Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study.

PURPOSE: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. PATIENTS AND METHODS: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. RESULTS: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. CONCLUSION: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

HER2 heterogeneity and treatment response-associated profiles in HER2-positive breast cancer in the NCT02326974 clinical trial.

BACKGROUNDHER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR).METHODSTo investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to NanoString spatial digital profiling.RESULTSPretreatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HER2 heterogeneity was associated with no pCR, basal-like features, and low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared with non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status.CONCLUSIONResistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT02326974.FUNDINGThis study was funded by Roche and the National Cancer Institute.

TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS: We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS: Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION: In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02876302. Registered 23 August 2016.

Prediction of Benefit From Adjuvant Pertuzumab by 80-Gene Signature in the APHINITY (BIG 4-11) Trial.

PURPOSE: At the primary analysis, the APHINITY trial reported a statistically significant but modest benefit of adding pertuzumab to standard adjuvant chemotherapy plus trastuzumab in patients with histologically confirmed human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer. This study evaluated whether the 80-gene molecular subtyping signature (80-GS) could identify patients within the APHINITY population who derive the most benefit from dual anti-HER2 therapy. METHODS: In a nested case-control study design of 1,023 patients (matched event to control ratio of 3:1), the 80-GS classified breast tumors into functional luminal type, HER2 type, or basal type. Additionally, 80-GS distinguished tumor subtypes that exhibited a single-dominant functional pathway versus tumors with multiple activated pathways. The primary end point was invasive disease-free survival (IDFS). Hazard ratios (HRs) were evaluated by Cox regression. After excluding patients without appropriate consent and those with missing data, 964 patients were included. RESULTS: The 80-GS classified 50% (n = 479) of tumors as luminal type, 28% (n = 275) as HER2 type, and 22% (n = 209) as basal type. Most luminal-type tumors (86%) displayed a single-activated pathway, whereas 49% of HER2-type and 42% of basal-type tumors were dual activated. There was no significant difference in IDFS among different conventional 80-GS subtypes (single- and dual-activated subtypes combined). However, basal single-subtype tumors were significantly more likely to have an IDFS event (hazard ratio, 1.69 [95% CI, 1.12 to 2.54]) compared with other subtypes. HER2 single-subtype tumors displayed a trend toward greater beneficial effect on the addition of pertuzumab (hazard ratio, 0.56 [95% CI, 0.27 to 1.16]) compared with all other subtypes. CONCLUSION: The 80-GS identified subgroups of histologically confirmed HER2-positive tumors with distinct biological characteristics. Basal single-subtype tumors exhibit an inferior prognosis compared with other subgroups and may be candidates for additional therapeutic strategies. Preliminary results suggest patients with HER2-positive, genomically HER2 single-subtype tumors may particularly benefit from added pertuzumab, which warrants further investigation.

Axillary Nodal Response to Neoadjuvant T-DM1 Combined with Pertuzumab in a Prospective Phase II Multi-Institution Clinical Trial.

BACKGROUND: Patients with ERBB2 (HER2)-positive breast cancer experience high pathologic complete response (pCR) rates after standard neoadjuvant anti-HER2 systemic therapy. We examined axillary pathologic nodal response to neoadjuvant dual HER2-targeted therapy alone, based on breast pathologic response, in a multi-institution clinical trial. STUDY DESIGN: Patients with HER2-positive breast cancer were enrolled to a phase II single-arm trial, which administered 6 cycles of neoadjuvant trastuzumab emtansine (T-DM1) plus pertuzumab. Rates of pathologic nodal disease (ypN) in patients who were clinically node-negative (cN0) and node-positive (cN1) were analyzed, by residual breast disease (pCR and residual cancer burden [RCB] I to III). RESULTS: One hundred fifty-eight patients completed preoperative treatment and proceeded to surgery. Of 92 patients who were cN0, 48 (52.2%) and 10 (10.9%) experienced breast pCR and RCB I, respectively. Of these, 100% were ypN0. Of 34 with RCB II to III, 26 (76.5%) were ypN0. Of 30 patients who were cN1 with breast pCR, 100% were ypN0; of the 12 patients who were cN1 with RCB I, 66.7% were ypN0; and of the 24 patients who were cN1 with RCB II to III, 25% were ypN0. ypN0 rates were significantly different between patients who did and did not experience a pCR, in both cN0 (p = 0.002) and cN1 (p < 0.001) subgroups. CONCLUSIONS: Patients with HER2-positive breast cancer treated with dual HER2-targeted therapy who experienced a breast pCR or RCB I response were frequently ypN0. These findings support future trials considering omission of axillary surgical staging for patients with HER2-positive breast cancer in neoadjuvant trials of active HER2-targeted regimens, particularly if they experience breast pCR or RCB I.

Immunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials.

The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease.

Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3-Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3-Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial.

PURPOSE: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study. METHODS: Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion. RESULTS: One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; mPFS, 11.0 months). Objective responses were observed in cancers with HER3-high and HER3-low membrane expression. Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, GI and hematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred. CONCLUSION: HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.

Correlation of SUV on Early Interim PET with Recurrence-Free Survival and Overall Survival in Primary Operable HER2-Positive Breast Cancer (the TBCRC026 Trial).

Predictive biomarkers of response to human epidermal growth factor receptor 2 (HER2)-directed therapy are essential to inform treatment decisions. The TBCRC026 trial reported that early declines in tumor SUVs corrected for lean body mass (SULmax) on 18F-FDG PET/CT predicted a pathologic complete response (pCR) to HER2 therapy with neoadjuvant trastuzumab and pertuzumab (HP) without chemotherapy in estrogen receptor (ER)-negative, HER2-positive breast cancer. We hypothesized that 18F-FDG PET/CT SULmax parameters would predict recurrence-free survival (RFS) and overall survival (OS). Methods: Patients with stage II/III ER-negative, HER2-positive breast cancer received neoadjuvant HP (n = 88). pCR after HP alone was 22% (18/83), additional nonstudy neoadjuvant therapy was administered in 28% (25/88), and the majority received adjuvant therapy per physician discretion. 18F-FDG PET/CT was performed at baseline and at cycle 1, day 15 (C1D15). RFS and OS were summarized using the Kaplan-Meier method and compared between subgroups using logrank tests. Associations between 18F-FDG PET/CT (≥40% decline in SULmax between baseline and C1D15, or C1D15 SULmax ≤ 3) and pCR were evaluated using Cox regressions, where likelihood ratio CIs were reported because of the small numbers of events. Results: Median follow-up was 53.7 mo (83/88 evaluable), with 6 deaths and 14 RFS events. Estimated RFS and OS at 3 y was 84% (95% CI, 76%-92%) and 92% (95% CI, 87%-98%), respectively. A C1D15 SULmax of 3 or less was associated with improved RFS (hazard ratio [HR], 0.36; 95% CI, 0.11-1.05; P = 0.06) and OS (HR, 0.14; 95% CI, 0.01-0.85; P = 0.03), the latter statistically significant. The association of an SULmax decline of at least 40% (achieved in 59%) with RFS and OS did not reach statistical significance. pCR was associated with improved RFS (HR, 0.25; 95% CI, 0.01-1.24; P = 0.10) but did not reach statistical significance. Conclusion: For the first time, we report a potential association between a C1D15 SULmax of 3 or less on 18F-FDG PET/CT and RFS and OS outcomes in patients with ER-negative, HER2-positive breast cancer receiving neoadjuvant HP alone. If confirmed in future studies, this imaging-based biomarker may facilitate early individualization of therapy.

Genomics of ERBB2-Positive Breast Cancer in Young Women Before and After Exposure to Chemotherapy Plus Trastuzumab.

PURPOSE: Erb-B2 receptor tyrosine kinase 2 (ERBB2)-positive breast cancer (BC) is particularly common in young women. Genomic features of ERBB2-positive tumors before and after chemotherapy and trastuzumab (chemo + H) have not been described in young women and are important for guiding study of therapeutic resistance in this population. METHODS: From a large prospective cohort of women age 40 years or younger with BC, we identified patients with ERBB2-positive BC and tumor tissue available before and after chemo + H. Whole-exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. RESULTS: Twenty-two women had successful WES on samples from at least one time point; 12 of these had paired sequencing results from before and after chemo + H and 10 had successful sequencing from either time point. TP53 was the only significantly recurrently mutated gene in both pre- and post-treatment samples. MYC gene amplification was observed in four post-treatment tumors. Seven of 12 patients with paired samples showed acquired and/or clonally enriched alterations in cancer-related genes. One patient had an increased clonality putative activating mutation in ERBB2. Another patient acquired a clonal hotspot mutation in TP53. Other genomic changes acquired in post-treatment specimens included alterations in NOTCH2, STIL, PIK3CA, and GATA3. There was no significant change in median ERBB2 CN (20.3 v 22.6; Wilcoxon P = .79) between paired samples. CONCLUSION: ERBB2-positive BCs in young women displayed substantial genomic evolution after treatment with chemo + H. Approximately half of patients with paired samples demonstrated acquired and/or clonally enriched genomic changes in cancer genes. ERBB2 CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.

