HER2-negative Advanced Breast Cancer Research Articles

A Canadian real-world, multi-center, prospective, observational study assessing the treatment duration, the treatment sequence, and the overall survival for patients treated with endocrine therapy ± targeted therapy in HR + HER2-negative advanced breast cancer.

Understanding real-world treatment patterns and their effectiveness in HR + HER2- advanced breast cancer (aBC) in Canadian patients. This was a multi-center, observational, prospective cohort study including men and pre-/peri-/postmenopausal women with HR + HER2- aBC receiving endocrine therapy (ET) or ET + targeted therapy (ET + TT). The primary objective was duration of treatment (DOT) with ET and ET + TT. Sequence of therapies, treatment patterns, and Overall Survival (OS) were also evaluated. DOT was prolonged in patients receiving ET + TT compared to ET (median DOT: ET + TT 397days vs ET 192days; Log-Rank test p value < .0001; HR = 0.66; 95% CI; 0.52, 0.85). An extended DOT was observed in ET + CDK4/6i subgroup when compared to ET (median DOT: ET + CDK4/6i 601days vs ET 192days; Log-Rank test p value < .0001). This increase was statistically significant irrespective of line of therapy at baseline (1L: median DOT: ET + CDK4/6i: 649days vs ET: 217days, p value = < .0001; 2L: median DOT: ET + CDK4/6i: 487days vs ET: 203days, p value = 0.0013; 3L: median DOT: ET + CDK4/6i: 597days vs ET: 143days therapy: p value = 0.0006). ET alone and ET + CDK4/6i were the most frequently administered therapies in both 1st (ET alone: 43.5% and ET + CDK4/6i: 43.3%) and 2nd lines (ET alone: 36.3% and ET + CDK4/6i: 24.6%). Among patients who received at least one CDK4/6i in 1st, 2nd, or 3rd line, CDK4/6i were mostly administered in 1st line (61.9%) and 2nd line (38.5%). gov ID: NCT02753686; Registration Date:20-04-2016. Results support current treatment recommendations of early introduction of CDK4/6i in HR + /HER2- aBC.

Neoadjuvant chemotherapy and hormonal therapy for locally advanced luminal HER2-negative breast cancer

Background. Treatment of locally advanced breast cancer (BC) should start with systemic therapy to achieve the possibility of surgical intervention. In luminal HER2-negative BC, 2 options for neoadjuvant systemic therapy are possible – chemotherapy and hormonal therapy. To date, there are no clear criteria for choosing the most optimal treatment option for a particular patient.Objective. To evaluate the efficacy of neoadjuvant hormone therapy (NHT) and chemotherapy (NCT) for patients with intermediate expected hormone sensitivity (high levels of ER/RP and Ki67&gt;30% or low levels of ER/RP and Ki67&lt;30%)Materials and methods. The study involved 75 pre- and postmenopausal patients with locally advanced luminal HER2-negative breast cancer who received NHT (tamoxifen/aromatase inhibitors) or NCT (4 cycles of AC and taxanes) in the preoperative period. The primary endpoint was a decrease in Ki67 levels by 50% or more.Results. The NGT group included 39 patients, the NCT group – 36 patients. Taking into account differences in patient characteristics between the groups, pseudorandomization (propensity matching analysis) was performed for correct comparison, after which 23 patients remained in each group. Operability was achieved in 87% of patients in the NHT group and 91.3% in the NCT group (p = 0.25). A decrease in Ki67 by 50% or more was noted in 47.1% of cases in the NHT group and in 57.1% in the NCT group (p = 0.284), and a decrease to &lt;10% – in 42.9% and 35.3% of cases, respectively (p = 0.66). The frequency of achieving complete pathomorphological regression (pCR) was 10% with NHT and 14.3% with NCT. The 4-year disease-free survival (DFS) with a median follow-up of 46 months in the NHT group was 89.1%, in the NCT group – 84.8% (p = 0.693).Conclusions. Neoadjuvant chemotherapy and hormonal therapy demonstrate similar efficacy in patients with intermediate hormone sensitivity in terms of the frequency of significant decrease in Ki67, achievement of pCR, DFS rates.

