ABSTRACT
BACKGROUND: The addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer having a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery in an earlier analysis of this phase 3 trial of neoadjuvant and adjuvant therapy. The primary results regarding event-free survival in this trial have not been reported. METHODS: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response (the results for which have been reported previously) and event-free survival, defined as the time from randomization to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed. RESULTS: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. The median follow-up at this fourth planned interim analysis (data cutoff, March 23, 2021) was 39.1 months. The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI], 81.7 to 86.9) in the pembrolizumab-chemotherapy group, as compared with 76.8% (95% CI, 72.2 to 80.7) in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% CI, 0.48 to 0.82; P<0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. CONCLUSIONS: In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Progression-Free Survival , Triple Negative Breast Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Adjuvant , Female , Humans , Intention to Treat Analysis , Kaplan-Meier Estimate , Middle Aged , Neoadjuvant Therapy , Triple Negative Breast Neoplasms/surgeryABSTRACT
Triple-negative breast cancer (TNBC) has a poor prognosis with limited therapeutic options available for affected patients. Efforts are ongoing to identify surrogate markers for tumor-specific CD8+ T cells that can predict the response to immune checkpoint inhibitor (ICI) therapies, such as programmed cell death protein 1 or programmed cell death ligand-1 blockade. We have previously identified tumor-specific CD39+CD8+ T cells in non-small cell lung cancer that might help predict patient responses to programmed cell death protein 1 or programmed cell death ligand-1 blockade. Based on this finding, we conducted a comparative interrogation of TNBC in an Asian cohort to evaluate the potential of CD39 as a surrogate marker of tumor-specific CD8+ T cells. Using ICI-treated TNBC mouse models (n = 24), flow cytometric analyses of peripheral blood mononuclear cells and tumor-infiltrating lymphocytes revealed that >99% of tumor-specific CD8+ T cells also expressed CD39. To investigate the relationship between CD39+CD8+ T-cell density and CD39 expression with disease prognosis, we performed multiplex immunohistochemistry staining on treatment-naive human TNBC tissues (n = 315). We saw that the proportion of CD39+CD8+ T cells in human TNBC tumors correlated with improved overall survival, as did the densities of other CD39+ immune cell infiltrates, such as CD39+CD68+ macrophages. Finally, increased CD39 expression on CD8+ T cells was also found to predict the response to ICI therapy (pembrolizumab) in a separate cohort of 11 TNBC patients. These findings support the potential of CD39+CD8+ T-cell density as a prognostic factor in Asian TNBC patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Triple Negative Breast Neoplasms , Humans , Female , Animals , Mice , CD8-Positive T-Lymphocytes , Prognosis , Triple Negative Breast Neoplasms/metabolism , Programmed Cell Death 1 Receptor/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Leukocytes, Mononuclear/metabolism , Ligands , Lung Neoplasms/metabolism , Biomarkers/metabolism , Lymphocytes, Tumor-Infiltrating , B7-H1 Antigen/metabolismABSTRACT
BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively. CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Epirubicin/administration & dosage , Female , Humans , Intention to Treat Analysis , Kaplan-Meier Estimate , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Paclitaxel/administration & dosage , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathologyABSTRACT
Mutations in the PI3K pathway, particularly PIK3CA, were reported to be intimately associated with triple-negative breast cancer (TNBC) progression and the development of treatment resistance. We profiled PIK3CA and other genes on 166 early-stage TNBC tumors from Singapore for comparison to publicly available TNBC cohorts. These tumors were profiled transcriptionally using a NanoString panel of immune genes and multiplex immunohistochemistry, then manually scored for PD-L1-positivity using 2 clinically relevant clones, SP142 and 22C3. We discovered a higher rate of PIK3CA mutations in our TNBC cohort than in non-Asian cohorts, along with TP53, BRCA1, PTPN11, and MAP3K1 alterations. PIK3CA mutations did not affect overall or recurrence-free survival, and when compared with PIK3CAWT tumors, there were no differences in immune infiltration. Using 2 clinically approved antibodies, PIK3CAmut tumors were associated with PD-L1 negativity. Analysis of comutation frequencies further revealed that PIK3CA mutations tended to be accompanied by MAP kinase pathway mutation. The mechanism and impact of PIK3CA alterations on the TNBC tumor immune microenvironment and PD-L1 positivity warrant further study.