Treatment patterns in advanced/metastatic non-small-cell lung cancer in China: results from the CancerMPact® survey 2021.

Aim: To report the treatment patterns of advanced/metastatic non-small-cell lung cancer (NSCLC) in China from a physician survey (CancerMPact®). Materials & methods: A total of 206 Chinese physicians from 27 cities in urban mainland China reported on their treatment of NSCLC in September 2021. Results: Platinum doublets received 70.5% utilization for squamous NSCLC with PD-L1 expression <1% in first-line, whereas nonsquamous NSCLC was treated with platinum doublets (35.2%) or bevacizumab with platinum doublets (35.3%). Checkpoint inhibitors were utilized in >50% of all PD-L1-positive NSCLC cases. Driver-mutated NSCLC was most frequently treated with targeted therapy or platinum-based combinations. Conclusion: NSCLC treatment in China varies by histology, PD-L1 status and driver mutations, illustrating the complexity of decision-making for Chinese physicians as treatment markets expand.

The most common type of lung cancer is called non-small-cell lung cancer (NSCLC). When lung cancer spreads beyond the lung, it is called advanced. Doctors in China who treat advanced NSCLC were identified. They were surveyed in September 2021 and asked about how they treat their patients. The survey included 206 doctors from 27 cities in China. There are many drugs available for NSCLC. This means that it can be hard for doctors to decide how to treat their patients. The doctors in China often reported using multiple drugs together, instead of using only one drug. One type of drug that can be used to treat NSCLC is called a checkpoint inhibitor (CPI). The doctors reported that they often used CPIs to treat their patients. They also reported that they were more likely to use CPIs made in China rather than CPIs that were made outside of China. Before receiving treatment, most patients were tested for biomarkers. Biomarkers can tell doctors important information about cancers. Doctors can use biomarkers to help decide which treatments to offer their patients. In China, the doctors often did use certain drugs based on patient biomarkers. This choice often depended on the specific biomarker that the patient had. There are many different factors for doctors to consider when treating NSCLC. More and more drugs are becoming available to use in China. While this is good news for patients with cancer, treatment decisions are becoming more complex for doctors.

Treatment of HR+/HER2- breast cancer in urban mainland China: results from the CancerMPact Survey 2019.

PURPOSE: To report the treatment utilization patterns for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer in urban mainland China (CancerMPact®). METHODS: The results presented are from an online survey conducted in September 2019 with 45 physicians treating breast cancer patients from 11 cities in mainland China. RESULTS: Surveyed physicians reported that Stage I HR+/HER2(-) breast cancer patients are often treated with surgery alone (42%), whereas the use of surgery in combination with systemic therapy with or without radiotherapy increases in later stages (Stage II 67%, Stage III 77%). Doxorubicin-cyclophosphamide (AC)-based regimens were the most common in both the neoadjuvant and adjuvant settings in HR+/HER2(-) breast cancer patients, across all stages. In metastatic patients, use of surgery and radiotherapy decreases in favor of utilization of systemic therapy alone. Pre- and post-menopausal metastatic patients were frequently treated with hormone therapy or AC-based regimens in first line. Regardless of the first-line therapy administered, capecitabine-based regimens were commonly used in second line. In third line, chemotherapy regimens containing capecitabine or gemcitabine were given to nearly 40% of HR+/HER2(-) breast cancer patients. There were no standard of care regimens established for fourth or greater lines of treatment. In metastatic HR+/HER2(-) breast cancer, physicians reported 50% objective response rates in first-line settings with a progression-free survival of 16 months. CONCLUSION: HR+/HER2(-) breast cancer patients in urban mainland China were prescribed chemotherapy regimens more frequently than CDK4/6 inhibitors. Treatment practices varied, with physicians reporting the use of multiple modalities and treatment regimens for their patients.

Human ribonuclease H1 resolves R-loops and thereby enables progression of the DNA replication fork.

Faithful DNA replication is essential for genome stability. To ensure accurate replication, numerous complex and redundant replication and repair mechanisms function in tandem with the core replication proteins to ensure DNA replication continues even when replication challenges are present that could impede progression of the replication fork. A unique topological challenge to the replication machinery is posed by RNA-DNA hybrids, commonly referred to as R-loops. Although R-loops play important roles in gene expression and recombination at immunoglobulin sites, their persistence is thought to interfere with DNA replication by slowing or impeding replication fork progression. Therefore, it is of interest to identify DNA-associated enzymes that help resolve replication-impeding R-loops. Here, using DNA fiber analysis, we demonstrate that human ribonuclease H1 (RNH1) plays an important role in replication fork movement in the mammalian nucleus by resolving R-loops. We found that RNH1 depletion results in accumulation of RNA-DNA hybrids, slowing of replication forks, and increased DNA damage. Our data uncovered a role for RNH1 in global DNA replication in the mammalian nucleus. Because accumulation of RNA-DNA hybrids is linked to various human cancers and neurodegenerative disorders, our study raises the possibility that replication fork progression might be impeded, adding to increased genomic instability and contributing to disease.

Low phosphate alters lateral root setpoint angle and gravitropism.