Antibody-drug conjugate review in breast cancer: A targeted approach

Antibody-drug conjugates (ADCs) provide specificity for cytotoxic drugs as well as monoclonal antibodies (mAbs) and represent an important step in the treatment of breast cancer. This review summarizes the current status, efficacy, safety, and future prospects of ADCs in the treatment of breast cancer. mAbs enable drug delivery by detecting specific antigens on cancer cells. Cytotoxic payloads cause cell death upon internalization. The linker binds the mAb to the payload and influences drug release. All three components together form an ADC. Transtuzumab Emtansine 1 (T-DM1) (Kadcyla) targets human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has shown activity against both metastatic and early disease. Fam-trastuzumab deruxtecan (T-DXd; Enhertu) has shown improved progression-free survival and overall survival for T-DM1 in HER2-positive metastatic breast cancer. Sacituzumab govitecan (SG) targets the Trophoblast Antigen 2 (TROP2) receptor and has been shown to be effective in triple-negative breast cancer and hormone receptor-positive, HER2-negative advanced breast cancer. Fatigue, nausea, and diarrhea are the most common. Some ADCs have their own side effects. T-DXd, which can cause interstitial lung disease, and SG, which increases the risk of diarrhea. Monitoring and controlling these adverse events is important to achieve good patient outcomes. There are ongoing issues with ADC use including drug-related and other issues. The drug-related issues include side effects and ADCs drug resistance. This resistance can be due to a variety of reasons including downregulation of the target antigen, reduced internalization, increased drug efflux, and reduced burden. Strategies to reduce resistance include the use of combination therapies, early detection of resistance, and the development of more effective products. Second-generation ADCs with improved structure and potency are under development. There is ongoing research focusing on novel targets beyond HER2, such as Trop-2 and Claudin-18.2. Non-drug-related issues include tumor heterogeneity, patient selection, manufacturing issues, and increased costs. In conclusion, ADCs are a huge improvement over conventional chemotherapy for breast cancer treatment. The importance and use of ADCs in cancer treatment is bound to increase. The future of ADCs in breast cancer treatment looks promising with ongoing research into new targets, new therapeutic agents, and advances in drug resistance leading to mediated and effective methods.

BRCA and Beyond: Impact on Therapeutic Choices Across Cancer.

Identifying patients with gBRCAm is crucial to facilitate screening strategies, preventive measures and the usage of targeted therapeutics in their management. This review examines the evidence for the latest predictive and therapeutic approaches in BRCA-associated cancers. Data supports the use of adjuvant olaparib in patients with gBRCAm high-risk HER2-negative breast cancer. In advanced gBRCAm HER2-negative breast cancer, the PARPis talazoparib and olaparib have demonstrated benefit over standard chemotherapy. In ovarian cancer, olaparib, niraparib or rucaparib can be used as monotherapy in frontline maintenance. Olaparib and bevacizumab as a combination can also be used as frontline maintenance. In the relapsed platinum-sensitive setting, olaparib, niraparib and rucaparib are effective maintenance options in BRCAm patients who are PARPi naive. Both olaparib and rucaparib are effective options in BRCAm metastatic castrate-resistant prostate cancer (mCRPC). Evidence also exists for the benefit of PARPi combinations in mCRPC. In metastatic pancreatic cancer, olaparib can be used in gBRCAm patients who are responding to platinum chemotherapy. However, there may be a development of PARPi resistance. Understanding the pathophysiology that contributes to such resistance may allow the development of novel therapeutics. Combination therapy appears to have promising results in emerging trials. Seeking avenues for subsidised genetic testing can reduce the total costs of cancer management, leading to improve detection rates. Identifying breast, ovarian, pancreatic and prostate cancer patients with gBRCAm plays a crucial predictive role in selecting those who will benefit significantly from PARPi therapy. The use of PARPi in gBRCAm HBOC-related cancers has resulted in significant survival benefits. Beyond BRCA1/2, HRR gene assessment and the consideration of other cancer predisposition syndromes may allow more patients to be eligible for and benefit from targeted therapies.

Low Skeletal Muscle Radiodensity Predicts Response to CDK4/6 Inhibitors Plus Aromatase Inhibitors in Advanced Breast Cancer.

