Availability of genome-matched therapy based on clinical practice.

BACKGROUND: Comprehensive genomic profiling (CGP) provides new opportunities for patients with advanced cancer to receive genome-matched therapies, but the availability rate of these remains low. We reviewed our CGP cases and suggested possible strategies to improve the current status from a clinical perspective. METHODS: Druggable genomic alterations and barriers to accessing genome-matched therapies were investigated in 653 patients with 30 various types of cancers who underwent CGP. RESULTS: While the availability rate of genome-matched therapies as a whole was 9.5%, CGP was useful in some cancer types. Patients with thyroid cancer and lung cancer harbored druggable genomic alterations at high rates, while sarcoma rarely harbored these alterations (100%, 76%, and 15.2%, respectively). In contrast, the availability rate of genome-matched therapies was highest in patients with sarcoma and head and neck cancer (HNC) (60% and 40%, respectively). One hundred thirteen patients (63.5%) had multiple barriers to accessing genome-matched therapy. Of 178 patients, 21 patients (11.8%) could not be considered for genome-matched therapies solely because of the deterioration of their performance status. CONCLUSION: This study demonstrated the usefulness of CGP for patients with sarcoma and HNC in addition to lung cancer in clinical practice. Performing CGP at the front line has the potential to improve the availability of genome-matched therapy.

Prognostic impact of cancer genomic profile testing for advanced or metastatic solid tumors in clinical practice.

Cancer genomic profile (CGP) testing, which is covered by the national health insurance system in Japan, has been introduced as a routine clinical practice. However, the effects of CGP testing on prognoses remain unclear. Drug accessibility rates and prognoses after CGP testing were retrospectively investigated in 713 patients who underwent CGP testing examined by our molecular tumor board between November 2019 and October 2022,. Overall survival (OS) was examined using the log-rank test and the Kaplan-Meier method. The median age of patients (326 males and 387 females) was 58 years (12-85 years). CGP testing revealed one or more gene mutations in 681 cases (95.5%), among which actionable gene mutations were detected in 439 (61.6%). Although treatment options were recommended for 285 cases (40.0%) by the molecular tumor board, only 45 received treatment based on their gene mutations. During the median observation period of 8.6 months, 351 (49.2%) patients died of the exacerbation of existing diseases. No significant differences were observed in OS between patients treated with and without genomically matched therapy (p = 0.285). According to clinical responses to treatment based on gene mutations, median OS was significantly longer in patients who achieved partial response and stable disease (26.5 months; 95% CI 14.4-38.6) than in those with progressive disease and not evaluated (9.8 months; 95% CI 5.8-13.8, p = 0.013). Responses to treatment based on gene mutations may improve prognoses, and it is important to increase the drug accessibility rate after CGP testing.

Influence of menopause on chemotherapy-induced nausea and vomiting in highly emetogenic chemotherapy for breast cancer: A retrospective observational study.

BACKGROUND: Female sex and younger age are reported risk factors for chemotherapy-induced nausea and vomiting (CINV) in highly emetogenic chemotherapy, but the underlying mechanism has not been elucidated. The purpose of this study was to clarify the impact of menopause on CINV. METHODS: This retrospective observational study analyzed data from consecutive patients who received their first cycle of perioperative anthracycline-based chemotherapy for breast cancer between January 2018 and June 2020. The endpoints were association between CINV (vomiting, ≥Grade 2 nausea, complete response [CR] failure) and menopause as well as the association between CINV and follicle-stimulating hormone [FSH]/estradiol [E2]. RESULTS: Data for 639 patients were analyzed. Among these patients, 109 (17.1%) received olanzapine (four antiemetic combinations) and 530 (82.9%) did not (three antiemetic combinations). Premenopausal state (amenorrhea lasting ≥12 months) was significantly associated with ≥Grade 2 nausea and CR failure in univariate analysis but not in multivariate analysis. The premenopausal FSH/E2 group (defined by serum levels; FSH <40 mIU/mL and E2 ≥20 pg/mL) had a significantly higher rate of ≥Grade 2 nausea than the postmenopausal FSH/E2 group (FSH ≥40 mIU/mL and E2 <20 pg/mL) (48.8% vs. 18.8%, p = 0.023). CONCLUSIONS: Our results suggest that changes in FSH and E2 due to menopause may affect the severity of nausea and that FSH and E2 (especially FSH) levels might be useful indicators for CINV risk assessment.

Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial).

BACKGROUND: Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies. METHODS: This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers. RESULTS: From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy. CONCLUSIONS: Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs. TRIAL REGISTRATION NUMBER: JapicCTI-194782, jRCT2080224706, UMIN000036970.

Evaluation of an inflammation-based score for identification of appropriate patients for comprehensive genomic profiling.

Performance status (PS) is widely used as an assessment of general condition in patients before performing comprehensive genomic profiling (CGP). However, PS scoring is dependent on each physician, and there is no objective and universal indicator to identify appropriate patients for CGP. Overall, 263 patients were scored using the modified Glasgow prognostic score (mGPS) from 0 to 2 based on the combination of serum albumin and c-reactive protein (CRP): 0, albumin ≥ 3.5 g/dl and CRP ≤ 0.5 mg/dl; 1, albumin < 3.5 g/dl or CRP > 0.5 mg/dl; and 2, albumin < 3.5 g/dl and CRP > 0.5 mg/dl. Overall survival was compared between mGPS 0-1 and mGPS 2 groups. The prognosis of patients with PS 0-1 and mGPS 2 was also evaluated. Thirty-nine patients (14.8%) were mGPS 2. Patients with mGPS 2 had significant shorter survival (14.7 months vs 4.6 months, p < 0.01). Twenty-eight patients were PS 0-1 and mGPS 2, and their survival was also short (5.6 months). Evaluation of mGPS is a simple and useful method for identifying patients with adequate prognosis using CGP.

Assessment of a cancer genomic profile test for patients with metastatic breast cancer.

Comprehensive cancer genomic profile (CGP) tests are being implemented under Japanese universal health insurance system. However, the clinical usefulness of CGP test for breast cancer patients has not been evaluated. Of the 310 patients who underwent CGP testing at our institution between November 2019 and April 2021, 35 patients with metastatic breast cancer whose treatment strategy was discussed by our molecular tumor board within the study period were investigated after exclusion of 2 cases that could not be analyzed. The turn-around time, drug accessibility, and germline identification detection were evaluated. The subtype was luminal in 20 patients (57.1%), triple-negative in 12 patients (34.3%), and luminal-HER2 in 3 patients (8.6%). Actionable gene mutations were detected in 30 patients (85.7%), and 7 patients (20.0%) were recommended for clinical trial participation, with the drug administered to 2 patients (5.7%). Three patients (8.6%) died due to disease progression before the test results were disclosed. We report the results of an initial assessment of the utility of CGP testing for patients with metastatic breast cancer under Japanese universal health insurance system. Conducting CGP tests at a more appropriate time could provide patients with greater benefit from treatments based on their specific gene mutations.

Serial circulating tumor DNA monitoring of CDK4/6 inhibitors response in metastatic breast cancer.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) significantly improve progression-free survival and have become the standard therapy for estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer patients. Treatment surveillance by radiological imaging has some limitations in detection and repeated biopsy genomic profiling is not clinically feasible. Serial circulating tumor DNA (ctDNA) analysis may provide insights into treatment response. Here we performed serial ctDNA analysis (n = 178) on 33 patients. Serial ctDNA analysis identified disease progression with sensitivity of 75% and specificity of 92%. In eight of 12 patients (61%) responding to CDK4/6i who eventually developed progressive disease, serial sampling every 3 or 6 months captured the initial rise of ctDNA with an average lead time of 3 months. In three of eight patients that did not respond to CDK4/6i (progressive disease at first radiological assessment, 3 months), biweekly sequencing within the first cycle of CDK4/6i treatment (1 month) detected sustained ctDNA levels (≥0.2% variant allele frequency), with lead time of 2 months. Serial ctDNA analysis tracked RECIST response, including clinically challenging scenarios (bone metastases or small-sized target lesions), as well as detecting acquired genetic alterations linked to CDK4/6i resistance in the G1 to S transition phase. Circulating tumor DNA analysis was more sensitive than carcinoembryonic antigen or cancer antigen 15-3 serum tumor markers at monitoring tumor response to CDK4/6i treatment. Our findings indicated the possible clinical utility of serial ctDNA analysis for earlier progressive disease detection and real-time monitoring of CDK4/6i response.