PREMISE OF THE STUDY: Lateral roots, responsible for water and nutrient uptake, maintain nonvertical angles throughout development. Soil phosphate is one limiting nutrient for plant growth that is known to induce changes to root system architecture, such as increased lateral root formation. This study seeks to determine whether phosphate concentration affects lateral root orientation in addition to its previously described influences on root architecture. METHODS: Images of intact Arabidopsis root systems were recorded for 24 h, and lateral root tip angles were measured for wild-type and mutant pgm-1 and pin3-1 roots on a full or low phosphate medium. Setpoint angles of unstimulated root systems were determined, as were gravitropic responses of lateral roots over time. KEY RESULTS: The root system setpoint angles of wild-type and mutant pin3-1 roots showed a shift toward a more vertical orientation on low orthophosphate (Pi) medium. The gravitropic responses of both pgm-1 and pin3-1 roots on low Pi medium was elevated relative to control Pi medium. Mutations in two phosphate transporters with high levels of expression in the root showed a gravitropic response similar to wild-type roots grown on low Pi, supporting a role for Pi status in regulating lateral root gravitropism. CONCLUSIONS: Lateral root orientation and gravitropism are affected by Pi status and may provide an important additional parameter for describing root responses to low Pi. The data also support the conclusion that gravitropic setpoint angle reacts to nutrient status and is under dynamic regulation.

p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy.

Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKα inhibition (p38i) limits tumor growth by reprogramming the metastatic tumor microenvironment in a CD4+ T cell-, IFNγ-, and macrophage-dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single-cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies. SIGNIFICANCE: Immunotherapy is rarely effective in breast cancer. We dissected the metastatic tumor stroma, which revealed a novel therapeutic approach that targets the stromal p38MAPK pathway and creates an opportunity to unleash an immunologic response. Our work underscores the importance of understanding the tumor stromal compartment in therapeutic design. This article is highlighted in the In This Issue feature, p. 1275.

Treatment patterns in non-small-cell lung cancer in China: Results from the CancerMPact survey 2020.

PURPOSE: To report the treatment patterns of non-small-cell lung cancer (NSCLC) patients in China based on a survey of physicians (CancerMPact). METHODS: 117 Chinese physicians from 27 cities in mainland China were recruited for an online survey in October 2020, reporting on how they treat their patients across all disease stages, including histology and relevant biomarkers in advanced or metastatic NSCLC. RESULTS: Surveyed physicians indicated that almost half of their stage I patients were treated with surgery only. For stage II patients, it is more common to treat with surgery in combination with radiation and/or systemic therapy (44.5%), whereas the use of surgery decreases for stage III patients and the overall use of systemic therapy increases (63.4%-68.8%). Physicians are more likely to use systemic therapy alone for stage IV patients (31.4%). Chosen treatment regimens for stage IV NSCLC varied by histology and biomarkers, and several observed treatment patterns differed from the USA. In China, platinum-based chemotherapy is standard of care for treating stage IV NSCLC patients, unlike the USA, where checkpoint inhibitors are the dominant choice in first-line. Further, Chinese physicians reported prescribing biomarker-targeted agents for one-third or less of their patients with EGFR, ALK, ROS-1, or BRAF driver mutations, compared to 60-95% in the USA. CONCLUSION: As treatment options expand in NSCLC in China, physicians face complex decisions for the treatment of their patients. Treatment patterns often vary, including by disease histology and clinically relevant biomarkers. The standard of care for NSCLC in China also differs from the USA.

Therapy-Induced Senescence Drives Bone Loss.

Chemotherapy is important for cancer treatment, however, toxicities limit its use. While great strides have been made to ameliorate the acute toxicities induced by chemotherapy, long-term comorbidities including bone loss remain a significant problem. Chemotherapy-driven estrogen loss is postulated to drive bone loss, but significant data suggests the existence of an estrogen-independent mechanism of bone loss. Using clinically relevant mouse models, we showed that senescence and its senescence-associated secretory phenotype (SASP) contribute to chemotherapy-induced bone loss that can be rescued by depleting senescent cells. Chemotherapy-induced SASP could be limited by targeting the p38MAPK-MK2 pathway, which resulted in preservation of bone integrity in chemotherapy-treated mice. These results transform our understanding of chemotherapy-induced bone loss by identifying senescent cells as major drivers of bone loss and the p38MAPK-MK2 axis as a putative therapeutic target that can preserve bone and improve a cancer survivor's quality of life. SIGNIFICANCE: Senescence drives chemotherapy-induced bone loss that is rescued by p38MAPK or MK2 inhibitors. These findings may lead to treatments for therapy-induced bone loss, significantly increasing quality of life for cancer survivors.

Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss.

The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase MK2 each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically affects quality of life for patients with cancer. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss.Significance: Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival. Cancer Res; 78(19); 5618-30. ©2018 AACR.

Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development.

More than 85% of advanced breast cancer patients suffer from metastatic bone lesions, yet the mechanisms that facilitate these metastases remain poorly understood. Recent studies suggest that tumor-derived factors initiate changes within the tumor microenvironment to facilitate metastasis. However, whether stromal-initiated changes are sufficient to drive increased metastasis in the bone remains an open question. Thus, we developed a model to induce reactive senescent osteoblasts and found that they increased breast cancer colonization of the bone. Analysis of senescent osteoblasts revealed that they failed to mineralize bone matrix and increased local osteoclastogenesis, the latter process being driven by the senescence-associated secretory phenotype factor, IL-6. Neutralization of IL-6 was sufficient to limit senescence-induced osteoclastogenesis and tumor cell localization to bone, thereby reducing tumor burden. Together, these data suggest that a reactive stromal compartment can condition the niche, in the absence of tumor-derived signals, to facilitate metastatic tumor growth in the bone.