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/pathology , B7-H1 Antigen/genetics , Singapore , Phosphatidylinositol 3-Kinases/genetics , Mutation , Class I Phosphatidylinositol 3-Kinases/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Tumor MicroenvironmentABSTRACT
Despite recent treatment advances, the prognosis for patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) remains poor. The antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) is composed of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable, cleavable linker. The phase III TROPION-Breast02 trial in patients previously untreated for locally recurrent inoperable or metastatic TNBC, who are not candidates for PD-1/PD-L1 inhibitors is evaluating efficacy and safety of Dato-DXd versus investigator's choice of chemotherapy (ICC). Approximately 600 patients will be randomized 1:1 to Dato-DXd 6 mg/kg iv. every 3 weeks or ICC (paclitaxel, nab-paclitaxel, carboplatin, capecitabine or eribulin mesylate). Dual primary end points are progression-free survival by blinded independent central review and overall survival.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is hard to treat. Tumors lack receptors for estrogen and progesterone, which means that standard endocrine therapy is ineffective, and it does not express HER2, so HER2 therapies are also not appropriate. However, the majority of TNBC tumors do possess a cell surface protein called TROP2 which provides a way of directing treatment inside tumor cells that is more selective than traditional chemotherapy. Datopotamab deruxtecan (Dato-DXd) is a drug that consists of two parts: datopotamab (an antibody) and DXd (the cancer-cell killing toxic component), which are joined via a stable linker. Datopotamab binds to the TROP2 protein found on TNBC tumors and is taken into the cell. The linker is then broken and releases DXd, which kills the tumor cell. By binding to cancer cells before releasing the payload, treatment is directed to the tumor, minimizing side effects in the rest of the body. The TROPION-Breast02 study aims to discover whether Dato-DXd is more effective than standard-of-care chemotherapy, allowing patients with TNBC to live longer without their breast cancer getting worse. This study is also looking at how Dato-DXd may affect patients' overall functioning and quality of life. TROPION-Breast02 will recruit approximately 600 patients who: Have cancer that has spread from the original site (metastatic), or cancer that returned to the same site (locally recurrent) that cannot be surgically removed Have not received any prior treatment for this stage of cancer Cannot receive an alternative type of anticancer treatment called PD-(L)1 inhibitors Had any length of time between their last treatment with the aim of cure and return of their disease Eligible patients will be randomly assigned to a treatment group in equal numbers to either Dato-DXd or an appropriate chemotherapy (one of five available options, chosen by the treating doctor). Each patient will generally continue to receive their designated treatments if the tumor is controlled by the drug, there are no unacceptable side effects, or the patient chooses to stop treatment. Clinical Trial Registration: NCT05374512 (ClinicalTrials.gov).
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Immunoconjugates , Triple Negative Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Prognosis , Antibodies, Monoclonal, Humanized/therapeutic use , Immunoconjugates/therapeutic use , Receptor, ErbB-2ABSTRACT
PURPOSE: PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib-paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). METHODS: Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: Overall, 146 patients were randomized to ipatasertib-paclitaxel and 76 to placebo-paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71-1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib-paclitaxel vs 1% with placebo-paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). CONCLUSION: Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib-paclitaxel safety profile was consistent with each agent's known adverse effects. Trial registration NCT03337724.