Trastuzumab and fulvestrant combination therapy for women with advanced breast cancer positive for hormone receptor and human epidermal growth factor receptor 2: a retrospective single-center study.

BACKGROUND: Trastuzumab and fulvestrant combination therapy is one of the treatment options for patients with hormone receptor- and human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer; however, there are limited studies evaluating the efficacy of this combination therapy. METHODS: We retrospectively reviewed the data of women with hormone receptor- and HER2-positive metastatic breast cancer who received trastuzumab and fulvestrant combination therapy between August 1997 and August 2020 at the Cancer Institute Hospital. The primary endpoint of this study was progression-free survival, and the secondary endpoints were response rate, overall survival and safety. RESULTS: We reviewed the data of 1612 patients with recurrent or metastatic breast cancer, of which 118 patients were diagnosed with hormone receptor- and HER2-positive breast cancer. Of these, 28 patients who received trastuzumab and fulvestrant combination therapy were eligible for this study. The median treatment line for advanced breast cancer was 6 (range, 1-14), the median progression-free survival was 6.4 months (95% confidence interval [CI], 3.46-8.17), and the median overall survival was 35.3 months (95% CI, 20.0-46.7). Of the 28 patients, partial response was observed in 1 (4%), stable disease in 17 (61%), and progressive disease in 10 (36%) patients. The disease control rate was 64%. Adverse events of grade ≥ 3 were not observed. CONCLUSIONS: Trastuzumab and fulvestrant combination therapy showed moderate clinical efficacy and no severe toxicity after standard anti-HER2 treatment, which is a reasonable treatment option for patients with hormone receptor- and HER2-positive metastatic breast cancer. These data contribute to understanding the efficacy of trastuzumab and fulvestrant combination therapy as control data for further development of anti-HER2 agents plus hormone therapy.

Molecular and cellular mechanisms underlying brain metastasis of breast cancer.

Metastasis of cancer cells to the brain occurs frequently in patients with certain subtypes of breast cancer. In particular, patients with HER2-positive or triple-negative breast cancer are at high risk for the development of brain metastases. Despite recent advances in the treatment of primary breast tumors, the prognosis of breast cancer patients with brain metastases remains poor. A better understanding of the molecular and cellular mechanisms underlying brain metastasis might be expected to lead to improvements in the overall survival rate for these patients. Recent studies have revealed complex interactions between metastatic cancer cells and their microenvironment in the brain. Such interactions result in the activation of various signaling pathways related to metastasis in both cancer cells and cells of the microenvironment including astrocytes and microglia. In this review, we focus on such interactions and on their role both in the metastatic process and as potential targets for therapeutic intervention.

HER2 Heterogeneity Is Associated with Poor Survival in HER2-Positive Breast Cancer.

Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity has been reported in 16⁻36% of HER2-positive breast cancer and its clinical impact is under discussion. We examined the biological effects of HER2-heterogeneity on mouse models and analyzed metastatic brains by RNA sequence analysis. A metastatic mouse model was developed using 231-Luc (triple negative cells) and 2 HER2-positive cell lines, namely, HER2-60 and HER2-90 which showed heterogeneous and monotonous HER2 expressions, respectively. Metastatic lesions developed in 3 weeks in all the mice injected with HER2-60 cells, and in 69% of the mice injected with HER2-90 and 87.5% of the mice injected with 231-Luc. The median survival days of mice injected with 231-Luc, HER2-60, and HER2-90 cells were 29 (n = 24), 24 (n = 22) and 30 (n = 13) days, respectively. RNA sequence analysis showed that CASP-1 and its related genes were significantly downregulated in metastatic brain tumors with HER2-60 cells. The low expression of caspase-1 could be a new prognostic biomarker for early relapse in HER2-positive breast cancer.

