly improves invasive disease-free survival (iDFS) compared with placebo when given as extended adjuvant therapy in patients with HER2-positive (HER2+) early breast cancer after trastuzumab-based adjuvant therapy. In the phase 3 ExteNET trial, an absolute iDFS benefit of 2.5% and distant disease-free survival (DDFS) benefit of 1.7% were observed with neratinib after 5 years’ follow-up. As reflected in the approved indication by the European Medicines Agency (EMA), patients with hormone receptor-positive (HR+) disease who initiated neratinib treatment within 1 year of completing trastuzumab (HR+/≤1 year) experienced an absolute iDFS benefit of 5.1% and DDFS benefit of 4.7% at 5 years. In HR+/≤1 year patients with residual disease after neoadjuvant therapy, absolute 5-year iDFS and DDFS benefits of 7.4% and 7.0%, respectively, were observed. Here we report the final protocol-defined, event-driven analysis of overall survival (OS) from ExteNET, and provide descriptive analyses of subgroups of primary interest according to the EU label and current clinical practice in early-stage HER2+ disease. Methods: ExteNET was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of women with early-stage HER2+ breast cancer who had completed neoadjuvant or adjuvant trastuzumab plus chemotherapy (NCT00878709). Patients were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year. Hazard ratios (HR) for OS were estimated from Cox proportional hazards models, and survival rates by the Kaplan-Meier method. The OS analysis was event-driven and powered for the intention-to-treat (ITT) population with a target of 248 events. Descriptive analyses were performed in the HR+/≤1 year subgroup per the approved indication in the EU, and in higher-risk patients, i.e. HR+/≤1 year who have residual disease after neoadjuvant therapy [i.e. those who did not achieve a pathologic complete response (pCR)]. Cut-off date: July 2019. Results: 2840 patients were randomized to study treatment (1420 per group). After a median follow-up of 8.1 years, 127 (8.9%) and 137 (9.6%) patients in the neratinib and placebo ITT groups had died, respectively. The 8-year OS rates were 90.1% (95% CI, 88.3–91.6) in the neratinib group and 90.2% (95% CI, 88.4–91.7) in the placebo group (absolute difference at 8 years -0.1%; stratified HR=0.95; 95% CI, 0.75–1.21; p=0.6914). A positive trend was seen in the prespecified HR+ subgroup (n=1631; absolute difference at 8 years 1.5%; HR=0.80; 95% CI, 0.58–1.12), and within this population, descriptive analyses suggested greater benefits with neratinib in the HR+/≤1 year subgroup (n=1334; absolute difference at 8 years 2.1%; HR=0.79; 95% CI, 0.55–1.13) and in the HR+/≤1 year subset with no pCR after neoadjuvant therapy (n=295; absolute difference at 8 years 9.1%; HR=0.47; 95% CI, 0.23–0.92). No new safety signals were reported with this long-term follow-up to 8 years. Conclusions: In this final OS analysis of ExteNET, there were fewer deaths with neratinib than placebo in the ITT population, but the results did not reach statistical significance. Analyses showed greater OS improvements with neratinib in subgroups including HR+/≤1 year, and HR+/≤1 year with residual disease after neoadjuvant therapy. These findings are consistent with the results based on the primary endpoint of iDFS, and support the use of neratinib in clinical practice in these patients. Citation Format: Frankie Ann Holmes, Beverly Moy, Suzette Delaloge, Stephen Chia, Bent Ejlertsen, Janine Mansi, Hiroji Iwata, Michael Gnant, Mark Buyse, Carlos Barrios, Tajana Silovski, Robert Separovic, Anna Bashford, Angel Guerrero-Zotano, Neelima Denduluri, Debra Patt, Erhan Gokmen, Ira Gore, John Smith, Richard Bryce, Feng Xu, Alvin Wong, Miguel Martin, Arlene Chan. Continued efficacy of neratinib in patients with HER2-positive early-stage breast cancer: Final overall survival analysis from the randomized phase 3 ExteNET trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-03.