Subject(s)
Breast Neoplasms , Paclitaxel , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Double-Blind Method , Female , Hormones , Humans , Neoplasm Recurrence, Local , PTEN Phosphohydrolase/genetics , Paclitaxel/adverse effects , Phosphatidylinositol 3-Kinases , Piperazines , Proto-Oncogene Proteins c-akt , Pyrimidines , Receptor, ErbB-2/geneticsABSTRACT
BACKGROUND: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer. METHODS: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657. FINDINGS: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax). INTERPRETATION: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer. FUNDING: Merck Sharp & Dohme.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , B7-H1 Antigen/genetics , Triple Negative Breast Neoplasms/drug therapy , Adolescent , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , B7-H1 Antigen/antagonists & inhibitors , Female , Humans , Middle Aged , Neoplasm Metastasis , Progression-Free Survival , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Young AdultABSTRACT
PURPOSE: In LOTUS (NCT02162719), adding the oral AKT inhibitor ipatasertib to first-line paclitaxel for locally advanced/metastatic triple-negative breast cancer (aTNBC) improved progression-free survival (PFS; primary endpoint), with an enhanced effect in patients with PIK3CA/AKT1/PTEN-altered tumors (FoundationOne next-generation sequencing [NGS] assay). We report final overall survival (OS) results. METHODS: Eligible patients had measurable previously untreated aTNBC. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status, and were randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8, 15) plus ipatasertib 400 mg or placebo (days 1-21) every 28 days until disease progression or unacceptable toxicity. OS (intent-to-treat [ITT], immunohistochemistry PTEN-low, and PI3K/AKT pathway-activated [NGS PIK3CA/AKT1/PTEN-altered] populations) was a secondary endpoint. RESULTS: Median follow-up was 19.0 versus 16.0 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively. In the ITT population (n = 124), median OS was numerically longer with ipatasertib-paclitaxel than placebo-paclitaxel (hazard ratio 0.80, 95% CI 0.50-1.28; median 25.8 vs 16.9 months, respectively; 1-year OS 83% vs 68%). Likewise, median OS favored ipatasertib-paclitaxel in the PTEN-low (n = 48; 23.1 vs 15.8 months; hazard ratio 0.83) and PIK3CA/AKT1/PTEN-altered (n = 42; 25.8 vs 22.1 months; hazard ratio 1.13) subgroups. The ipatasertib-paclitaxel safety profile was unchanged. CONCLUSIONS: Final OS results show a numerical trend favoring ipatasertib-paclitaxel and median OS exceeding 2 years with ipatasertib-paclitaxel. Overall, results are consistent with the reported PFS benefit; interpretation within biomarker-defined subgroups is complicated by small sample sizes and TNBC heterogeneity.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Disease-Free Survival , Double-Blind Method , Female , Humans , Paclitaxel/adverse effects , Phosphatidylinositol 3-Kinases , Piperazines , Pyrimidines , Triple Negative Breast Neoplasms/drug therapyABSTRACT
OBJECTIVE: Many patients with advanced illness are unrealistically optimistic about their prognosis. We test for the presence of several cognitive biases, including optimism bias, illusion of superiority, self-deception, misattribution, and optimistic update bias, that could explain unrealistically optimistic prognostic beliefs among advanced cancer patients and quantifies the extent to which hope exacerbates these biases. METHODS: A cross-sectional survey was administered to 200 advanced cancer patients with physician-estimated prognoses of one year or less. Hope was measured using the Herth Hope Index (HHI). Hypotheses were tested using linear and logistic regressions and a structural-equation model. RESULTS: Results are consistent with the presence of optimism bias, illusion of superiority, self-deception, and misattribution. All of these biases are amplified by higher levels of hope. Each 1-point higher HHI is associated with a 6% (OR: 1.06; 95% CI: 1.01-1.11) greater odds of believing their illness is curable, a 0.33-year (95% CI: 0.17-0.49) longer expected survival, a 6% (OR: 1.06; 95% CI: 1.02-1.11) higher probability of believing that survival outcomes are better than the average patient, a 5% higher odds of believing primary intent of treatment is curative (OR: 1.05; 95% CI: 1.00-1.10), and a 12% (OR: 1.12; 95% CI: 1.05-1.17) higher odds of believing they are well-informed. Mediation analyses revealed that hope significantly mediates the effect of mental-well-being and loneliness on expected survival. CONCLUSIONS: Results suggest advanced cancer patients succumb to several cognitive biases which are exacerbated by greater levels of hope. As a result, they are susceptible to possible over-treatment and regret.
