Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. METHODS: In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. INTERPRETATION: Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. FUNDING: Daiichi Sankyo and AstraZeneca.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population. METHODS: This randomised, open-label, multicentre, phase 3 trial was conducted at 227 sites (hospitals, university hospitals, clinics, community centres, and private oncology centres) in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive metastatic breast cancer, previously received trastuzumab emtansine, disease progression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate renal and hepatic function. Patients were randomly assigned (2:1) to receive trastuzumab deruxtecan (intravenously at 5·4 mg/kg once every 3 weeks) or treatment of physician's choice using block randomisation. Treatment of physician's choice was either capecitabine (1250 mg/m2; orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint was progression-free survival based on blinded independent central review in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03523585. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). 608 (100%) patients were included in the full analysis set. The median age was 54·2 years (IQR 45·5-63·4) in the trastuzumab deruxtecan group and 54·7 years (48·0-63·0) in the treatment of physician's choice group. 384 (63%) patients were White, 603 (99%) were female, and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (8·8-26·0) in the treatment of physician's choice group. Median progression-free survival by blinded independent central review was 17·8 months (95% CI 14·3-20·8) in the trastuzumab deruxtecan group versus 6·9 months (5·5-8·4) in the treatment of physician's choice group (HR 0·36 [0·28-0·45]; p<0·0001). The most common treatment-emergent adverse events were nausea (293 [73%] of 404 with trastuzumab deruxtecan vs 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] vs 25 [13%]), alopecia (150 [37%] vs eight [4%]), fatigue (147 [36%] vs 52 [27%]), diarrhoea (109 [27%] vs 105 [54%]), and palmar-plantar erythrodysaesthesia (seven [2%] vs 100 [51%]). Grade 3 or higher treatment-emergent adverse events occurred in 213 (53%) patients receiving trastuzumab deruxtecan versus 86 (44%) receiving treatment of physician's choice; whereas drug-related interstitial lung disease occurred in 42 (10%; including two grade 5 death events) versus one (<1%). INTERPRETATION: DESTINY-Breast02 shows the favourable benefit-risk profile of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer, as previously reported in DESTINY-Breast01, and is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one. FUNDING: Daiichi Sankyo and AstraZeneca.

Association of Neutrophil-to-Lymphocyte Ratio and Absolute Lymphocyte Count With Clinical Outcomes in Advanced Breast Cancer in the MONARCH 2 Trial.

BACKGROUND: Established prognostic factors for treatment response to cyclin-dependent kinases 4 and 6 inhibitors are currently lacking. We aimed to investigate the relationship of pretreatment neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) to abemaciclib outcomes. PATIENTS AND METHODS: This was a post hoc analysis of data from MONARCH 2, a phase III study of abemaciclib or placebo plus fulvestrant in hormone-receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer that progressed on endocrine therapy. Patients were divided into high and low categories based on baseline NLR (cutoff: 2.5) and ALC (cutoff: 1.5 × 109/L). The association of baseline NLR and ALC with progression-free survival (PFS) and overall survival (OS) was explored using Cox models and Kaplan-Meier estimates. Tumor response and safety were also examined. RESULTS: NLR and ALC data were available for 645 patients (abemaciclib: N = 426; placebo: N = 219). Low-baseline NLR or high-baseline ALC was consistently associated with positive PFS and OS trends; low-baseline NLR subgroups also showed trends for better response. The abemaciclib treatment effect against placebo was observed regardless of baseline NLR or ALC. Univariate analyses showed baseline NLR and ALC were prognostic of PFS and OS. Baseline NLR remained significant in the multivariate model (P < .0001). No unexpected differences in safety were observed by baseline NLR or ALC. CONCLUSION: Baseline NLR was independently prognostic of PFS and OS. Low-baseline NLR was associated with numerically better efficacy outcomes, but the benefit of adding abemaciclib to fulvestrant was similar irrespective of baseline NLR status.

Prognostic value of the 21-Gene Breast Recurrence Score® assay for hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer: subanalysis from Japan Breast Cancer Research Group-M07 (FUTURE trial).

PURPOSE: This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial). METHODS: Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV). RESULTS: In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04-0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06-0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B. CONCLUSION: We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required.