Hereditary breast cancer associated with Cowden syndrome-related PTEN mutation with Lhermitte-Duclos disease.

BACKGROUND: Cowden syndrome is characterized by multiple hamartomas in various tissues, including the skin, brain, breast, thyroid, mucous membrane, and gastrointestinal tract, and is reported to increase the risk of malignant disease. CASE PRESENTATION: We describe the case of a 52-year-old woman in whom a tumor was diagnosed in the left cerebellar hemisphere and treated by surgical resection. Phosphatase and tensin homolog (PTEN) mutation in exon 8 insertion was found in the brain tumor tissue and leukocytes. This finding supported the diagnosis of Cowden syndrome. She consequently developed endometrial cancer and underwent abdominal total hysterectomy with bilateral salpingo-oophorectomy. Four years later, hormone receptor-positive breast cancer was found in the right breast, and breast-conserving surgery with radiation therapy and sentinel lymph node biopsy was performed. CONCLUSIONS: Herein, we describe a patient who was diagnosed as having familial breast cancer associated with PTEN mutation-related Cowden syndrome. We also reviewed reports of this syndrome in the literature for disease appraisal.

RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis.

Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non-small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients.

Objection to postoperative radiation therapy in breast cancer with one to three lymph nodes involvements.

My arguments regarding postmastectomy radiotherapy (PMRT) for this case are based on the following 4 reasons: (1) high rate of local recurrence in the no PMRT group in the Early Breast Cancer Trialists' Collaborative Group meta-analysis on which the present guideline is based, (2) stage migration by sentinel node biopsy, (3) possible adverse events of radiotherapy, and (4) problems on extrapolation of data from western countries.

Expression of CD24 is associated with HER2 expression and supports HER2-Akt signaling in HER2-positive breast cancer cells.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is treated with HER2-targeted agents, such as trastuzumab and lapatinib, that suppress signaling by phosphatidylinositol 3-kinase (PI3K)-Akt and MAPK pathways. However, resistance to HER2-targeted therapy remains a major clinical problem. Overexpression of CD24 has been detected in many cancers and is associated with a poor prognosis in women with breast cancer. HER2-positive breast tumors are predominantly positive for CD24, suggesting that the expression of the two molecules is related. To investigate the relation between HER2 and CD24, we overexpressed HER2 in breast cancer cells that were triple-negative for the estrogen receptor, progesterone receptor and HER2. We found that expression of CD24 was increased by stable overexpression of HER2. Flow cytometry thus revealed that the percentage of CD24-positive cells was markedly higher in the HER2-positive fraction than in the HER2-negative fraction. Knockdown of CD24 in breast cancer cells positive for endogenous HER2 downregulated HER2 expression, whereas knockdown of HER2 did not affect the expression of CD24. Knockdown of CD24 also suppressed the phosphorylation of Akt, which functions downstream of HER2 and PI3K to promote cell survival. Moreover, knockdown of CD24 increased the sensitivity of HER2-positive breast cancer cells to lapatinib treatment. Our results thus indicate that CD24 supports both the expression of HER2 and the consequent activation of PI3K-Akt signaling. Furthermore, CD24 may contribute to resistance to HER2-targeted therapy and, therefore, is itself a potential therapeutic target in HER2-positive breast cancer.

Accuracy and validity of sentinel lymph node biopsy for breast cancer using a photosensitizer: 8-year follow-up.

