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While the outcomes for patients diagnosed with hormone receptor positive (HR+) and/or human epidermal growth factor receptor 2-positive (HER2+) breast cancers have continued to improve with the development of targeted therapies, the same cannot be said yet for those affected with triple-negative breast cancer (TNBC). Currently, the mainstay of treatment for the 10–15% of patients diagnosed with TNBC remains cytotoxic chemotherapy, but it is hoped that through an enhanced characterization of TNBC biology, this disease will be molecularly delineated into subgroups with targetable oncogenic drivers. This review will focus on recent therapeutic innovations for TNBC, including poly-ADP-ribosyl polymerase (PARP) inhibitors, phosphoinositide 3-kinase (PI3K) pathway inhibitors, immune checkpoint inhibitors, and cyclin-dependent kinase (CDK) inhibitors.

Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24–0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56–0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 . Secondary and selected exploratory endpoints of the DESTINY-Breast03 trial of trastuzumab deruxtecan or trastuzumab emtansine in patients with advanced HER2-positive breast cancer are reported, including updated efficacy and safety data after a median follow-up of 41 months.

Purpose The phosphatidylinositol 3-kinase (PI3K) pathway is involved in several physiological processes, including glucose metabolism, cell proliferation, and cell growth. Hyperactivation of this signaling pathway has been associated with tumorigenesis and resistance to treatment in various cancer types. Mutations that activate PIK3CA , encoding the PI3K isoform p110α, are common in breast cancer, particularly in the hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) subtype. A number of PI3K inhibitors have been developed and evaluated for potential clinical use in combinations targeting multiple signaling pathways in cancer. The purpose of this review is to provide an overview of PI3K inhibitor mechanisms of action for antitumor activity and adverse events in advanced breast cancer (ABC). Methods Published results from phase 3 trials evaluating the efficacy and safety of PI3K inhibitors in patients with ABC and relevant literature were reviewed. Results Although PI3K inhibitors have been shown to prolong progression-free survival (PFS), the therapeutic index is often unfavorable. Adverse events, such as hyperglycemia, rash, and diarrhea are frequently observed in these patients. In particular, hyperglycemia is intrinsically linked to the inhibition of PI3Kα, a key mediator of insulin signaling. Off-target effects, including mood disorders and liver toxicity, have also been associated with some PI3K inhibitors. Conclusion Recent clinical trial results show that specifically targeting PI3Kα can improve PFS and clinical benefit. Broad inhibition of class I PI3Ks appears to result in an unfavorable safety profile due to off-target effects, limiting the clinical utility of the early PI3K inhibitors.

Background Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2− breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. Methods In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. Results We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2− breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2− breast cancer models. Conclusions These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2− breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer. In this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment for advanced disease except endocrine therapy. Patients were randomly assigned (2:1) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m2 on days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added during the course of the study, before unmasking based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here. This trial is registered with ClinicalTrials.gov, number NCT00876395. Between Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41·3 months (IQR 35·4–46·6). In the full population, median progression-free survival was 14·95 months (95% CI 14·55–17·91) with everolimus versus 14·49 months (12·29–17·08) with placebo (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·1166). In the HR-negative subpopulation (n=311), median progression-free survival with everolimus was 20·27 months (95% CI 14·95–24·08) versus 13·08 months (10·05–16·56) with placebo (hazard ratio 0·66, 95% CI 0·48–0·91; p=0·0049); however, the protocol-specified significance threshold (p=0·0044) was not crossed. The most common adverse events with everolimus were stomatitis (314 [67%] of 472 patients in the everolimus group vs 77 [32%] of 238 patients in the placebo group), diarrhoea (267 [57%] vs 111 [47%] patients), and alopecia (221 [47%] vs 125 [53%]). The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia (117 [25%] vs 35 [15%]), stomatitis (59 [13%] vs three [1%]), anaemia (46 [10%] vs six [3%]) and diarrhoea (43 [9%] vs 10 [4%]) On-treatment adverse event-related deaths were reported in 17 (4%) patients in the everolimus group and none in the placebo group. Although progression-free survival was not significantly different between groups in the full analysis population, the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative, HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial. Novartis Pharmaceuticals.

Background KRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II–III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE. Methods Patients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive. Results Biomarker analyses included data from all 444 patients (T-DM1 + P, n  = 223; TCH + P, n  = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA ) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups. Conclusions Although our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer. Trial Registration : ClinicalTrials.gov NCT02131064. Registered 06 May 2014.

Sacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate with an SN-38 payload. In the ASCENT study, patients with metastatic triple-negative breast cancer (mTNBC) relapsed/refractory to ≥2 prior chemotherapy regimens (≥1 in the metastatic setting), received SG or single-agent treatment of physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine). This ASCENT safety analysis includes the impact of age and UGT1A1 polymorphisms, which hinder SN-38 detoxification. SG demonstrated a manageable safety profile in patients with mTNBC, including those ≥65 years; neutropenia/diarrhea are key adverse events (AE). Patients with UGT1A1 *28/*28 genotype versus those with 1/*28 and *1/*1 genotypes had higher rates of grade ≥3 SG-related neutropenia (59% vs 47% and 53%), febrile neutropenia (18% vs 5% and 3%), anemia (15% vs 6% and 4%), and diarrhea (15% vs 9% and 10%), respectively. Individuals with UGT1A1 *28/*28 genotype should be monitored closely; active monitoring and routine AE management allow optimal therapeutic exposure of SG.