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer.

In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.

Intratumoral Tumor Infiltrating Lymphocytes (TILs) are Associated With Cell Proliferation and Better Survival But Not Always With Chemotherapy Response in Breast Cancer.

OBJECTIVE: To investigate the clinical relevance of intratumoral tumor infiltrating lymphocytes (TILs) in breast cancer as measured by computational deconvolution of bulk tumor transcriptomes. SUMMARY BACKGROUND DATA: Commonly assessed TILs, located in tumor stroma without direct contact with cancer cells (stromal TILs), correlate with breast cancer treatment response and survival. The clinical relevance of intratumoral TILs has been less studied partly due to their rarity; however, they may have nonnegligible effects given their direct contact with cancer cells. METHODS: In all, 5870 breast cancer patients from TCGA, METABRIC, GSE96058, GSE25066, GSE163882, GSE123845, and GSE20271 cohorts were analyzed and validated. RESULTS: The intratumoral TIL score was established by the sum of all types of lymphocytes using the xCell algorithm. This score was the highest in triple-negative breast cancer (TNBC) and the lowest in the ER-positive/HER2-negative subtype. It correlated with cytolytic activity and infiltrations of dendritic cells, macrophages, and monocytes, and uniformly enriched immune-related gene sets regardless of subtype. Intratumoral TIL-high tumors correlated with higher mutation rates and significant cell proliferation on biological, pathological, and molecular analyses only in the ER-positive/HER2-negative subtype. It was significantly associated with pathological complete response after anthracycline- and taxane-based neoadjuvant chemotherapy in about half of the cohorts, regardless of the subtype. Intratumoral TIL-high tumors correlated with better overall survival in HER2-positive and TNBC subtypes consistently in 3 cohorts. CONCLUSIONS: Intratumoral TILs estimated by transcriptome computation were associated with increased immune response and cell proliferation in ER-positive/HER2-negative and better survival in HER2-positive and TNBC subtypes, but not always with pathological complete response after neoadjuvant chemotherapy.

Baseline interleukin-6 is a prognostic factor for patients with metastatic breast cancer treated with eribulin.

PURPOSE: Eribulin is a unique anti-cancer drug which can improve overall survival (OS) of patients with metastatic breast cancer (MBC), probably by modulating the tumor immune microenvironment. The aim of this study was to investigate the clinical significance of serum levels of immune-related and inflammatory cytokines in patients treated with eribulin. Furthermore, we investigated the association between cytokines and immune cells, such as myeloid-derived suppressor cells (MDSCs) and cytotoxic and regulatory T cells, to explore how these cytokines might affect the immune microenvironment. METHODS: Sixty-eight patients with MBC treated with eribulin were recruited for this retrospective study. The relationship of cytokines, including interleukin (IL)-6, to progression-free survival and OS was examined. CD4+ and CD8+ lymphocyte, MDSCs and regulatory T cell levels were determined in the blood by flow cytometry analysis. RESULTS: In our cohort, patients with high IL-6 at baseline had shorter progression-free survival and OS compared with those with low IL-6 (p = 0.0017 and p = 0.0012, respectively). Univariable and multivariable analyses revealed that baseline IL-6 was an independent prognostic factor for OS (p = 0.0058). Importantly, CD8+ lymphocytes were significantly lower and MDSCs were significantly higher in patients with high IL-6, compared to those with low IL-6. CONCLUSION: Baseline IL-6 is an important prognostic factor in patients with MBC treated with eribulin. Our results show that high IL-6 is associated with higher levels of MDSCs which suppress anti-tumor immunity, such as CD8+ cells. It appears that eribulin is not particularly effective in patients with high IL-6 due to a poor tumor immune microenvironment.

Early assessment of tumor response using 18F-FDG PET/CT after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer.