Purpose This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor–positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. Patients and Methods Women age 40 to 49 with estrogen receptor–positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for ≥ 1 year were treated with letrozole (2.5 mg) daily for ≥ 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. Results The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naïve patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. Conclusion These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.

Summary Background Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. Methods We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1–3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2–3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1–3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. Findings Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20–25) in the neratinib group and 24 months (22–25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50–0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4–95·2) in the neratinib group and 91·6% (90·0–93·0) in the placebo group. The most common grade 3–4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [ vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [ vs n=2 [ Interpretation Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. Funding Wyeth, Pfizer, Puma Biotechnology.

To provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community. A recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice. Level 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2−, mBC. Currently, there are no biomarkers that reliably define patients who will, or will not, benefit from the addition of a CDK 4/6 inhibitor to their endocrine therapy. Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as the optimal duration of therapy; at present, evidence suggests that use in the upfront setting is better than waiting for a later line of therapy, or adding after endocrine therapy has started. Thus far, three CDK 4/6 inhibitors—palbociclib, ribociclib, and more recently, abemaciclib—have been approved for use in the setting of HR+, HER2−, mBC. The degrees to which these agents differ in terms of CDK4/6 affinity, side-effect profiles, dosing, degree of central nervous system (CNS) penetration, optimal use in combination with antiestrogen therapy, and across other subsets of breast cancer, remain an active area of investigation.

Purpose: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T). Experimental Design: Treatment comprised eight cycles of AC→T (T dose: 100 mg/m2 on day 1) or AC→XT (X dose: 825 mg/m2 twice daily, days 1–14; T dose: 75 mg/m2 on day 1). The primary endpoint was 5-year disease-free survival (DFS). Results: Of 2,611 women, 1,304 were randomly assigned to receive AC→T and 1,307 to receive AC→XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67–1.05; P = 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC→XT versus AC→T (HR, 0.68; 95% CI, 0.51–0.92; P = 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)–positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of Conclusions: The very low event rate in patients with ER-positive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients. Clin Cancer Res; 21(19); 4305–11. ©2015 AACR.

