Real-world use of multigene signatures in early breast cancer: differences to clinical trials.

PURPOSE: In Italy, Lombardy was the first region to reimburse multigene assays (MGAs) for patients otherwise candidates for chemotherapy. This is a real-world experience of MGAs usage in six referral cancer centers in Lombardy. METHODS: Among MGAs, Oncotype DX (RS) was used in 97% of cases. Consecutive patients tested with Oncotype DX from July 2020 to July 2022 were selected. The distribution of clinicopathologic features by RS groups (low RS: 0-25, high RS: 26-100) was assessed using chi-square and compared with those of the TAILORx and RxPONDER trials. RESULTS: Out of 1,098 patients identified, 73% had low RS. Grade and Ki67 were associated with RS (p < 0.001). In patients with both G3 and Ki67 > 30%, 39% had low RS, while in patients with both G1 and Ki67 < 20%, 7% had high RS. The proportion of low RS in node-positive patients was similar to that in RxPONDER (82% vs 83%), while node-negative patients with low RS were significantly less than in TAILORx (66% vs 86%, p < 0.001). The distribution of Grade was different from registration trials, with more G3 and fewer G1 (38% and 3%) than in TAILORx (18% and 27%) and RxPONDER (10% and 24%) (p < 0.001). Patients ≤ 50 years were overrepresented in this series (41%) than in TAILORx and RxPONDER (31% and 24%, respectively) (p < 0.001) and, among them, 42% were node positive. CONCLUSIONS: In this real-world series, Oncotype DX was the test almost exclusively used. Despite reimbursement being linked to pre-test chemotherapy recommendation, almost 3/4 patients resulted in the low-RS group. The significant proportion of node-positive patients ≤ 50 years tested indicates that oncologists considered Oncotype DX informative also in this population.

Role and evaluation of pathologic response in early breast cancer specimens after neoadjuvant therapy: consensus statement.

Pathologic evaluation of early breast cancer after neoadjuvant therapy is essential to provide prognostic information based on tumor response to treatment (pathologic complete response [pCR] or non-pCR) and to inform therapy decisions after surgery. To harmonize the pathologist's handling of surgical specimens after neoadjuvant therapy, a panel of experts in breast cancer convened to developed a consensus on six main topics: (1) definition of pCR, (2) required clinical information, (3) gross examination and sampling, (4) microscopic examination, (5) evaluation of lymph node status, and (6) staging of residual breast tumor. The resulting consensus statements reported in this document highlight the role of an accurate evaluation of tumor response and define the minimum requirements to standardize the assessment of breast cancer specimens after neoadjuvant therapy.

PET/MRI for Staging the Axilla in Breast Cancer: Current Evidence and the Rationale for SNB vs. PET/MRI Trials.

Axillary surgery in breast cancer (BC) is no longer a therapeutic procedure but has become a purely staging procedure. The progressive improvement in imaging techniques has paved the way to the hypothesis that prognostic information on nodal status deriving from surgery could be obtained with an accurate diagnostic exam. Positron emission tomography/magnetic resonance imaging (PET/MRI) is a relatively new imaging tool and its role in breast cancer patients is still under investigation. We reviewed the available literature on PET/MRI in BC patients. This overview showed that PET/MRI yields a high diagnostic performance for the primary tumor and distant lesions of liver, brain and bone. In particular, the results of PET/MRI in staging the axilla are promising. This provided the rationale for two prospective comparative trials between axillary surgery and PET/MRI that could lead to a further de-escalation of surgical treatment of BC. • SNB vs. PET/MRI 1 trial compares PET/MRI and axillary surgery in staging the axilla of BC patients undergoing primary systemic therapy (PST). • SNB vs. PET/MRI 2 trial compares PET/MRI and sentinel node biopsy (SNB) in staging the axilla of early BC patients who are candidates for upfront surgery. Finally, these ongoing studies will help clarify the role of PET/MRI in BC and establish whether it represents a useful diagnostic tool that could guide, or ideally replace, axillary surgery in the future.

Personalized Risk-Benefit Ratio Adaptation of Breast Cancer Care at the Epicenter of COVID-19 Outbreak.