New HER2-targeted regimens, including chemotherapy-free options, are needed for metastatic breast cancer. In an ongoing, two-part, phase 2a study, we assessed the safety and antitumour activity of zanidatamab, a HER2-targeted bispecific antibody, plus palbociclib and fulvestrant, in heavily pretreated patients with hormone receptor-positive, HER2-positive advanced or metastatic breast cancer. This multicentre, single-arm, two-part, phase 2a study is being conducted at 13 university hospitals, cancer centres, or research institutes in Spain, Canada, and the USA. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, and with pathologically confirmed unresectable or metastatic breast cancer, assessed locally to be hormone receptor-positive and HER2-positive, with disease progression during or after previous HER2-targeted therapies. Patients were enrolled in part 1, part 2, or part 1 followed by part 2. In part 1, patients received starting doses of zanidatamab (20 mg/kg intravenously once every 2 weeks on days 1 and 15 of a 28-day cycle) with palbociclib (125 mg orally once a day on days 1–21 of each cycle) and fulvestrant (500 mg intramuscular injection once every 2 weeks for the first three doses [cycle 1: days 1 and 15, cycle 2: day 1], then once every 4 weeks [all subsequent cycles: day 1]). In part 1, primary endpoints were safety of the triplet combination and confirmation of recommended doses for part 2. In part 2, patients received the recommended doses confirmed in part 1, and the primary endpoint was progression-free survival at 6 months. Safety and progression-free survival were assessed in all enrolled patients who received any dose of zanidatamab, palbociclib, or fulvestrant. Patients in part 1 who were treated at the recommended doses were analysed together with the patients in part 2. This study is registered with ClinicalTrials.gov, NCT04224272, and is active with recruitment completed. Overall, 51 patients (49 [96%] female and two [4%] male; median age 54·0 [46·0–62·0] years; 42 [82%] White) were enrolled: eight in part 1 (June 10, 2020–Feb 7, 2021) and 43 in part 2 (Feb 8, 2021–Oct 31, 2022). All 51 patients had received study treatment at the data cutoff (Aug 3, 2023); median follow-up was 16·1 months (IQR 9·9–23·4) and the median duration of triplet regimen treatment was 7·4 months (3·4–14·8). The median number of previous HER2-targeted therapies was 4 (IQR 3–4). 12 (24%) of 51 patients had previously received trastuzumab deruxtecan. The planned starting drug doses administered in part 1 of the study were confirmed as the recommended doses for part 2. All 51 patients were treated at the recommended doses. All 51 patients had at least one treatment-related adverse event of any grade, with diarrhoea being the most common (41 [80%] patients, with 34 [67%] having grade 1–2 events). Grade 3 or 4 treatment-related adverse events occurred in 34 (67%) patients, with neutropenia being the most common (26 [51%] patients). One (2%) patient had a serious grade 3 treatment-related adverse event of increased transaminases. No treatment-related deaths occurred. In the overall sample (N=51), progression-free survival at 6 months was 66·7% (95% CI 52·1–79·2). Zanidatamab plus palbociclib and fulvestrant was generally safe and showed promising antitumour activity, supporting further evaluation of this chemotherapy-free triplet regimen. Zymeworks, Jazz Pharmaceuticals, and Pfizer.

In this post hoc analysis of the ASCENT study, we compared outcomes with sacituzumab govitecan (SG) vs single-agent chemotherapy in clinically important subgroups of patients with metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC refractory to/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG or treatment of physician’s choice (TPC) until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by central review in patients without brain metastases. Patients with brain metastases were allowed if metastases were stable ≥4 weeks. In the intention-to-treat (ITT) population, 19% of patients were age ≥65 years; 12% were Black, and 12% had brain metastases. SG improved PFS and overall survival (OS), respectively, vs TPC in patients age ≥65 years (7.1 vs 2.4 months and 14.7 vs 8.9 months), or of Black race (5.4 vs 2.2 months and 13.8 vs 8.5 months), consistent with outcomes in the ITT population. Patients with brain metastases had numerically higher median PFS with SG vs TPC, but median OS was similar between treatment groups. SG was well tolerated and had a manageable safety profile consistent with the full safety population across all subgroups; neutropenia and diarrhea were the most common treatment-emergent adverse events. These findings confirm the meaningful clinical benefit of SG vs standard chemotherapy in patient subgroups with high unmet needs. SG should be considered an effective and safe treatment option for patients with mTNBC eligible for second-line or later therapy. ClinicalTrials.gov Number: NCT02574455.

The implications of the results of the DESTINY-Breast04 trial reported by Modi et al. 1 in this issue of the Journal are difficult to overstate. Immediately practice-changing, these data show that a human epidermal growth factor receptor 2 (HER2)–directed therapy, trastuzumab deruxtecan, leads to significant and striking improvements in both progression-free survival and overall survival as compared with chemotherapy among patients with metastatic breast cancer with low expression of HER2. Consistent benefit was observed in patients with poor prognostic indicators, including triple-negative cancer. Although the trophoblast cell-surface antigen 2 (Trop-2)–targeted antibody–drug conjugate sacituzumab govitecan has improved outcomes in patients with heavily . . .