Recent evidence indicates that a dysregulated host metabolism influences treatment outcomes in patients with breast cancer. We investigated the association of computed tomography (CT)-derived body composition indices with therapeutic responses in patients with hormone receptor-positive, HER2-negative advanced breast cancer (ABC) on endocrine plus CDK4/6 inhibitor (CDK4/6i) treatment. The study involved a retrospective cohort of patients with ABC at the Yonsei Cancer Center who received CDK4/6i and aromatase inhibitors as first-line therapy between January 2017 and October 2020. Body composition parameters were estimated from the non-enhanced CT images of the third lumbar spine by commercialized deep learning software. Patients with low skeletal muscle radiodensity (SMD) were defined as patients with SMD of low tertile (≤ 28.7 Hounsfield Units). The primary outcome was progression-free survival (PFS). Among the 247 female participants (median age, 53 years; mean body mass index [BMI], 23.7 kg/m2), 45.7% had disease progression or death during a median follow-up of 36.4 months. After adjusting for age and visceral metastasis, SMD was the only independent predictor among body composition parameters for worse PFS (adjusted hazard ratio [HR] = 1.20 per standard deviation decrement, 95% CI: 1.01-1.42, p = 0.041), whereas BMI, muscle area, and fat area were not. Participants with low SMD had a higher risk of progression than those without (PFS, 27.2 vs. 51.1 months, p = 0.009; adjusted HR 1.84, 95% CI: 1.22-2.76, p = 0.003). Strong associations between low SMD and poor PFS were observed in groups with pre-menopause status (HR, 3.04 vs. 1.19 in post-menopause; 95% CI: 1.54-5.99, p for interaction < 0.05) and without visceral metastases (HR, 2.95 vs. 1.19 in with visceral metastases; 95% CI: 1.59-5.49, p for interaction < 0.05). CT-defined low SMD predicts poor treatment outcomes in patients with ABC undergoing first-line treatment with aromatase inhibitors and CDK4/6i.

Real-World Efficacy and Adherence to Palbociclib in HR-Positive, HER2-Negative Advanced Breast Cancer: Insights from a Romanian Cohort.

The first reimbursed prescription for palbociclib (Palbo) in breast cancer patients in Romania was issued in July 2018. The objective of this study is to assess the efficacy, safety, and adherence to Palbo in combination with aromatase inhibitor (AI) or fulvestrant in a real-world cohort of HR+/HER2- breast cancer patients from Romania. A retrospective analysis of reimbursed Palbo prescriptions was conducted using data extracted from the electronic database of the Romanian Health Insurance House, Dolj County, for disease code 124 (breast cancer), covering the period from 2018 to 2023. The primary outcome assessed was time to treatment discontinuation (TTD), with secondary outcomes including overall survival (OS) and Palbo adherence (which was measured by medication possession ratio). A total of 125 patients were identified, with a median age of 62 years (IQR, 53-70), and 98% were female. Two treatment combinations were observed: Palbo + Aromatase Inhibitor (AI) in 104 patients (83.2%) and Palbo + fulvestrant in 21 patients (16.8%). The median TTD for the entire cohort was 19 months (95%CI, 19.3-24.9 months). In patients treated with Palbo + AI, the median TTD was not available/reached [NA] (95%CI, 36.0-NA months). For those receiving Palbo+fulvestrant, the median TTD was 25.0 months (95%CI, 13.0-NR months). No significant differences in TTD were observed among the two treatment combinations (χ2 = 1.33, df = 1, log-rank p = 0.249). The 12- and 36-month TTD rates were higher for Palbl combined with AI than combined with fulvestrant: 77.8% [95%CI, 69.7-86.7%] vs. 71.8% [95%CI, 53.6-96.2%], and 56.3% [95%CI, 45.9-69%] vs. 49.7% [95%CI, 29.7-83.2%], respectively. The median OS was 38 months (95%CI, 25.5-50.9). When treatment involved Palbo + AI, the median OS was NA (95%CI, 54.8-NA) months. When treatment involved Palbo + fulvestrant, the median was 50.8 (95%CI, 34.1-NA) months. Related to OS, no significant differences were found between the two types of treatments (log-rank p = 0.638). The 24- and 36-month OS rates were higher for Palbo combined with AI than combined with fulvestrant: 76.9% [95%CI, 69.2-85.5%] vs. 81% [95%CI, 65.8-99.6%], and 67.9% [95%CI, 59.2-77.8%] vs. 65.3% [95%CI, 47.4-90.0%], respectively. The mean adherence in our study was 0.91 ± 0.1. We found no correlation between adherence to Palbo and OS (Spearman's rho = 0.04, p = 0.593). While both AI and fulvestrant remain viable options, the lack of significant differences in survival between these combinations suggests that treatment choice can be tailored to individual patient needs.

