Collagen prolyl 4-hydroxylase 1 is essential for HIF-1α stabilization and TNBC chemoresistance.

Collagen prolyl 4-hydroxylase (P4H) expression and collagen hydroxylation in cancer cells are necessary for breast cancer progression. Here, we show that P4H alpha 1 subunit (P4HA1) protein expression is induced in triple-negative breast cancer (TNBC) and HER2 positive breast cancer. By modulating alpha ketoglutarate (α-KG) and succinate levels P4HA1 expression reduces proline hydroxylation on hypoxia-inducible factor (HIF) 1α, enhancing its stability in cancer cells. Activation of the P4HA/HIF-1 axis enhances cancer cell stemness, accompanied by decreased oxidative phosphorylation and reactive oxygen species (ROS) levels. Inhibition of P4HA1 sensitizes TNBC to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived models. We also show that increased P4HA1 expression correlates with short relapse-free survival in TNBC patients who received chemotherapy. These results suggest that P4HA1 promotes chemoresistance by modulating HIF-1-dependent cancer cell stemness. Targeting collagen P4H is a promising strategy to inhibit tumor progression and sensitize TNBC to chemotherapeutic agents.

Should Histologic Grade Be Incorporated into the TNM Classification System for Small (T1, T2) Node-Negative Breast Adenocarcinomas?

Prognosis of invasive ductal carcinoma (IDC) strongly correlates with tumor grade as determined by Nottingham combined histologic grade. While reporting grade as low grade/favorable (G1), intermediate grade/moderately favorable (G2), and high grade/unfavorable (G3) is recommended by American Joint Committee on Cancer (AJCC) staging system, existing TNM (Primary Tumor/Regional Lymph Nodes/Distant Metastasis) classification does not directly incorporate these data. For large tumors (T3, T4), significance of histologic grade may be clinically moot as those are nearly always candidates for adjuvant therapy. However, for small (T1, T2) node-negative (N0) tumors, grade may be clinically relevant in influencing treatment decisions, but data on outcomes are sparse and controversial. This retrospective study analyzes clinical outcome in patients with small N0 IDC on the basis of tumor grade. Our results suggest that the grade does not impact clinical outcome in T1N0 tumors. In T2N0 tumors, however, it might be prognostically significant and relevant in influencing decisions regarding the need for additional adjuvant therapy and optimal management.

Size of sentinel node tumor deposits and extent of axillary lymph node involvement: which breast cancer patients may benefit from less aggressive axillary dissections?

BACKGROUND: In most breast cancer series, nearly 30% to 40% of all patients are sentinel node positive; however, in a large proportion of these, the disease is limited to three or fewer positive nodes. On the basis of these observations, the object of this study is to identify a subset of patients who might benefit from a less aggressive axillary dissection, without compromising staging or local disease control. We reviewed known clinicopathologic variables associated with a higher risk for axillary metastasis in 467 patients who underwent sentinel node mapping at our institution. We then compared the incidence of these variables in patients with N1a versus N2-3 stage disease. RESULTS: Although the presence of lymphvascular invasion in the primary tumor and extracapsular extension of tumor in the sentinel node were statistically significantly different between N1a and N2-3 patients (P < .025 and P < .01, respectively), the variable that most reliably separated N1a from N2-3 patients was the size of the tumor deposits in the sentinel node (P < .001). All patients with sentinel node tumor deposits

Ultrasound-guided fine-needle aspiration of clinically negative lymph nodes versus sentinel node mapping in patients at high risk for axillary metastasis.

BACKGROUND: Sonographically directed fine-needle aspiration is a less invasive and less costly alternative to sentinel node (SN) mapping in breast cancer patients at high risk for metastatic disease but with clinically negative axillae. METHODS: Radiographic, cytological, and histological diagnostic data on breast primary tumors from 114 consecutive SN candidates were prospectively assessed for clinicopathologic variables associated with an increased incidence of axillary metastases. Patients in whom these variables were identified underwent sonographic examination of their axillae followed by fine-needle aspiration when abnormal nodes were detected. SN mapping was performed in patients with normal axillary sonogram results or negative cytological results. Patients with positive cytological results proceeded to complete axillary dissection. Final axillary histological outcomes from patients not meeting the high-risk criteria were recorded. Additionally, a cost analysis was performed in which the costs of ultrasonography and ultrasound-guided fine-needle aspiration of the axilla were compared with those of SN mapping. RESULTS: According to our selection criteria, a third of the patients with clinically negative axillae (37 of 114; 32%) were considered at high risk for axillary metastases. Fifty-nine percent of these patients (22 of 37) had metastatic disease on final histological analysis. Forty percent (15 of 37) of high-risk patients were spared SN mapping, with a reduction in health care costs of 20% in this patient population. Eighty-seven percent of patients not meeting high-risk criteria were SN negative. CONCLUSIONS: This study suggests that in patients at increased risk for axillary metastases, the use of sonographic evaluation of the axilla in combination with fine-needle aspiration is not only clinically justified, but also cost-effective.

Ultrasound-guided fine-needle aspiration biopsy remains a valid approach in the evaluation of nonpalpable breast lesions.

The use of ultrasound-guided fine-needle aspiration (FNA) biopsy for nonpalpable breast lesions varies considerably. This retrospective study stresses the role of breast FNA in evaluating sonographically suspicious nonpalpable breast masses using a probabilistic reporting system. One hundred and eight consecutive ultrasound-guided FNA biopsies diagnosed as positive (32), suspicious (8), atypical (11), benign (55), and unsatisfactory (2) were analyzed and correlated with 61 subsequent surgical specimens. All positive cytologies showed carcinoma on histology; suspicious cases were followed by 5 carcinomas, 2 fibroadenomas, and 1 papillary lesion. Follow-up of atypical cases included 4 carcinomas, 3 fibroadenomas, and 2 papillary lesions, while all 10 biopsies following benign cytology showed fibrocystic changes. Two cases with suspicious sonographic findings but unsatisfactory cytology had lobular carcinoma. The remainder of the benign and atypical cases were followed clinically and radiographically for at least 10 months and had no evidence of carcinoma. Positive predictive values were positive, 100%; suspicious, 63%; atypical, 36%; benign, 0%. Most (40/43; 93%) carcinomas were invasive. In conclusion, ultrasound-guided FNA for nonpalpable breast lesions is highly accurate, and probabilistic reporting helps direct patient management.