Subject(s)
Motivation , Neoplasms , Bias , Cross-Sectional Studies , Humans , OptimismABSTRACT
PURPOSE OF REVIEW: Breast cancer is a relative latecomer in the success story of immuno-oncology. In this review, we focus on the preclinical and clinical lines of evidence to justify the evaluation of immune checkpoint inhibition (ICI) for the curative-intent treatment of breast cancer, the latest and ongoing trials of (neo)adjuvant immunotherapy, and practical considerations in clinical practice associated with this new treatment paradigm. RECENT FINDINGS: Insights from the immunobiology of breast cancer have paved the way for the new frontier of immunotherapy in this malignancy, starting from advanced stages and moving onto curable cases. Tumor-infiltrating lymphocyte quantification and PD-L1 immunohistochemistry are forerunners of predictive biomarkers for sensitivity to ICI in breast cancers. Preliminary results from phase III trials of combinatorial immunochemotherapy to treat early high-risk or locally advanced triple-negative breast cancer are encouraging for pathological complete response. Additional efficacy and patient-reported outcomes of (neo)adjuvant immunochemotherapy trials are awaited. SUMMARY: The prospect of integrating ICI in the treatment of early-stage breast cancer is promising. Questions regarding patient selection, the choice of ICI agent and combination partner in escalation strategies, sequencing and duration of treatments, cost-effectiveness and mechanisms of resistance remain to be answered by future research.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/immunology , Immune Checkpoint Inhibitors/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Breast Neoplasms/pathology , Clinical Trials, Phase III as Topic , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Neoadjuvant Therapy , Neoplasm Staging , Randomized Controlled Trials as TopicABSTRACT
PURPOSE: We used multiplex immunofluorescence (mIF) to determine whether mitotic rate represents an independent prognostic marker in triple-negative breast cancer (TNBC). Secondary aims were to confirm the prognostic significance of immune cells in TNBC, and to investigate the relationship between immune cells and proliferating tumour cells. METHODS: A retrospective Asian cohort of 298 patients with TNBC diagnosed from 2003 to 2015 at the Singapore General Hospital was used in the present study. Formalin-fixed, paraffin-embedded breast cancer samples were analysed on tissue microarrays using mIF, which combined phospho-histone H3 (pHH3) expression with cytokeratin (CK) and leukocyte common antigen (CD45) expression to identify tumour and immune cells, respectively. RESULTS: Multivariate analysis showed that a high pHH3 index was associated with significantly improved overall survival (OS; p = 0.004), but this was not significantly associated with disease-free survival (DFS; p = 0.22). Similarly, multivariate analysis also revealed that a pHH3 positive count of > 1 cell per high-power field in the malignant epithelial compartment was an independent favourable prognostic marker for OS (p = 0.033) but not for DFS (p = 0.250). Furthermore, a high CD45 index was an independent favourable prognostic marker for DFS (p = 0.018), and there was a significant positive correlation between CD45 and pHH3 index (Spearman rank correlation coefficient, 0.250; p < 0.001). CONCLUSIONS: Mitotic rates as determined by pHH3 expression in epithelial cells are significantly associated with improved survival in TNBC. mIF analysis of pHH3 in combination with CK and CD45 could help clinicians in prognosticating patients with TNBC.
Subject(s)
Histones/metabolism , Triple Negative Breast Neoplasms/metabolism , Biomarkers , Female , Fluorescent Antibody Technique , Gene Expression , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Leukocyte Common Antigens , Phosphorylation , Prognosis , Reproducibility of Results , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathologyABSTRACT
The PD-L1 inhibitor atezolizumab received US FDA accelerated approval as treatment for PD-L1-positive metastatic triple-negative breast cancer (TNBC). In IMpassion130, combining atezolizumab with first-line nab-paclitaxel for metastatic TNBC significantly improved progression-free survival and showed a clinically meaningful effect on overall survival in patients with PD-L1-positive tumors. The placebo-controlled randomized Phase III IMpassion132 (NCT03371017) trial is evaluating atezolizumab with first-line chemotherapy (capecitabine [mandatory in platinum-pretreated patients] or gemcitabine/carboplatin) for inoperable locally advanced/metastatic TNBC recurring ≤12 months after completing standard (neo)adjuvant anthracycline and taxane chemotherapy. Stratification factors are: visceral metastases, tumor immune cell PD-L1 status and selected chemotherapy. Patients are randomized to atezolizumab 1200 mg or placebo every 3 weeks with the chosen chemotherapy, continued until progression, unacceptable toxicity or withdrawal. The primary end point is overall survival.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Neoplasm Recurrence, Local/drug therapy , Triple Negative Breast Neoplasms/therapy , Adult , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , B7-H1 Antigen/metabolism , Capecitabine/therapeutic use , Carboplatin/therapeutic use , Chemotherapy, Adjuvant/methods , Clinical Trials, Phase III as Topic , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Female , Humans , Mastectomy , Multicenter Studies as Topic , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Placebos/administration & dosage , Randomized Controlled Trials as Topic , Treatment Outcome , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathology , GemcitabineABSTRACT
PURPOSE: Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy. METHODS: This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates. RESULTS: A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1-6%; p = 0.009). CONCLUSIONS: This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.