Imlunestrant with or without Abemaciclib in Advanced Breast Cancer.

Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1). In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently. Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib. Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P = 0.12). Among 426 patients in the comparison of imlunestrant-abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant-abemaciclib. Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. (Funded by Eli Lilly; EMBER-3 ClinicalTrials.gov number, NCT04975308.).

Capivasertib:the Breakthrough Cancer Treatment of the Decade's

Capivasertib (TRUQAP), a novel oral AKT inhibitor, targets the PI3K/AKT/mTOR pathway to overcome tumour resistance in advanced breast cancer.Capivasertib has a unique pyrrolopyrimidine derivative structure and is a highly strong ATP-competitive inhibitor of all three AKT isoforms (AKT1, AKT2, and AKT3).This article provides a thorough examination of capivasertib's synthesis, mechanisms of action, physical and chemical properties, and preclinical and clinical efficacy.Its advantages over existing treatments, possible adverse effects, and prospective use in combination therapy are examined.We also examine possible future paths for managing resistance, optimising the therapeutic advantages of capivasertib, and selecting the best patients using biomarkers.Preclinical research has demonstrated the potential of capivasertib in conjunction with endocrine therapy and anti-HER2 drugs. Its clinical importance is highlighted by the FDA's recent approval of TRUQAP in conjunction with Faslodex in November 2023 for advanced HR-positive and HER2-negative breast cancer.

Elacestrant Monotherapy as a Second-Line Treatment for ER-Positive, HER2-Negative Advanced Breast Cancer with ESR1 Mutations

Elacestrant Monotherapy as a Second-Line Treatment for ER-Positive, HER2-Negative Advanced Breast Cancer with ESR1 Mutations

Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study

Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. Between Aug 14, 2017, and Jul 29, 2022 (data cutoff), 127 patients with at least 18 months' follow-up were enrolled into cohort A. 119 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 21·8 months (IQR 10·8-37·6). 64 (53·8%; 95% CI 44·4-63·0) of 119 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (37 [29%] of 127 patients), rash (13 [10%]), and rash maculopapular (11 [9%]). Serious adverse events occurred in 37 (29%) of 127 patients. No treatment-related deaths were reported. BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. Novartis Pharmaceuticals.

Hormone therapy enhances anti-PD1 efficacy in premenopausal estrogen receptor-positive and HER2-negative advanced breast cancer.

The efficacy of immunotherapy for estrogen receptor-positive/HER2-negative (ER+/HER2-) metastatic breast cancer (MBC) has not been proven. We conduct a phase 1b/2 trial to assess the efficacy of combining pembrolizumab (anti-PD1 antibody), exemestane (nonsteroidal aromatase inhibitor), and leuprolide (gonadotropin-releasing hormone agonist) for 15 patients with premenopausal ER+/HER2- MBC who had failed one to two lines of hormone therapy (HT) without chemotherapy. The primary endpoint of progression-free survival rate at 8months (i.e., 64.3%) is achieved. Moreover, 5 of the 14 evaluable subjects exhibited partial responses (overall response rate= 35.7%). The combination of anti-PD1 antibody and anti-hormone therapy is associated with an enhanced immunoreactive microenvironment influencing treatment efficacy, as observed in pre- and post-treatment tumor samples through NanoString analysis. Post-treatment tumors are associated with increased immune response and immune cells. The findings indicate that combining HT with anti-PD1 antibody is a promising treatment strategy for patients with premenopausal ER+/HER2- MBC. This study was registered at ClinicalTrials.gov (NCT02990845).

Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy improve the outcomes of patients with hormone-receptor (HR)-positive, HER2-negative advanced breast cancer and can be used early as first-line treatment or deferred to second-line treatment1-7. Randomized data comparing the use of CDK4/6i in the first- and second-line setting are lacking. The phase 3 SONIA trial (NCT03425838) randomized 1,050 patients who had not received previous therapy for advanced breast cancer to receive CDK4/6i in the first- or second-line setting8. All of the patients received the same endocrine therapy, consisting of an aromatase inhibitor for first-line treatment and fulvestrant for second-line treatment. The primary end point was defined as the time from randomization to disease progression after second-line treatment (progression-free survival 2 (PFS2)). We observed no statistically significant benefit for the use of CDK4/6i as a first-line compared with second-line treatment (median, 31.0 versus 26.8 months, respectively; hazard ratio = 0.87; 95% confidence interval = 0.74-1.03; P = 0.10). The health-related quality of life was similar in both groups. First-line CDK4/6i use was associated with a longer CDK4/6i treatment duration compared with second-line use (median CDK4/6i treatment duration of 24.6 versus 8.1 months, respectively) and more grade ≥3 adverse events (2,763 versus 1,591, respectively). These data challenge the need for first-line use of a CDK4/6i in all patients.

Time from Final Oncologist Visit to Death and Palliative Systemic Treatment Use Near the End of Life in Heavily Pretreated Patients with Luminal Breast Cancer.

Background: Palliative care must be tailored for patients with extended disease trajectories, such as those with hormone receptor-positive, Human Epidermal Growth Factor Receptor 2 (HER2)-negative advanced breast cancer (ABC), including the appropriate timing of discontinuing treatment. This study aimed to assess the interval between the last oncologist visit and death and the application of systemic treatment near the end of life in this patient population. Methods: This retrospective study included patients with luminal ABC who received at least two lines of palliative systemic treatment at the National Research Institute of Oncology in Poland, and died between November 2020 and March 2024. Results: Seventy-six women, with a median age 62.8 years (range: 35.3-91.5), were included. The median number of prior palliative systemic treatment lines was three (range: 2-6). At their last recorded oncologist visit, 75% of the patients were receiving active treatment (53% with hormonal therapy and 22% with chemotherapy). Only 25% were under continuous palliative care at this visit. Treatment was administered within the last month of life to 53% of the patients. The median duration from the last oncologist visit to death was 23 days (range: 0-408). The duration of this time interval was only associated with the performance status at the last visit (p < 0.05). Conclusions: Oncologists frequently delay the recognition of the need to discontinue systemic therapy. Patients with luminal HER2-negative ABC may be offered numerous effective lines of systemic treatment, complicating this decision further. Implementing clearer guidelines for end-of-life care for this group and providing proper training for healthcare providers is essential.

Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial

Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing. Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 16·6 months (IQR 12·9-19·4) for the camizestrant 75 mg group, 16·3 months (12·9-18·3) for the camizestrant 150 mg group, and 14·7 months (12·7-20·1) for the fulvestrant 500 mg group. Median progression-free survival was 7·2 months (90% CI 3·7-10·9) with camizestrant 75 mg, 7·7 months (5·5-12·9) with camizestrant 150 mg, and 3·7 months (2·0-6·0) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 0·59 (90% CI 0·42-0·82; p=0·017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 0·64 (0·46-0·89; p=0·0090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred. Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer. AstraZeneca.

Capivasertib and fulvestrant for patients with HR-positive/HER2-negative advanced breast cancer: analysis of the subgroup of patients from Japan in the phase 3 CAPItello-291 trial

BackgroundIn CAPItello-291, capivasertib–fulvestrant significantly improved progression-free survival (PFS) versus placebo–fulvestrant in the overall and PIK3CA/AKT1/PTEN-altered population with hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer. Capivasertib–fulvestrant is approved in Japan for the treatment of patients with one or more tumor biomarker alterations (PIK3CA, AKT1 or PTEN). Here, we report outcomes in the CAPItello-291 subgroup of patients from Japan.MethodsAdults with HR-positive/HER2-negative advanced breast cancer whose disease had relapsed or progressed during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy, were randomly assigned (1:1 ratio) to receive capivasertib or placebo, plus fulvestrant. The dual primary endpoint was investigator-assessed PFS in the overall and PIK3CA/AKT1/PTEN-altered population. Safety was a secondary endpoint.ResultsOf 708 patients randomized in CAPItello-291, 78 were from Japan (37 randomized to capivasertib–fulvestrant and 41 to placebo–fulvestrant). In the Japan subgroup, PFS numerically favored the capivasertib–fulvestrant arm (hazard ratio 0.73; 95% CI 0.40–1.28), consistent with the analysis of PFS in the global population. Similarly, in the Japan subgroup of patients with PIK3CA/AKT1/PTEN–altered tumors, PFS favored the capivasertib–fulvestrant arm (hazard ratio 0.65; 95% CI 0.29–1.39), consistent with the global population. The adverse event profile of capivasertib–fulvestrant in the Japan subgroup was broadly similar to that in the global population; no new safety concerns were identified.ConclusionOutcomes in the Japan subgroup were broadly similar to those of the global population, supporting the clinical benefit of capivasertib–fulvestrant in treating HR-positive/HER2-negative advanced breast cancer that has progressed on, or after, an endocrine-based regimen.