A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer.

PURPOSE: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-"addicted" tumors who may benefit from a chemotherapy-sparing strategy. EXPERIMENTAL DESIGN: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor-positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA. RESULTS: In TBCRC023, 72 breast cancer specimens had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio ≥ 4.6 and %3+ IHC staining ≥ 97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (WT). For clinical implementation, the classifier was locked as HER2 ratio ≥ 4.5, %3+ IHC staining ≥ 90%, and PIK3CA-WT and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier's high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment deescalation. CONCLUSIONS: Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable with chemotherapy plus dual anti-HER2 therapy in unselected patients.

Impact of Neoadjuvant Paclitaxel/Trastuzumab/Pertuzumab on Breast Tumor Downsizing for Patients with HER2+ Breast Cancer: Single-Arm Prospective Clinical Trial.

BACKGROUND: The impact of abbreviated neoadjuvant regimens for HER2+ breast cancer on rates of breast conservation therapy (BCT) is unclear. We aimed to determine BCT rates in a single-arm prospective trial of neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP) in patients with stage II or III HER2+ breast cancer. STUDY DESIGN: BCT eligibility was prospectively recorded before and after THP. Pre- and posttreatment mammogram and breast ultrasound were required; breast MRI was encouraged. Patients with a large tumor to breast size ratio were eligible for downsizing. Multifocal/multicentric tumors, extensive calcifications, and contraindications to radiation were considered BCT contraindications. RESULTS: Overall, 92 patients who received neoadjuvant THP on trial were included. At presentation, 39 (42.4%) were considered eligible for BCT and 53 (57.6%) were not. BCT-eligible patients were older (median 54 vs 47 years, respectively; p = 0.006) and had smaller tumors by palpation (median 2.5 vs 3 cm, respectively; p = 0.004). Of 53 BCT-ineligible patients, 28 were candidates for tumor downsizing, whereas 25 had contraindications to BCT. Overall, 51 (55.4%) patients underwent BCT. Of the 28 patients who were candidates for downsizing, 22 (78.6%) became BCT-eligible after THP and 18 of 22 (81.8%) underwent BCT. In total, 44 of 92 (47.8%) patients experienced breast pathologic complete response (ypT0), including 11 of 25 (44.0%) patients with BCT contraindications at presentation. CONCLUSIONS: De-escalated neoadjuvant systemic therapy led to high BCT rates in this cohort. The impact of de-escalated systemic therapy on local therapy and outcomes in early stage HER2+ breast cancer warrants further investigation.

Assessment of the HER2DX Assay in Patients With ERBB2-Positive Breast Cancer Treated With Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab.

Importance: Patients with early-stage ERBB2 (formerly HER2)-positive breast cancer (ERBB2+ BC) who experience a pathologic complete response (pCR) after receiving neoadjuvant therapy have favorable survival outcomes. Predicting the likelihood of pCR may help optimize neoadjuvant therapy. Objective: To test the ability of the HER2DX assay to predict the likelihood of pCR in patients with early-stage ERBB2+ BC who are receiving deescalated neoadjuvant therapy. Design, Setting, and Participants: In this diagnostic/prognostic study, the HER2DX assay was administered on pretreatment tumor biopsy samples from patients enrolled in the single-arm, multicenter, prospective phase 2 DAPHNe clinical trial who had newly diagnosed stage II to III ERBB2+ BC that was treated with neoadjuvant paclitaxel weekly for 12 weeks plus trastuzumab and pertuzumab every 3 weeks for 4 cycles. Interventions and Exposures: The HER2DX assay is a classifier derived from gene expression and limited clinical features that provides 2 independent scores to predict prognosis and likelihood of pCR in patients with early-stage ERBB2+ BC. The assay was administered on baseline tumor samples from 80 of 97 patients (82.5%) in the DAPHNe trial. Main Outcomes and Measures: The primary aim was to test the ability of the HER2DX pCR likelihood score (as a continuous variable from 0-100) to predict pCR (ypT0/isN0). Results: Of 80 participants, 79 (98.8%) were women and there were 4 African American (5.0%), 6 Asian (7.5%), 4 Hispanic (5.0%), and 66 White individuals (82.5%); the mean (range) age was 50.3 (26.0-78.0) years. The HER2DX pCR score was significantly associated with pCR (odds ratio, 1.05; 95% CI, 1.03-1.08; P < .001). The pCR rates in the HER2DX high, medium, and low pCR score groups were 92.6%, 63.6%, and 29.0%, respectively (high vs low odds ratio, 30.6; P < .001). The HER2DX pCR score was significantly associated with pCR independently of hormone receptor status, ERBB2 immunohistochemistry score, HER2DX ERBB2 expression score, and prediction analysis of microarray 50 ERBB2-enriched subtype. The correlation between the HER2DX pCR score and prognostic risk score was weak (Pearson coefficient, -0.12). Performance of the risk score could not be assessed due to lack of recurrence events. Conclusions and Relevance: The results of this diagnostic/prognostic study suggest that the HER2DX pCR score assay could predict pCR following treatment with deescalated neoadjuvant paclitaxel with trastuzumab and pertuzumab in patients with early-stage ERBB2+ BC. The HER2DX pCR score might guide therapeutic decisions by identifying patients who are candidates for deescalated or escalated approaches.

Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial.

BACKGROUND: We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis. METHODS: In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m2) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual. FINDINGS: Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1-11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3-94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3-98·3), 10-year overall survival was 94·3% (95% CI 91·8-96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6-100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00-1·52]; p=0·047) and recurrence-free interval (1·45 [1·09-1·93]; p=0·011). INTERPRETATION: Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population. FUNDING: Genentech.

Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

Purpose: To examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAT). Patients and Methods: We identified responders (RCB-0/1) and matched non-responders (RCB-2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel vs. cisplatin in TNBC. We collected plasma samples at baseline, three weeks, and twelve weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. Results: Of 139 patients, 68 had complete samples and no additional NAT. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3, and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10 -4 (range: 7.9 × 10 -7 to 4.9 × 10 -1 ). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10/11 patients with RCB-0, 3/8 with RCB-1, 4/15 with RCB-2, and 0/4 with RCB-3. Among 6 patients with known recurrence five had persistent ctDNA at week 12. Conclusion: NAT for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine if ctDNA-guided approaches can improve outcomes.

ER+, HER2- advanced breast cancer treated with taselisib and fulvestrant: genomic landscape and associated clinical outcomes.

Taselisib is a potent ß-sparing phosphatidylinositol 3-kinase (PI3K) inhibitor that, with endocrine therapy, improves outcomes in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated (PIK3CAmut) advanced breast cancer. To understand alterations associated with response to PI3K inhibition, we analysed circulating tumour DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CAmut or PIK3CA no mutation was detected (NMD) per baseline ctDNA. The top mutated genes and tumour fraction estimates identified were analysed for their association with outcomes. In participants with PIK3CAmut ctDNA treated with taselisib + fulvestrant, tumour protein p53 (TP53; encoding p53) and fibroblast growth factor receptor 1 (FGFR1) alterations were associated with shorter progression-free survival (PFS) compared to participants with NMD in these genes. Conversely, participants with PIK3CAmut ctDNA harbouring a neurofibromin 1 (NF1) alteration or high baseline tumour fraction estimate experienced improved PFS upon treatment with taselisib + fulvestrant compared to placebo + fulvestrant. Broadly, alterations in oestrogen receptor (ER), PI3K and p53 pathway genes were associated with resistance to taselisib + fulvestrant in participants with PIK3CAmut ctDNA. Altogether, we demonstrated the impact of genomic (co-)alterations on outcomes with one of the largest clinico-genomic datasets of ER+, HER2-, PIK3CAmut breast cancer patients treated with a PI3K inhibitor.

Nodal Positivity in Early-Stage Triple-Negative Breast Cancer: Implications for Preoperative Immunotherapy.

BACKGROUND: Adding pembrolizumab to preoperative chemotherapy improves event-free survival in patients with early-stage triple-negative breast cancer (TNBC). However, owing to potential toxicities, the risk-benefit ratio of pembrolizumab must be considered. There is consensus that the addition of immunotherapy should be recommended in node-positive patients. This study is undertaken to determine nodal positivity rates in patients with TNBC presenting with cT1-2N0 disease undergoing upfront surgery and to evaluate the utility of axillary ultrasound and biopsy in the setting of a negative clinical examination. PATIENTS AND METHODS: Patients with cT1-2N0 TNBC undergoing upfront surgery were identified from our institutional database (January 2016-February 2021; n = 343) and from the National Cancer Database (NCDB) (n = 46,015). Pathologic nodal status was determined. A second cohort of patients with cT1-T2 TNBC with a negative clinical examination was defined in our institutional database (n = 499), and utilization of axillary ultrasound was examined. RESULTS: For patients undergoing upfront surgery, pathologically positive nodes were found in 14.6% patients of our institutional cohort: 9.4% cT1a/b, 14.9% cT1c, and 20.8% cT2 tumors. In the NCDB cohort, 13.7% patients were node positive: 4.9% cT1a/b, 11.4% cT1c, and 19.7% cT2 tumors. For patients with a normal clinical examination undergoing axillary ultrasound, 7.5% of cT1c and 8.7% of cT2 had suspicious nodes biopsied and confirmed positive for metastasis. CONCLUSIONS: Pathologic node-positive disease is found in > 10 and 20% patients with cT1cN0 and cT2N0 TNBC, respectively. Axillary ultrasound can be used to identify patients presenting with a normal clinical examination for whom preoperative pembrolizumab should be considered.

Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor-Positive Breast Cancer.

PURPOSE: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. PATIENTS AND METHODS: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2- advanced breast cancer who progressed on prior ET (N = 36; NCT02448771). RESULTS: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0-7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5-13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment. CONCLUSIONS: The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2- breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.

Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis.

DESTINY-Breast01 (NCT03248492) evaluated trastuzumab deruxtecan (T-DXd; DS-8201) in patients with heavily pretreated HER2-positive metastatic breast cancer (mBC). We present a subgroup of 24 patients with a history of treated brain metastases (BM), a population with limited treatment options. In patients with BMs, the confirmed objective response rate (cORR) was 58.3% [95% confidence interval (CI), 36.6%-77.9%], and the median progression-free survival (mPFS) was 18.1 months (95% CI, 6.7-18.1 months). In patients without BMs (n = 160), cORR was 61.3% and mPFS was 16.4 months. Eight patients (47.1%) experienced a best overall intracranial response of partial response or complete response. Seven patients (41.2%) had a best percentage change in brain lesion diameter from baseline consistent with stable disease. Two patients (8.3%) with BMs and two (1.3%) without BMs experienced progression in the brain. The safety profile of T-DXd was consistent with previous studies. The durable clinical activity of T-DXd in this population warrants further investigation. SIGNIFICANCE: Advances in treating HER2-positive metastatic breast cancer have greatly improved patient outcomes, but intracranial progression remains an important risk for which few therapeutic options are currently available. T-DXd demonstrated durable efficacy in patients with stable, treated BMs. This article is highlighted in the In This Issue feature, p. 2711.

Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast cancer.

BACKGROUND: Preclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown. METHODS: This was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-naïve. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored. RESULTS: 20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg/kg T-DM1 every 21 days plus 200 mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) ≥grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade >4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95% CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort. CONCLUSIONS: T-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer. TRIAL REGISTRATION NUMBER: NCT03032107.

Circulating Tumor DNA and Late Recurrence in High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

PURPOSE: To examine the prevalence and dynamics of circulating tumor DNA (ctDNA) and its association with metastatic recurrence in patients with high-risk early-stage hormone receptor-positive breast cancer (HR+ BC) more than 5 years from diagnosis. METHODS: We enrolled 103 patients with high-risk stage II-III HR+ BC diagnosed more than 5 years prior without clinical evidence of recurrence. We performed whole-exome sequencing (WES) on primary tumor tissue to identify somatic mutations tracked via a personalized, tumor-informed ctDNA test to detect minimal residual disease (MRD). We collected plasma at the time of consent and at routine visits every 6-12 months. Patients were followed for clinical recurrence. RESULTS: In total, 85 of 103 patients had sufficient tumor tissue; of them, 83 of 85 (97.6%) patients had successful whole-exome sequencing. Personalized ctDNA assays were designed targeting a median of 36 variants to test 219 plasma samples. The median time from diagnosis to first sample was 8.4 years. The median follow-up was 10.4 years from diagnosis and 2.0 years from first sample. The median number of plasma samples per patient was two. Eight patients (10%) had positive MRD testing at any time point. Six patients (7.2%) developed distant metastatic recurrence, all of whom were MRD-positive before overt clinical recurrence, with median ctDNA lead time of 12.4 months. MRD was not identified in one patient (1.2%) with local recurrence. Two of eight MRD-positive patients had not had clinical recurrence at last follow-up. CONCLUSION: In this prospective study, in patients with high-risk HR+ BC in the late adjuvant setting, ctDNA was identified a median of 1 year before all cases of distant metastasis. Future studies will determine if ctDNA-guided intervention in patients with HR+ BC can alter clinical outcomes.