Breast cancer (BC) is the most commonly diagnosed cancer worldwide. Advanced BC with brain metastasis (BM) is a major cause of mortality with no specific or effective treatment. Therefore, better ...knowledge of the cellular and molecular mechanisms underlying breast cancer brain metastasis (BCBM) is crucial for developing novel therapeutic strategies and improving clinical outcomes. In this review, we focused on the latest advances and discuss the contribution of the molecular subtype of BC, the brain microenvironment, exosomes, miRNAs/lncRNAs, and genetic background in BCBM. The blood–brain barrier and blood–tumor barrier create challenges to brain drug delivery, and we specifically review novel approaches to bypass these barriers. Furthermore, we discuss the potential application of immunotherapies and genetic editing techniques based on CRISPR/Cas9 technology in treating BCBM. Emerging techniques and research findings continuously shape our views of BCBM and contribute to improvements in precision therapies and clinical outcomes.
Platinum (Pt) derivatives such as cisplatin and carboplatin are the class of drugs with proven activity against triple-negative breast cancer (TNBC). This is due to the ability of Pt compounds to ...interfere with the DNA repair mechanisms of the neoplastic cells. Taxanes have been efficacious against estrogen receptor-negative tumors and act by disruption of microtubule function. Due to their distinct mechanisms of action and routes of metabolism, the combination of the Pt agents and taxanes results in reduced systemic toxicity, which is ideal for treating TNBC. Also, the sensitivity of
-mutated cells to taxanes remains unsolved as
evidence indicates resistance against taxanes due to
mutations. Recent evidence suggests that the combination of carboplatin and paclitaxel resulted in better pathological complete response (pCR) in patients with TNBC, both in neoadjuvant and adjuvant settings.
studies showed sequential dependency and optimal time scheduling of Pt- and taxane-based chemotherapy. Also, combining carboplatin with docetaxel in the NAC regimen yields an excellent pCR in patients with
-associated and wild-type TNBC. TNBC is a therapeutic challenge that can be tackled by identifying new therapeutic sub-targets and specific cross-sections that can be benefitted from the addition of Pt- and taxane-based chemotherapy. This review summarizes the merits as well as the mechanism of Pt- and taxane-based adjuvant and neoadjuvant chemotherapies in early TNBC from the available and ongoing clinical studies.
The objective of this multicenter, single‐arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by ...docetaxel, trastuzumab, and pyrotinib (ECPy‐THPy) in the treatment of patients with stage II–III HER2‐positive breast cancer. The present study enrolled patients with stage II–III HER2‐positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21‐day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention‐to‐treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7–75.8%), while the objective response rate was 89.1%. In the post‐hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy‐THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II–III HER2‐positive breast cancer.
In this multicenter, single‐arm trial, we investigated the efficacy and safety of the ECPy‐THPy regimen (epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib) as neoadjuvant therapy for patients with stage II–III HER2‐positive breast cancer. Our results revealed that tpCR was achieved in 107 (68.6%) out of 156 patients, which was in line with our previous pilot study and numerically higher than the tpCR rate in previous phase III KRISTINE trial and the phase III POENY trial.
Lessons Learned
This is the first trial to explore the neoadjuvant therapy of pyrotinib in HER2‐positive operable and locally advanced breast cancer, in combination with epirubicin plus ...cyclophosphamide followed by docetaxel plus trastuzumab.
Results primarily showed that pyrotinib in combination with epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab was effective and safe in HER2‐positive operable and locally advanced breast cancer.
A subsequent randomized controlled trial is still warranted to confirm these results.
Background
The efficacy and safety of neoadjuvant therapy of pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI), was first estimated in patients with HER2‐positive breast cancer in this phase II study, in combination with trastuzumab and chemotherapy.
Methods
Between February 19, 2019, and November 20, 2019, 20 female Chinese patients with stage I–III HER2‐positive breast cancer were assigned to receive eight cycles of neoadjuvant pyrotinib (P) in combination with four cycles of epirubicin (E) and cyclophosphamide (C) followed by four cycles of docetaxel (T) and trastuzumab (H), once every 3 weeks, referred to as P + EC‐TH.
Results
A total of 19 patients completed the therapy and final surgery. The total pathological complete response (tpCR) rate was 73.7% (95% confidence interval CI, 48.8–90.9), and no recurrence or metastasis occurred during the short‐term follow‐up period. The objective response rate (ORR) was 100% (95% CI, 82.4–100). The most common adverse events (AEs) were diarrhea and leukopenia in 18 of 20 patients (90%), but no grade 5 AEs were reported.