OBJECTIVE: This study was conducted to evaluate the usefulness of early assessment of tumor response using fluorine-18-fludeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) after one cycle of systemic therapy in patients with recurrent and metastatic breast cancer. SUBJECT AND METHODS: Thirty-three patients with recurrent or metastatic breast cancer underwent 18F-FDG PET/CT before and after one cycle of systemic therapy. Based on the European Organization for Research and Treatment of Cancer (EORTC) criteria, the maximum standardized uptake value (SUVmax) of the same lesions (up to a total of five) noted in the baseline and follow-up scans were summed (maximum of two per organ) as target lesions, and therapeutic response was evaluated. Log-rank and Cox methods were employed to determine progression-free survival (PFS) and overall survival (OS). RESULTS: Complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD) was seen in 2, 16, 11, and 4 patients, respectively. The mean reduction rates of SUVmax between 84 target lesions in 18 responders (CMR/PMR) and 75 target lesions in 15 non-responders (SMD/PMD) were -55.8% (range, -100%- -1.2%) and 0.47% (range, -48.7%- +209.4%), respectively, with a significant difference (P<0.0001). Every lesion site (local lesion, lymph node metastasis, bone metastasis, lung metastasis, and liver metastasis) showed a similar tendency. Thirty patients showed progression, and 17 died due to breast cancer after a median of 38.5 months. Responders showed significantly longer PFS than non-responders (P=0.0038). CONCLUSION: Fluorine-18-FDG PET/CT after one cycle of systemic therapy was able to reflect early metabolic changes regardless of the lesion site, and showed accuracy for early response evaluation and prediction of progression in patients with recurrent or metastatic breast cancer.

Significant association between high serum CCL5 levels and better disease-free survival of patients with early breast cancer.

Analysis of anticancer immunity aids in assessing the prognosis of patients with breast cancer. From 250 operated breast cancers, we focused on serum levels of C-C motif chemokine ligand 5 (CCL5), which is involved in cancer immune reactions. Serum levels of CCL5 were measured using a cytometric bead-based immunoassay kit and CCL5 expression in cancer cells was determined using immunohistochemical staining. In addition, mRNA in cancer and stromal cells was analyzed by microdissection and comparison with the public dataset. Disease-free survival (DFS) of patients with high CCL5 levels (cut-off, 13.87 ng/mL; n = 192) was significantly better than those with low CCL5 levels (n = 58; hazard ratio, 0.20; 95% confidence interval, 0.10-0.39; P < .0001). An improved overall survival was observed in patients with high CCL5 levels compared to those with low CCL5 levels (P = .024). On the contrary, high immunohistochemical expression of CCL5 in cancer cells was significantly associated with decreased DFS. As serum CCL5 levels did not correlate with CCL5 expression in cancer cells and the relative expression of mRNA CCL5 was elevated in stromal cells in relation to cancer cells, serum CCL5 might be derived not from cancer cells, but from stromal cells. Expression of CCL5 in serum, but not in cancer cells, might contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms. Determination of circulating CCL5 levels could be useful for predicting patient prognosis.

Harmonized pretreatment quantitative volume-based 18F-FDG PET/CT parameters for stage IV breast cancer prognosis. Multicenter study in Japan.

OBJECTIVE: The prognostic value of harmonized pretreatment volume-based quantitative fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters in metastatic breast cancer patients was investigated. SUBJECTS AND METHODS: Records of 65 stage IV breast cancer patients, including 29 estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 23 HER2-positive, and 13 triple-negative cases, from four different institutions were retrospectively reviewed. Harmonized standardized uptake value (SUVmax) of the primary tumor (pSUVmax), highest SUVmax of all malignant lesions (wSUVmax), whole-body metabolic tumor volume (WB MTV), and whole-body total lesion glycolysis (WB TLG) shown by pretreatment 18F-FDG PET/CT imaging were calculated. Cox proportional hazards model and log-rank test results were used to evaluate relationships among clinicopathological factors, volume-based quantitative 18F-FDG PET/CT parameters, progression-free survival, and overall survival (OS). RESULTS: Disease progression occurred in 54 patients and 28 died during a median follow-up period of 52.5 months (range 2.6-133.6 months). Univariate analysis of all cases showed associations of negative ER and progesterone receptor (PR) status (P=0.0025), and high T/N stage (P=0.037/P=0.019), pSUVmax (P=0.049), WB MTV (P=0.021), and WB TLG (P=0.0010) with significantly shorter OS. Multivariate analysis confirmed negative ER and PR status (hazard ratio [HR]: 6.42, 95% confidence interval [CI]: 2.27-19.38; P=0.0054), high T stage (HR: 5.10, 95% CI:1.96-18.61, P=0.0064) and WB TLG (HR: 4.69, 95% CI:1.67-12.79, P=0.049) as independent negative OS predictors. In two groups of ER-positive/HER2-negative and triple-negative, WB TLG had a significant association with death (P=0.021 and P=0.037, respectively) on univariate analysis. In a HER2-positive group, no independent negative OS predictors were observed. CONCLUSION: In metastatic breast cancer patients, harmonized pretreatment quantitative volume-based 18F-FDG PET/CT parameters, especially whole-body TLG, are potential surrogate markers for prognosis.