Subject(s)
Breast Neoplasms/drug therapy , Cognitive Dysfunction/blood , DNA, Mitochondrial/blood , Fatigue/blood , Adult , Aged , Anthracyclines/administration & dosage , Anthracyclines/adverse effects , Breast Neoplasms/blood , Breast Neoplasms/complications , Breast Neoplasms/pathology , Bridged-Ring Compounds/administration & dosage , Bridged-Ring Compounds/adverse effects , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/genetics , Cognitive Dysfunction/pathology , DNA, Mitochondrial/genetics , Fatigue/complications , Fatigue/genetics , Fatigue/pathology , Female , Humans , Logistic Models , Middle Aged , Neoplasm Staging , Taxoids/administration & dosage , Taxoids/adverse effectsABSTRACT
BACKGROUND: Advanced cancer significantly impacts quality of life of patients and families as they cope with symptom burden, treatment decision-making, uncertainty and costs of treatment. In Singapore, information about the experiences of advanced cancer patients and families and the financial cost they incur for end-of-life care is lacking. Understanding of this information is needed to inform practice and policy to ensure continuity and affordability of care at the end of life. The primary objectives of the Cost of Medical Care of Patients with Advanced Serious Illness in Singapore (COMPASS) cohort study are to describe changes in quality of life and to quantify healthcare utilization and costs of patients with advanced cancer at the end of life. Secondary objectives are to investigate patient and caregiver preferences for diagnostic and prognostic information, preferences for end-of-life care, caregiver burden and perceived quality of care and to explore how these change as illness progresses and finally to measure bereavement adjustment. The purpose of this paper is to present the COMPASS protocol in order to promote scientific transparency. METHODS: This cohort study recruits advanced cancer patients (n = 600) from outpatient medical oncology clinics at two public tertiary healthcare institutions in Singapore. Patients and their primary informal caregiver are surveyed every 3 months until patients' death; caregivers are followed until 6 months post patient death. Patient medical and billing records are obtained and merged with patient survey data. The treating medical oncologists of participating patients are surveyed to obtain their beliefs regarding care delivery for the patient. DISCUSSION: The study will allow combination of self-report, medical, and cost data from various sources to present a comprehensive picture of the end-of-life experience of advanced cancer patients in a unique Asian setting. This study is responsive to Singapore's National Strategy for Palliative Care which aims to identify opportunities to meet the growing need for high quality care for Singapore's aging population. Results will also be of interest to policy makers and researchers beyond Singapore who are interested to understand and improve the end-of-life experience of cancer patients. TRIAL REGISTRATION: NCT02850640 (Prospectively registered on June 9, 2016).