Conclusion
This study showed that in HER2‐positive operable or locally advanced breast cancer, the tpCR rate of P + EC‐TH neoadjuvant therapy was about twice as high as that of EC‐TH neoadjuvant therapy reported in other trials, with tolerable side effects.
Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency ...of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next‐generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non‐BRCA1/2 gene. Major mutant non‐BRCA1/2 genes were TP53 (n = 18), PALB2 (n = 11), CHEK2 (n = 6), ATM (n = 6) and BARD1 (n = 5). No factors predicted pathologic mutations in non‐BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER‐2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non‐BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non‐BRCA1/2 genes, some clinical features were associated with mutations of several particular genes.
What's new?
The prevalence of mutations in breast cancer predisposition genesare not well investigated in Asia. We assessed germline mutations of 40 cancer susceptibility genes in 937 consecutive selected breast cancer patients from 26 centers of China, and discovered 23.8% of participates carried the pathogenic mutation, including 6.8% with mutations in non‐BRCA1/2 genes, while TP53 and PALB2 had a relatively high mutation rates (1.9% and 1.2%).There was no factors predicted for detrimental mutations in non‐BRCA1/2 genes when treated as a whole.
Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency ...of germline mutations in 40 cancer predisposition genes, including
BRCA1
and
BRCA2
, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next‐generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in
BRCA1/2
, 61 in 15 other BC susceptibility genes and 3 in both
BRCA1/2
and non‐
BRCA1/2
gene. Major mutant non‐
BRCA1/2
genes were
TP53
(n = 18),
PALB2
(n = 11),
CHEK2
(n = 6),
ATM
(n = 6) and
BARD1
(n = 5). No factors predicted pathologic mutations in non‐
BRCA1/2
genes when treated as a whole.
TP53
mutations were associated with HER‐2 positive BC and younger age at diagnosis; and
CHEK2
and
PALB2
mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non‐
BRCA1/2
genes.
TP53
and
PALB2
had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non‐
BRCA1/2
genes, some clinical features were associated with mutations of several particular genes.
What's new?
The prevalence of mutations in breast cancer predisposition genesare not well investigated in Asia. We assessed germline mutations of 40 cancer susceptibility genes in 937 consecutive selected breast cancer patients from 26 centers of China, and discovered 23.8% of participates carried the pathogenic mutation, including 6.8% with mutations in non‐
BRCA1/2
genes, while
TP53
and
PALB2
had a relatively high mutation rates (1.9% and 1.2%).There was no factors predicted for detrimental mutations in non‐
BRCA1/2
genes when treated as a whole.
The role of supraclavicular lymph node dissection (SCLD) in the treatment of breast cancer with ipsilateral supraclavicular lymph node metastasis (ISLM) remains controversial. We evaluated the role ...of SCLD in the treatment of breast cancer with ISLM and identified patients who may benefit from SCLD.
Data on patients presenting with breast cancer to the Breast Disease Center, Southwest Hospital, The Army Medical University from January 2004 and December 2017 were retrospectively screened. The median duration of follow-up was 36 months (2-175 months). 305 patients who were recently diagnosed with ISLM were eligible for the analysis.
Overall, 9,236 women presented with breast cancer during the study period. Among the patients included, 146 and 159 received SCLD with radiotherapy (RT) and RT alone, respectively. Synchronous ISLM without distant metastases were present in 3.6% cases. The 3- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 79.5% and 73.9%, respectively, and 67.5% and 54.8%, respectively. However, SCLD with RT was not associated with superior survival on both univariate and multivariate analyses. On stratified analyses, patients with non-luminal A tumors with 4-9 positive axillary lymph nodes who underwent SCLD with RT had both superior OS (HR =5.296; 95% CI: 1.857-15.107; P=0.001) and DFS (HR =5.331; 95% CI: 2.348-12.108; P<0.001) compared with those who received RT alone.
SCLD may not beneficial in improving survival for unselected breast cancer patients with ISLNM. There is less of a tendency to perform SCLD in the luminal A group.