Participants in a randomized controlled trial had longer overall survival than non-participants: a prospective cohort study.

PURPOSE: While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely. METHODS: This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival. RESULTS: The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006). CONCLUSIONS: This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

Significance of Metabolic Tumor Volume at Baseline and Reduction of Mean Standardized Uptake Value in 18F-FDG-PET/CT Imaging for Predicting Pathological Complete Response in Breast Cancers Treated with Preoperative Chemotherapy.

BACKGROUND: The usefulness of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography for evaluating the treatment efficacy of breast cancers is well-established; however, the predictive values of parameters such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) remain unknown. METHODS: This study examined 199 breast cancers treated with primary systemic chemotherapy (PSC) followed by operation, and determined the values of maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), MTV, and TLG at baseline. Among these cases, data on early changes in these metabolic parameters in 70 breast cancers were also assessed. RESULTS: A pathological complete response (pCR) was achieved in 64 breast cancers. Breast cancers with low MTV at baseline had a significantly higher pCR rate than breast cancers with high MTV (47.9% vs. 23.4%; p = 0.0005). High reduction rates (∆) of SUVmax (p = 0.0001), SUVpeak (p = 0.0001), and SUVmean (p < 0.0001) resulted in an increased pCR compared with those for low ∆. The pCR rate was highest for the combination of low MTV and high ∆SUVmean (86.7%), and lowest for high MTV and low ∆SUVmean (15.4%); the remaining combinations were intermediate (58.6%; p < 0.0001). The combination of low MTV at baseline and high ∆SUVmean was a significant and independent predictor for pCR (odds ratio 28.63; 95% confidence interval 1.94-422.42; p = 0.0146) in multivariable analysis. CONCLUSIONS: Low levels of MTV at baseline and a high reduction of SUVmean after PSC was significantly associated with pCR. These findings suggest the usefulness of these metabolic parameters for predicting the treatment efficacy of breast cancers.

Prognostic value of 18F-FDG PET/CT prior to breast cancer treatment. Comparison with magnetic resonance spectroscopy and diffusion weighted imaging.

OBJECTIVE: To investigate the prognostic value of pretreatment fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), magnetic resonance spectroscopy (MRS), and diffusion weighted imaging (DWI) in breast cancer patients. SUBJECTS AND METHODS: Eighty-three patients who had a tumor larger than 2cm shown by 18F-FDG PET/CT and by 3-Tesla breast MRI, received neoadjuvant chemotherapy (NAC) and subsequent surgical resection. Relationships of PET parameters, including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), as well as total choline peak and mean apparent diffusion coefficient (ADCmean) of the primary tumor were evaluated, along with the clinicopathologic factors relapse-free survival (RFS) and overall survival (OS) using log-rank and Cox tests. RESULTS: Median overall follow-up was 36.3 months (16.1-76.9 months), during which 11 patients had recurrence and 4 died. Results of receiver operating characteristics curve analysis and log-rank tests showed that high primary tumor SUVmax (≥6.20), MTV (≥5.39), TLG (≥23.23), and total choline peak (≥12.1) values indicated significantly worse RFS as compared to lower values (<6.20, <5.39, <23.23, <12.1, respectively) (P=0.0085, P=0.0029, P=0.013, P=0.016, respectively). The ADC cut-off value (0.833×10-3) was not significant. Furthermore, elevated SUVmax, MTV, TLG, and choline peak levels, progesterone receptor (PR) negative finding, high Ki-67 expression, metastasis to an axillary lymph node, and advanced TNM staging were significantly associated with recurrence, and elevated SUVmax and TLG, PR-negative finding, and axillary node metastases were significantly associated with death. CONCLUSION: Fluorine-18-FDG PET/CT was superior as compared to MRS and DWI for determining recurrence and death prognostic factors, especially primary tumor SUVmax and TLG, in patients with breast cancer.