Background: MM-121 is a fully human monoclonal antibody that targets ErbB3 and blocks heregulin (HRG), the principal ligand for ErbB3, from binding. HRG-driven ErbB3 signaling has been widely implicated in the development of resistance to conventional chemotherapies and targeted agents. Recently, as part of a broader Phase 2 program designed to identify responders to MM-121, HRG was identified as a key biomarker that correlates with poor response to standard-of-care therapies and benefit from co-treatment with MM-121 in the metastatic setting in patients with NSCLC, ovarian cancer and breast cancer. Here we present data on the impact of HRG and MM-121 co-treatment in the pre-operative setting in HER2- breast cancer. Methods: Patients enrolled had locally advanced HR+, HER2-negative invasive breast cancer (Group 1) or TN (Group 2), no distant metastatic disease, no prior treatment for the disease under study, and ≥T2. Patients were randomized in a 2:1 fashion to receive MM-121 plus paclitaxel or paclitaxel alone followed by doxorubicin and cyclophosphamide, followed by surgery. The primary endpoint of this study was to describe pCR rates, defined as the absence of invasive cancer in the breast and lymph nodes (i.e. ypT0, ypN0). Residual cancer burden index (RCBI) was also recorded for each patient. Pre- and post-treatment tumor biopsies were collected in order to assess the levels of HRG and other potential biomarkers. Results: 200 patients (101 HR+, 99 TN) entered the study. For Group 1 (HR+), 96 of the 101 patients were Efficacy Evaluable (EE) and the pCR rate in the MM-121 treatment arm was 7/66 (10.6%, 95% CI [5.2%, 20.3%]) compared to 1/30 (3.3%, 95% CI [0.6%, 16.7%]) on the control arm. For Group 2 (TN), 85 of the 99 patients were Efficacy Evaluable (EE) and the pCR rate in the MM-121 treatment arm was 23/56 (41.1%, 95% CI [29.2%, 54.1%]) compared to 14/29 (48.3%, 95% CI [31.4%, 65.6%]) on the control arm. Preliminary analysis of pretreatment biopsies (52% of samples analyzed) suggests a potential link between HRG levels and both pCR rates and RCBI. For both groups, the overall incidence of adverse events, regardless of relationship, was comparable between the two arms. A higher frequency of any grade AEs (Treatment vs. Control) was reported for diarrhea, rash, stomatitis, fatigue, epistaxis, nail disorder and dysgeusia. A higher frequency of Grade 3 or higher AEs (Treatment vs. Control) was reported for febrile neutropenia (HR+: 10.4% vs. 3.0%), diarrhea (HR+: 7.5% vs. 0%, TN: 7.8% vs. 0%), fatigue (HR+: 6.0% vs. 3.0%), anemia (HR+: 7.5% vs. 3.0%, TN: 7.8% vs. 3.1%), hypokalemia (HR+: 7.5% vs. 3.0%), infusion-related reactions (TN: 4.7% vs. 0%), pulmonary embolisms (TN: 4.7% vs. 0%), and hyperglycemia (TN: 4.7% vs. 0%). Conclusion: Although a potential signal of benefit from MM-121 was observed in the HR+ group, the same was not observed in the TN group, and overall the results are inconclusive. Biomarker analyses, including pharmacodynamics studies, are ongoing. The observed safety profile is consistent with the expected toxicities associated with ErbB inhibitors and weekly paclitaxel, and did not impact exposure or compliance on treatment. Citation Format: Frankie A Holmes, Kristi J McIntyre, Ian E Krop, Cynthia R Osborne, John W Smith II, Manuel R Modiano, Manish Gupta, Leona B Downey, Rita Nanda, Mansoor N Saleh, Jonathan R Young, Kerry E Horgan, William Kubasek, Gavin MacBeath, Michael A Danso, Joyce A O'Shaughnessy. A randomized, phase 2 trial of preoperative MM-121 with paclitaxel in triple negative (TN) and hormone receptor (HR) positive, HER2-negative breast cancer [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 P3-11-03.

Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial.To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects.Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized.Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device.The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale.At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events.Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects.clinicaltrials.gov Identifier: NCT01986140.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

e12037 Background: Disease-free survival (DFS) in patients with EBC has improved over time. Trials of systemic agents for adj rx of HER2+ BC, including chemotherapies (CT), endocrine, and HER2-targeted agents have reported improved DFS. This review is a high-level overview describing DFS improvements in adj rx HER2+ BC. Methods: Therapeutic agents listed in NCCN guidelines for adj rx HER2+ BC were evaluated for relative and absolute improvements in DFS. Information was derived from US product labels and publications. Hazard ratios, 95% CI, p-values, and DFS differences at 2 and 5 years (if available) are reported. Results: At 2−3 years, adj rx of HER2+ BC with CT and HER2 treatments reported DFS improvements of 4−5% and 0.9−11.3%, respectively. For hormone receptor positive (HR+) BC, unselected by HER2 status, extended adj letrozole had a 1.9% DFS improvement at 2 years; in HR+ HER2+ BC, extended adj neratinib had 4.5% DFS at 2 years. Conclusions: Relative and absolute improvements in DFS in the adj rx BC setting have been largely incremental and cumulative. Absolute improvements in DFS were 0.9−11.3% with CT, HER2 agents, and AIs. In the subset of HR+ / HER2-positive patients, neratinib showed higher DFS improvement compared to non-steroidal AIs. Similar hazard ratios did not always correspond to similar DFS improvements, possibly reflecting differences in baseline risks in the study populations. [Table: see text]