Subject(s)
Clinical Protocols , Critical Illness/economics , Critical Illness/epidemiology , Health Care Costs , Adult , Aged , Critical Illness/psychology , Health Expenditures , Health Knowledge, Attitudes, Practice , Humans , Middle Aged , Patient Acceptance of Health Care , Public Health Surveillance , Quality of Life , Severity of Illness Index , Singapore/epidemiology , Stress, Psychological , Young AdultABSTRACT
OBJECTIVES: Currently, there are no studies that have established the self-perceived cognitive trajectories experienced by breast cancer patients (BCPs) post-chemotherapy. Therefore, we characterized the long-term trajectory of self-perceived cognitive function among Asian early-stage BCPs using the minimal clinically important difference of a subjective measure of cognitive function. METHODS: Early-stage BCPs who received chemotherapy were recruited and assessed at 4 time points: Before chemotherapy initiation (T1), 6 weeks post-chemotherapy initiation (T2), 12 weeks post-chemotherapy initiation (T3), and 15-months post-chemotherapy initiation (T4). All assessments were performed approximately within 2 weeks post-chemotherapy. Subjective and objective cognitive function were assessed using Functional Assessment of Cancer Therapy-Cognitive (version 3) and Headminder™. RESULTS: A total of 166 BCPs were recruited, of whom 131 completed assessment at all time points. Using the minimal clinically important difference of Functional Assessment of Cancer Therapy-Cognitive, 5 distinct cognitive trajectories were established. Of the 131 patients, 70 (53.4%) did not report any clinically significant cognitive impairment. Twenty-one (16.0%) patients reported acute cognitive changes during chemotherapy (T2 and/or T3) but not at T4. Forty patients (30.5%) reported clinically significant cognitive impairment at T4, of whom 18 did not report any cognitive impairment at earlier time points. Fifteen (11.5%) patients reported persistent cognitive impairment throughout all time points, while 7 (5.3%) patients reported intermittent cognitive impairment at T2 and T4 but not at T3. CONCLUSION: This is the first study to establish the existence of heterogeneous cognitive trajectories based on clinically significant thresholds of self-perceived cognitive impairment. The findings have important implications on the window for screening and management of post-chemotherapy cognitive impairment.
Subject(s)
Asian People/psychology , Breast Neoplasms/psychology , Cancer Survivors/psychology , Cognitive Dysfunction/psychology , Self Concept , Adult , Aged , Cognition , Disease Progression , Female , Humans , Longitudinal Studies , Middle Aged , Prospective Studies , SingaporeABSTRACT
PURPOSE: To investigate the natural history of taxane-associated acute pain syndrome (TAPS) in a docetaxel patient cohort and to examine the long-term manifestation of TAPS. PATIENTS AND METHODS: For three consecutive treatment cycles, taxane-naive breast cancer patients completed diaries on days 1-7, 14, and 21 and telephone questionnaires 1, 3, 6, 9, and 12 months following treatment. Questionnaires to assess pain and interference were adapted from the Brief Pain Inventory. To examine the experience of arthralgia and myalgia as one syndrome, information on patient experiences with arthralgia or myalgia was elicited separately in order to determine how closely experiences of each toxicity correlated with each other. A ≥2 point increase from baseline was defined as an arthralgia or myalgia "pain flare," and only those with "flare" were included in calculations of incidence. RESULTS: A total of 278 patients were accrued. Thirty-eight patients were omitted due to missing information, and 24 patients were omitted due to metastatic disease, for a total of 216 patients overall and 188 in the docetaxel cohort. A total of 74.5% of docetaxel patients experienced joint pain flare, and 78.2% experienced muscle pain flare at some point in the overall course of three treatment cycles. Joint and muscle pain peaked on days 4-5 for each cycle, and median pain severity for both joint and muscle pain was 4/10 during the 21-day period. Median onset of joint pain flare was 3 days for cycle 1 and 4 days for cycles 2 and 3, with an average median duration of 4 days. Median onset of muscle pain flare was 4 days for all three cycles, with a median duration of 4 days for cycles 1 and 2, and 5 days for cycle 3. Both joint and muscle pain persisted 1 year after treatment in approximately half of responding patients. CONCLUSION: This study documents the significant incidence of TAPS in patients treated with docetaxel chemotherapy and shows a long-term persistence of the syndrome.
Subject(s)
Arthralgia/chemically induced , Breast Neoplasms/drug therapy , Myalgia/chemically induced , Taxoids/adverse effects , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Pain/chemically induced , Docetaxel , Female , Humans , Incidence , Middle Aged , Prospective Studies , Surveys and Questionnaires , Taxoids/administration & dosageABSTRACT
BACKGROUND: The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1-21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719). FINDINGS: Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5-14·1) in the ipatasertib group and 10·2 months (6·0-13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8-9·0) with ipatasertib versus 4·9 months (3·6-5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37-0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6-9·1) with ipatasertib versus 3·7 months (1·9-7·3) with placebo (stratified HR 0·59, 95% CI 0·26-1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group. INTERPRETATION: Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer. FUNDING: F Hoffmann-La Roche.