Abundant tumor infiltrating lymphocytes after primary systemic chemotherapy predicts poor prognosis in estrogen receptor-positive/HER2-negative breast cancers.

PURPOSE: The therapeutic effect of systemic treatment for breast cancer (BC) generally depends on its intrinsic subtypes. In addition, tumor infiltrating lymphocytes (TILs) are considered to be an independent factor for tumor shrinkage and disease prognosis. High TILs at baseline or after primary systemic chemotherapy are reported to be associated with better survival in triple-negative or human epithelial growth factor receptor 2 (HER2)-positive BCs. However, the prognostic value of TILs in estrogen receptor (ER)-positive and HER2-negative (ER+/HER2-) BC is still controversial. METHODS: We assessed TIL score (low, intermediate, and high) before and after primary systemic chemotherapy in every subtype of BC, and compared the clinical outcomes. Biopsy specimens of 47 triple-negative, 58 HER2+ and 91 ER+/HER2- BCs were used to assess TILs before treatment. To assess TILs after treatment, we examined residual invasive carcinoma in surgically resected samples of 28 triple-negative, 30 HER2+ and 80 ER+/HER2- BCs. RESULTS: A high TIL score in triple-negative BC before treatment resulted in a significantly higher proportion of pathological complete response (pCR). In contrast, ER+/HER2- BC exhibited fewer instances of pCR than other subtypes. Although not statistically significant, ER+/HER2- cases with a high TIL score also tended to achieve pCR (p = 0.088). Moreover, we revealed that low TIL BCs after chemotherapy, but not at baseline, had significantly better relapse-free survival in ER+/HER2- BC (p = 0.034). CONCLUSION: Pathological examination of TILs after treatment may be a surrogate marker for prognosis in ER+/HER2- BC.

Response to neoadjuvant chemotherapy for breast cancer judged by PERCIST - multicenter study in Japan.

PURPOSE: The purpose of this study was to evaluate therapeutic response to neoadjuvant chemotherapy (NAC) and predict breast cancer recurrence using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). MATERIALS AND METHODS: Fifty-nine breast cancer patients underwent fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) before and after NAC prior to planned surgical resection. Pathological complete response (pCR) of the primary tumor was evaluated using PERCIST, while effects of clinicopathological factors on progression-free survival (PFS) were examined using log-rank and Cox methods. RESULTS: Fifty-six patients and 54 primary tumors were evaluated. Complete metabolic response (CMR), partial metabolic response, stable metabolic disease, and progressive metabolic disease were seen in 45, 7, 3, and 1 patients, respectively, and 43, 7, 3, and 1 primary tumors, respectively. Eighteen (33.3%) of the 54 primary tumors showed pCR. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PERCIST to predict pCR were 100% (18/18), 30.6% (11/36), 41.9% (18/43), 100% (11/11), and 53.7% (29/54), respectively. An optimal percent decrease in peak standardized uptake value for a primary tumor corrected for lean body mass (SULpeak) of 84.3% was found to have a sensitivity of 77.8% (14/18), specificity of 77.8% (28/36), PPV of 63.6% (14/22), NPV of 87.5% (28/32), and accuracy of 77.8% (42/54). Seven (12.5%) of the 56 patients developed recurrent disease (median follow-up 28.1 months, range 11.4-96.4 months). CMR (p = 0.031), pCR (p = 0.024), and early TNM stage (p = 0.033) were significantly associated with longer PFS. CONCLUSION: PERCIST is useful for predicting pathological response and prognosis following NAC in breast cancer patients. However, FDG-PET/CT showed a tendency toward underestimation of the residual tumor, and relatively low specificity and PPV of PERCIST showed that a combination of other imaging modalities would still be needed to predict pCR.

Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel.

BACKGROUND: Although peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). METHODS: Data from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/µL, 2, and 250, respectively. RESULTS: PFS was significantly improved in patients with ALC ≥1500/µL compared to those with ALC 1000-, <1500/µL or ALC < 1000/µL (P = 0.0106). High baseline ALC was significantly associated with improved PFS (≥1500/µL; hazard ratio [HR]: 0.3715; 95% confidence interval [CI]: 0.1735-0.7955; P = 0.0108). In contrast, improved PFS was not significantly associated with NLR or PLR. Improved PFS in patients with ALC ≥1500/µL was observed irrespective of visceral metastasis or chemotherapy regimen. CONCLUSIONS: Our results showed that baseline ALC was a predictive factor for PFS in HER2-positive ABC treated with PT irrespective of combined chemotherapy regimen. Anti-tumor effects might be mediated not only by the tumor microenvironment, but also by systemic peripheral circulating lymphocytes. Baseline systemic parameters such as peripheral lymphocyte count might be beneficial in addition to disease extent for predicting the efficacy of PT treatment. TRIAL REGISTRATION: UMIN000012375 , registration date: 21NOV2013, and UMIN000006838 , registration date: 6DEC2011.

High levels of serum CA15-3 and residual invasive tumor size are associated with poor prognosis for breast cancer patients with non-pathological complete response after neoadjuvant chemotherapy.

BACKGROUND AND OBJECTIVES: To identify surrogate markers for prognosis of breast cancer patients with non-pathological complete response (non-pCR) to neoadjuvant chemotherapy (NAC), our investigation focused on the serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA15-3) as well as clinicopathological factors both before and after NAC. METHODS: A total of 185 breast cancer patients treated with NAC were recruited. Serum carcinoembryonic antigen and CA15-3 were measured at baseline and at completion of NAC. RESULTS: Among the non-pCR cancers (n = 142), the disease-free survival (DFS) of patients with CA15-3-low at baseline (3-year DFS: 0.908, n = 73) was significantly better than of those with CA15-3-high (3-year DFS: 0.681, n = 69, P = .0134). Multivariable analysis demonstrated that baseline CA15-3 levels (hazard ratio: 3.31, 95% confidence interval: 1.28-10.23; P = .0122) and residual invasive size (hazard ratio: 4.47, 1.26-28.39; P = .0171) were significant independent factors for DFS. The combination of these factors proved to be an accurate predictor for DFS regardless of breast cancer subtypes. CONCLUSIONS: The combination of residual invasive size and serum CA15-3 levels at baseline seems to be a significant and independent surrogate marker of poor outcome for patients with non-pCR. These findings suggest that these markers may be useful for identifying patients with inferior prognosis and candidates for additional adjuvant treatments.

Independent prognostic impact of preoperative serum carcinoembryonic antigen and cancer antigen 15-3 levels for early breast cancer subtypes.

BACKGROUND: Although the prognosis for operable breast cancers is reportedly worse if serum carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels are above normal, the usefulness of this prognosis is limited due to the low sensitivity and specificity; in addition, the optimal cutoff levels remain unknown. METHODS: A total of 1076 patients who were operated for breast cancers (test set = 608, validation set = 468) without evidence of metastasis were recruited, and their baseline and postoperative serum CEA and CA15-3 levels were analyzed. The optimal cutoff values of CEA and CA15-3 for disease-free survival (DFS) were 3.2 ng/mL and 13.3 U/mL, respectively, based on receiver operating characteristic curve and area under the curve analyses. RESULTS: The DFS of patients with high CEA levels (CEA-high: n = 191, 5-year DFS 70.6%) was significantly worse (p < 0.0001) than that of CEA-low patients (n = 885, 5-year DFS 87.2%). There was a significant difference in DFS (p < 0.0001) between CA15-3-high and CA15-3-low patients (n = 314 and n = 762, respectively; 5-year DFS 71.8 vs. 89.3%). Significant associations between DFS and CA15-3 levels were observed irrespective of the subtypes. Multivariable analysis indicated that tumor size, lymph node metastasis, tumor grade, and CEA (p = 0.0474) and CA15-3 (p < 0.0001) levels were independent prognostic factors (hazard ratio [HR] 1.520, 95% confidence interval [CI] 1.005-2.245 for CEA; HR 2.088, 95% CI 1.457-2.901 for CA15-3). CONCLUSIONS: These findings suggest that CEA and CA15-3 levels might be useful for predicting the prognosis of patients with operable early breast cancer irrespective of the subtype. Serum levels at baseline may reflect tumor characteristics for metastatic potential even when these levels are within the normal ranges.