Impact of low HER2 expression on response to CDK4/6 inhibitor treatment in advanced HR + /HER2- breast cancer: a multicenter real-world data analysis.

CDK4/6 inhibitors (CDK4/6i) represent the first-line therapy approach of choice for patients with hormone receptor-positive, HER2-negative advanced breast cancer (HR + /HER-ABC). Approximately 50% of HR + /HER2-ABC displays low HER2 expression (HER2 low). Recent data emerging from the DESTINY-Breast04 trial demonstrated practice-changing efficacy of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in patients with low HER2 expression. Here, we aimed to analyze the impact of low HER2 expression on CDK4/6i therapy response in a well-characterized multicenter HR + /HER-ABC cohort. Patients diagnosed with HR + /HER2-ABC who were treated with CDK4/6i in clinical routine between November 2016 and December 2020 at four certified German Breast Cancer Centers were retrospectively identified. The cohort was stratified according to graduation of positivity in HER2 immunohistochemistry (IHC; HER2 zero = IHC score 0 and HER2 low = IHC score 1 + , 2 + /fluorescence in situ hybridization negative). Subgroups were analyzed with regard to progression-free survival (PFS) following CDK4/6i initiation. The study cohort comprised n = 448 patients. For n = 311 patients, HER2 status from the metastatic site was available. n = 91 (29.3%) cases were HER2 zero and n = 220 cases (70.7%) were HER2 low. There was no significant difference in PFS between the two groups (PFS: 17months versus 18months, log-rank p = 0.42). Further, we examined the influence of HER2 expression changes between primary and metastatic tissue (n = 171; HER2 gain/HER2 loss/HER2 stable expression) on CDK4/6i treatment response. Again, there was no significant difference between these three groups, respectively (PFS: 16months versus 13months versus 17months, log-rank p = 0.86). In our analysis, HER2 status did not have a significant impact on treatment response to CDK4/6i.

Effectiveness of combined targeted and hormonal therapies for post-menopausal women with hormone receptor-positive and HER2-negative advanced breast cancer: A systematic review and meta-analysis of RCTs.

we aim to synthesize available evidence on the effectiveness of hormonal plus targeted therapies for post-menopausal women with hormone receptor-positive and HER2-negative advanced breast cancer. We searched the following databases: Medline, PubMed, Cochrane Library, CINAHL, Web of Science, Scopus, and African Journal. Only studies that investigated the effectiveness of hormonal therapy combined with targeted therapy for HR+/HER2- advanced breast cancer treatment were included. The outcomes were progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). A random-effect meta-analysis model was employed. Statistical analysis was performed using Comprehensive Meta-analysis version 3. 24 studies were included in the meta-analysis with an overall sample size of 7635. Median PFS, OS and ORR were found to be significantly increased in the combination group compared to hormonal monotherapy [SMD = 6.072 (95% CI = 3.785-8.360), p < 0.001], [SMD = 1.614 (95% CI = 0.139-3.089), p = 0.032] and [OR = 1.584 (CI 1.134-2.213), p = 0.007] respectively. Subgroup analysis showed a significant difference in PFS and ORR between patients who received "hormonal therapy + CDK4/6 inhibitors" vs hormonal therapy only [SMD = 6.015 (CI 3.069-8.960), p < 0.001], (OR = 1.828 (CI 1.030-3.243), p = 0.039] respectively. Compared with hormonal monotherapy, targeted plus hormonal therapy significantly improves PFS, OS and ORR in postmenopausal women with HR+/HER2- advanced breast cancer.