BACKGROUND AND OBJECTIVE: We evaluated an alternative procedure for sentinel lymph node biopsy (SLNB) for breast cancer after approval of the study by the Ethics Committee of Tokyo Medical University Hospital in 2004. We examined the efficacy and safety of SLNB using the photosensitizer talaporfin sodium (Laserphyrin®, Meiji Seika Pharma, Tokoyo, Japan), compared with current methods. STUDY DESIGN/PATIENTS AND METHODS: The study included 21 breast cancer patients (Japanese women; median age, 54 years; range, 35-75). All patients received a breast cancer operation combined with SLNB between June 2004 and May 2005. Three milliliters of talaporfin solution was locally injected into the subareolar region just before the operation. We attempted to identify a sentinel lymph node (SLN) that exhibited fluorescence and was consistent with a radioisotope (RI) localization technique. Our purpose was to verify the accuracy and validity of the talaporfin fluorescence imaging method after 8 years of application. RESULTS: There was no consistent correlation between fluorescence and pathological SLN metastasis, although all four cases of pathological SLN metastasis revealed positive fluorescence. In some cases in which we could not identify SLNs by the RI technique, we could identify SLNs using talaporfin. The method using talaporfin did not adversely affect the patients after the operation, even the chronic renal failure patient. After 8 years, all patients are alive, and none had lymph node recurrence. Side effects were not observed. CONCLUSION: SLNB using the photosensitizer talaporfin sodium in breast cancer patients is considered to be useful as complementary to other current methods. We could evaluate the accuracy and validity of this method 8 years after all of the procedures were performed. In the future, a large-scale clinical study with statistical analyses should be conducted.

Induction of ZEB proteins by inactivation of RB protein is key determinant of mesenchymal phenotype of breast cancer.

We previously showed that depletion of the retinoblastoma protein (RB) induces down-regulation of the adhesion molecule E-cadherin and thereby triggers the epithelial-mesenchymal transition. To further characterize the effect of RB inactivation on the phenotype of cancer cells, we have now examined RB expression in human breast cancer cell lines and clinical specimens. We found that RB-inactive cells exhibit a mesenchymal-like morphology and are highly invasive. We also found that ZEB proteins, transcriptional repressors of the E-cadherin gene, are markedly up-regulated in these cells in a manner sensitive to the miR-200 family of microRNAs. Moreover, depletion of ZEB in RB-inactive cells suppressed cell invasiveness and proliferation and induced epithelial marker expression. These results implicate ZEB in induction of the epithelial-mesenchymal transition, as well as in maintenance of the mesenchymal phenotype in RB-inactive cells. We also developed a screening program for inhibitors of ZEB1 expression and thereby identified several cyclin-dependent kinase inhibitors that blocked both ZEB1 expression and RB phosphorylation. Together, our findings suggest that RB inactivation contributes to tumor progression not only through loss of cell cycle control but also through up-regulation of ZEB expression and induction of an invasive phenotype.

A lower dose of docetaxel at 60 mg/m(2) could be continued longer for controlling peripheral edema in patients with metastatic breast cancer.

BACKGROUND: Docetaxel is a key drug for metastatic breast cancer (MBC). In patients with MBC, the treatment objective is durable response with minimum toxicity. In Japan, the approved dose of docetaxel is 60-70 mg/m(2) every 3 weeks, whereas 75-100 mg/m(2) docetaxel is common in the West. METHODS: We retrospectively examined the prevalence of edema in patients with MBC who were treated with docetaxel. Seventy-seven patients received docetaxel at a dose of 60 mg/m(2) every 3 weeks with prophylactic premedication of dexamethasone, 8 mg daily for 3 days. RESULTS: Median follow-up time was 28 months (range 4.3-98). Overall response was 25% (95% CI 15-34). Median time to progression and median survival time from the beginning of any systemic therapy for metastatic disease were 10 and 66 months, respectively. Neutropenia was the most common toxicity, with grade 3-4 observed in 66%. Fifty-one percent of the patients experienced peripheral edema that could be controlled with oral diuretics. Grade 3 edema was observed in 4 patients only, and discontinuation because of edema was 9%. Other grade 3 or 4 toxicity was <5%. Median cumulative dose of docetaxel to onset of peripheral edema was 480 mg/m(2) (range 60-780), and median cumulative given dose was 600 mg/m(2) (range 84-2,928). CONCLUSIONS: These results suggest that treatment with docetaxel at 60 mg/m(2) could be continued longer than the higher dose with manageable peripheral edema in patients with MBC. Further investigation is required to determine the superiority of low-dose docetaxel.