Due to lack of systematic reviews, BRCA, DNA Repair Associated (
) mutations in the Chinese population are not completely understood. The following study investigates the prevalence and type of
...mutations in Chinese patients with high hereditary risk of breast cancer (BC). Patients Drwere recruited from 14 cities between October 2015 and February 2016, and were selected based on family and personal medical history.
mutations were analyzed by collecting blood samples from all participants. 437 BC patients were included. A total of seventy-six (17.4%) mutation carriers were identified with no geographic difference. The mutation rate in the early-onset BC patients was lower compared to family history of breast/ovarian cancer (OC), bilateral BC, male BC, BC&OC or meeting ≥2 criteria (9.2 vs. 21.7, 24.0, 22.2, 16.7 and 24.3%, respectively, P=0.007). A total of 61 mutation sites were identified (
32,
29) including 47.5% novel sites and extra 10 variants of uncertain significance. A total of five sites were repeated in more than one unrelated patient. A total of 11 sites were associated with hereditary breast and ovarian cancer syndrome, two of which were confirmed by family pedigrees. Compared with
patients, patients with
mutation tended to be triple-negative BC (P<0.001), whereas patients with
mutation were more likely to be hormone receptor positive BC (P=0.02). The present study provides a general
mutation profile in the Chinese population. The prevalence of
mutation in BC patients with high hereditary risk is lower compared with Western populations. Chinese mutation type is different with Western people, without obvious founder mutation.
Objective To determine the clinicopathological features and prognostic differences between ductal carcinoma in situ (DCIS) and ductal carcinoma in situ with microinvasion (DCIS-MI) of breast cancer. ...Methods A cohort of 489 female patients with surgically diagnosed DCIS (n=240, 49.1%) and DCIS-MI (n=249, 50.9%) in our hospital from January 2004 to December 2014 were recruited in this study. Their clinicopathological data and follow-up data were collected and analyzed for the differences in clinicopathological data, molecular subtypes and prognosis between DCIS and DCIS-MI patients. Results The age of initial diagnosis was usually younger than 55 years old (60.3%) in the 2 groups. Compared with DCIS patients, DCIS-MI patients had larger tumor size (P=0.034), higher histological grade (P < 0.05), and lower ER positive rate (P < 0.05); DCIS-MI patients had lower proportion of luminal-A type (54.6% vs 63.8%, P=0.040), while higher HER-2 over-expressed type (18.1% vs 9.2%, P=0.004). Statistical differences were see
Ion adsorption-type rare earth element (REE) ore deposits in South China are a major source of heavy rare earth elements (HREE) around the world, which are of considerable economic and strategic ...significance. In these ores, REE is enriched in the clay minerals, specifically kaolinite and halloysite, which are derived from their parent granitoid by the weathering process. However, the mechanisms of supergene REE mineralization remain unclear. We investigated the nature and origin of supergene REE mineralization, based on a nanoscale study of a typical REE-mineralized granite regolith profile (ΣREEmax = 1201 ppm) in the Dazhou super-large, ion adsorption-type REE deposit, Guangxi Province, South China. Bulk mineralogical and geochemical analyses, coupled with novel nano-characterization techniques i.e., hollow fiber flow field-flow fractionation inductively coupled plasma-mass spectrometry (HF5-ICP-MS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM), were used to determine the nature of the nano-minerals and nanoparticles in the regolith samples. X-ray diffraction and SEM-EDS analyses revealed that ion-adsorption clay minerals are dominated by platy-shaped kaolinite and rod-like halloysite (10 and 7 Å) within the regolith. The average clay mineral contents decreased from 38 to 15% from the fully weathered horizon to the semi-weathered horizon, whereas the proportion of halloysite increased in the clay mineral fraction in the deep horizons. The REE-bearing nanoparticles consist predominantly of macromolecules of organic matter (2-5 nm) and clay minerals (5-40 and 40-80 nm) according to the HF5-ICP-MS analysis. There is a close association between REE and Al contents in particles with sizes of 5-40 nm in the semi-weathered horizons and 40-80 nm in the highly weathered horizons, which indicates that nanoscale clay minerals (halloysite and kaolinite, respectively) are important REE carriers. In addition, nanoscale secondary REE mineral phases, including oxide, silicate, and phosphate, were identified by the SEM and TEM observations. These phases are typically adsorbed onto the surfaces of clay minerals, specifically rod-like halloysite, but have different occurrences in the regolith profile. Cesium-oxide (cerianite) and Ce-silicate (cerite) occur mainly in the upper horizon of the regolith profile, whereas low-crystallinity REE phosphates rhabdophane-(La) occur mainly in the lower horizon of the profile. Our results indicate that nano-minerals and nanoparticles affect REE enrichment and fractionation during granite weathering. Migration and accumulation of REE-bearing nano-minerals were caused by leaching and neoformation of REE-bearing nano-minerals during secondary precipitation. These processes contribute to the formation of supergene REE mineralization in granite regolith.
PDF