A plain language summary of the CAPItello-291 study: Capivasertib in hormone receptor-positive advanced breast cancer.

This is a summary of the article discussing the results of the CAPItello-291 study. In the study, participants had advanced breast cancer that could not be completely removed with surgery, and that was diagnosed as a type of breast cancer where tumor cells had hormone receptors (HR-positive) but did not have HER2 receptors (HER2-negative). All participants were also required to have previously received treatment with a type of therapy called an aromatase inhibitor (with or without a CDK4/6 inhibitor), but over time their cancer cells had still grown or spread. The CAPItello-291 study researchers wanted to find out if a treatment combination of the medications capivasertib plus fulvestrant worked better than placebo plus fulvestrant. Capivasertib is a drug that blocks the activity of a protein called AKT, which is found inside breast cancer cells. The main finding was that participants who took capivasertib plus fulvestrant lived longer without their disease getting worse (progressing) compared with those treated with placebo plus fulvestrant. This is called progression-free survival. This result was seen across all participants (median progression-free survival of 7.2months with capivasertib plus fulvestrant vs 3.6months with placebo plus fulvestrant). It was also seen in participants whose tumors had detectable genetic alterations in genes called PIK3CA, AKT1, and/ or PTEN (median progression-free survival of 7.3months with capivasertib plus fulvestrant vs 3.1months with placebo plus fulvestrant). The most common side effects experienced by participants included diarrhea and different types of rash. These were as expected (given how capivasertib works). The CAPItello-291 study is still ongoing, and more results are expected to be released in the future. Results from the CAPItello-291 study showed that capivasertib plus fulvestrant compared with placebo plus fulvestrant improved progression-free survival in participants with HR-positive/ HER2-negative advanced breast cancer whose cancer had grown or spread despite hormone therapy (with/without a CDK4/6 inhibitor).Clinical Trial Registration: NCT04305496 (CAPItello-291) (ClinicalTrials.gov).

Neutrophil-to-lymphocyte ratio at the end of treatment with CDK4/6 inhibitors is an independent prognostic factor for ER-positive HER2-negative advanced breast cancer.

The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR), at the end of treatment (EOT) with CDK4/6 inhibitors abemaciclib and palbociclib in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer. We included 67 patients treated with fulvestrant plus abemaciclib or palbociclib. Overall survival (OS) since the EOT with CDK/4/6 inhibitors was compared in relation to the levels of ALC and NLR. The cut-off values of ALC and NLR were set at 1000/μL and 3, respectively. Patients with a high ALC at EOT showed significantly longer OS than those with a low ALC (p = 0.0358). Moreover, patients with a low NLR at EOT showed significantly longer OS than those with a high NLR at EOT (p = 0.0044). Looking at the changes of ALC and NLR between baseline and the EOT, patients with a high ALC both at baseline and at the EOT showed significantly longer OS than others (p = 0.0201). Similarly, patients with a low NLR both at baseline and at the EOT showed significantly longer OS after EOT than others (p = 0.0136). Multivariable analysis revealed that the NLR at EOT (low vs. high) and changes in NLR (low at baseline to low at EOT vs. others) were significant and independent prognostic factors for OS after EOT (p = 0.0337, p = 0.0039, respectively). NLR at EOT with CDK4/6 inhibitors is a significant and independent prognostic marker for patients with ER-positive HER2-negative advanced breast cancer.

Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial

CAPItello-291 is an ongoing phase 3 trial in which capivasertib-fulvestrant significantly improved progression-free survival versus placebo-fulvestrant in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had relapse or disease progression during or after aromatase inhibitor treatment, in both the overall population and in patients with PIK3CA, AKT1, or PTEN-altered tumours. This study further explored patient-reported health-related quality of life (HRQOL), functioning, symptoms, and symptom tolerability in CAPItello-291. This phase 3, randomised, double-blind, placebo-controlled trial, which was conducted across 193 hospitals and cancer centres in 19 countries, enrolled women with any menopausal status or men, aged ≥18 years (≥20 years in Japan), with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase (CDK) 4 or 6 inhibitor therapy. Patients had an Eastern Cooperative Oncology Group/WHO performance score of 0 or 1 and could have received up to two previous lines of endocrine therapy and up to one previous line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) using block randomisation (stratified according to the presence or absence of liver metastases, previous use of a CDK4/6 inhibitor [yes vs no], and geographical region) to receive oral capivasertib 400 mg (twice daily for 4 days, followed by 3 days off) plus intramuscular fulvestrant 500 mg (every 14 days for the first three injections, then every 28 days) or placebo with matching fulvestrant dosing. The dual primary endpoint of the trial was investigator-assessed progression-free survival assessed both in the overall population and among patients with PIK3CA, AKT1, or PTEN-altered tumours. The EORTC Quality of Life Questionnaire 30-item core module (QLQ-C30) and breast module (QLQ-BR23), Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT) questionnaires were used to assess patient-reported outcomes. Evaluation of EORTC QLQ-C30 and EORTC QLQ-BR23 were secondary endpoints and evaluation of PRO-CTCAE and PGI-TT were pre-defined exploratory endpoints, and these endpoints are the subject of analysis in this Article. Data were collected at baseline and prespecified timepoints. Patient-reported outcomes were analysed in all randomly assigned patients with an evaluable baseline assessment and at least one evaluable post-baseline assessment. Change from baseline was assessed using mixed model with repeated measures for EORTC QLQ-C30 and summarised for QLQ-BR23. Time to deterioration was described using the Kaplan-Meier method. PGI-TT and PRO-CTCAE responses were summarised at each treatment cycle. Patient-reported outcomes were not prospectively powered for statistical comparison. The trial is registered with ClinicalTrials.gov, NCT04305496. Between June 2, 2020, and Oct 13, 2021, 901 patients were enrolled, of whom 708 patients were randomly assigned to receive capivasertib-fulvestrant (n=355) or placebo-fulvestrant (n=353). The median age of the patients was 59 years (IQR 51-67) in the capivasertib-fulvestrant group and 58 years (IQR 49-66) in the placebo-fulvestrant group. At data cutoff (Aug 15, 2022), the median duration of follow-up for progression-free survival in censored patients was 13·0 months (IQR 9·1-16·7) for capivasertib-fulvestrant and 12·7 months (IQR 2·0-16·4) for placebo-fulvestrant in the overall population. EORTC QLQ-C30 global health status/quality of life (GHS/QOL) scores were maintained from baseline and were similar between treatment groups throughout the study period (difference in mean change from baseline of -2·5 [95% CI -4·5 to -0·6] with capivasertib-fulvestrant vs -5·6 [-7·9 to -3·4] with placebo-fulvestrant; treatment difference 3·1 [95% CI 0·2 to 6·0]). Median time to deterioration in EORTC QLQ-C30 GHS/QOL was 24·9 months (95% CI 13·8 to not reached) in the capivasertib-fulvestrant group and 12·0 months (10·2 to 15·7) in the placebo-fulvestrant group (hazard ratio [HR] 0·70, 95% CI 0·53 to 0·92). Time to deterioration HRs for all EORTC QLQ-C30 and QLQ-BR23 subscale scores showed little difference between the treatment groups, except for diarrhoea, which was worse in the capivasertib-fulvestrant group than in the placebo-fulvestrant group (HR 2·75, 95% CI 2·01-3·81). In PRO-CTCAE symptom assessment, the proportion of patients reporting loose and watery stools "frequently" or "almost constantly" was 29% higher at cycle 1, day 15 in the capivasertib-fulvestrant group than in the placebo-fulvestrant group, decreasing at subsequent cycles. Other PRO-CTCAE-reported symptoms (rash, mouth or throat sores, itchy skin, and numbness or tingling in hands or feet) were absent or mild in most patients in both groups throughout treatment. According to the PGI-TT, most patients in both groups reported "not at all" or "a little bit" of bother from treatment side-effects. Patient-reported outcomes from CAPItello-291 demonstrated that capivasertib-fulvestrant delayed time to deterioration of GHS/QOL and maintained other dimensions of HRQOL (except symptoms of diarrhoea) similarly to fulvestrant. With the clinical efficacy and manageable safety profile, these exploratory results further support the positive benefit-risk profile of capivasertib-fulvestrant in this population. AstraZeneca.