Assessment of tumor response to neoadjuvant chemotherapy in patients with breast cancer using MRI and FDG-PET/CT-RECIST 1.1 vs. PERCIST 1.0.

Therapeutic response to neoadjuvant chemotherapy (NAC) for breast cancer based on Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 with FDG-PET/CT measurements was evaluated, and the results compared to those obtained with currently widely used Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, based on MRI measurements. MRI and FDG-PET/CT examinations were performed in 32 breast cancer patients before and after the NAC prior to a surgical resection. Chemotherapeutic response of the primary tumor and relapse-free survival (RFS) were investigated using RECIST 1.1 and PERCIST 1.0. Pathological complete response (pCR) was seen in 14 (43.8%) patients, while complete response (CR) was noted in 5, partial response in 25, stable disease in 2, and progressive disease in 0 with RECIST 1.1, and in 28, 2, 1, and 1, respectively, with PERCIST 1.0. For pCR prediction, the sensitivity, specificity, and accuracy with RECIST 1.1 were 28.6% (4/14), 94.4% (17/18), and 65.6% (21/32), and those with PERCIST 1.0 were 100% (14/14), 22.2% (4/18), and 56.3% (18/32). Five patients (15.6%) had recurrent development after a median period of 24 months (range 7.8-66.8 months). Patients who achieved CR shown by RECIST 1.1 showed slightly longer RFS than those who did not (p=0.46), whereas those with complete metabolic response (CMR) based on PERCIST 1.0 showed a relatively longer RFS than non-CMR patients (p=0.087). For prediction of pathological response to NAC in breast cancer, RECIST 1.1 and PERCIST 1.0 have complementary functions, however, FDG-PET as a post-NAC treatment assessment modality remains to be confirmed.

HP1 regulates the localization of FANCJ at sites of DNA double-strand breaks.

The breast and ovarian cancer predisposition protein BRCA1 forms three mutually exclusive complexes with Fanconi anemia group J protein (FANCJ, also called BACH1 or BRIP1), CtIP, and Abraxas/RAP80 through its BRCA1 C terminus (BRCT) domains, while its RING domain binds to BRCA1-associated RING domain 1 (BARD1). We recently found that the interaction between heterochromatin protein 1 (HP1) and BARD1 is required for the accumulation of BRCA1 and CtIP at sites of DNA double-strand breaks. Here, we investigated the importance of HP1 and BARD1-HP1 interaction in the localization of FANCJ together with the other BRCA1-BRCT binding proteins to clarify the separate role of the HP1-mediated pathway from the RNF8/RNF168-induced ubiquitin-mediated pathway for BRCA1 function. FANCJ interacts with HP1γ in a BARD1-dependent manner, and this interaction was enhanced by ionizing radiation or irinotecan hydrochloride treatment. Simultaneous depletion of all three HP1 isoforms with shRNAs disrupts the accumulation of FANCJ and CtIP, but not RAP80, at double-strand break sites. Replacement of endogenous BARD1 with a mutant BARD1 that is incapable of binding to HP1 also disrupts the accumulation of FANCJ and CtIP, but not RAP80. In contrast, RNF168 depletion disrupts the accumulation of only RAP80, but not FANCJ or CtIP. Consequently, the accumulation of conjugated ubiquitin was only inhibited by RNF168 depletion, whereas the accumulation of RAD51 and sister chromatid exchange were only inhibited by HP1 depletion or disruption of the BARD1-HP1 interaction. Taken together, the results suggest that the BRCA1-FANCJ and BRCA1-CtIP complexes are not downstream of the RNF8/RNF168/ubiquitin pathway, but are instead regulated by the HP1 pathway that precedes homologous recombination DNA repair.