Northern Italy has been one of the European regions reporting the highest number of COVID-19 cases and deaths. The pandemic spread has challenged the National Health System, requiring reallocation of most of the available health care resources to treat COVID-19-positive patients, generating a competition with other health care needs, including cancer. Patients with cancer are at higher risk of developing critical illness after COVID-19 infection. Thus, mitigation strategies should be adopted to reduce the likelihood of infection in all patients with cancer. At the same time, suboptimal care and treatments may result in worse cancer-related outcome. In this article, we attempt to estimate the individual risk-benefit balance to define personalized strategies for optimal breast cancer management, avoiding as much as possible a general untailored approach. We discuss and report the strategies our Breast Unit adopted from the beginning of the COVID-19 outbreak to ensure the continuum of the best possible cancer care for our patients while mitigating the risk of infection, despite limited health care resources. IMPLICATIONS FOR PRACTICE: Managing patients with breast cancer during the COVID-19 outbreak is challenging. The present work highlights the need to estimate the individual patient risk of infection, which depends on both epidemiological considerations and individual clinical characteristics. The management of patients with breast cancer should be adapted and personalized according to the balance between COVID-19-related risk and the expected benefit of treatments. This work also provides useful suggestions on the modality of patient triage, the conduct of clinical trials, the management of an oncologic team, and the approach to patients' and health workers' psychological distress.

Sentinel node biopsy after primary systemic therapy in node positive breast cancer patients: Time trend, imaging staging power and nodal downstaging according to molecular subtype.

BACKGROUND: The management of axilla after Primary Systemic Therapy (PST) for breast cancer is a highly debated field. Despite the proven axillary downstaging occurring after PST, there is still some degree of reluctance in applying sentinel node biopsy (SNB) in the neoadjuvant setting. PATIENTS AND METHODS: We performed a retrospective analysis on 181 PST patients with axillary positive nodes at presentation treated between 2005 and 2017 at San Raffaele Hospital in Milan. The aim was to observe the application time trend of SNB, to determine the imaging staging power and the axillary downstaging according to molecular subtypes. RESULTS: Median follow-up after surgery was 32.5(IQR: 12-59) months. After PST, 119 (65.7%) patients had no clinically palpable nodes, 72 (39.7%) converted to N0 on final imaging and 34 (18.8%) underwent SNB with an increasing application trend. Axillary-US showed the highest accuracy (69.3%) in re-staging axilla after PST. Staging power of preoperative testing varied with tumour biology: Positive Predictive Value was higher in Luminal A (80% for clinical examination and 100% for axillary-US) and Luminal B (72% and 70.5%) tumours, whilst Negative Predictive Value was higher in HER2 positive (100% and 93.3%), and triple negative (71.4% and 93.3%) tumours. Ninety five (52.5%) patients experienced axillary downstaging after PST, by molecular subtype 15% (3/20) in Luminal A, 46.4% (45/97) in Luminal B, 90.9% (20/22) in HER2+ and 70.3% (26/37) in triple negative breast tumours. CONCLUSION: SNB application after PST for breast cancer in node positive patients at presentation is increasing. Pre-operative axillary imaging and tumour biology help identify patients who might be candidates for SNB as a single staging procedure.

Short formalin fixation and rapid microwave processing do not affect HER2 testing.

Correct and consistent results in estrogen and progesterone receptors, HER2 and Ki67 proliferation rate testing are a basic prerequisite for selecting therapy and individualizing prognosis in patients with breast carcinoma. Preanalytic factors, including time from excision to fixation and time and type of fixation, are critical to obtain reproducible and reliable results in these immunohistochemical assays and their relevance has long been stressed. The ASCO-CAP guidelines on HER2 testing indicated that histologic material including both biopsies and surgical specimens must be fixed for at least 6 h in order to obtain reliable results; however, there is a very limited scientific support regarding the setting at 6 h the minimum fixation time. We demonstrate that with a short fixation time (30') and rapid processing with MW technology (69'), it is possible to achieve an adequate and reproducible assessment of HER2 status. We obtained similar results in HER2 evaluation in breast carcinoma biopsies treated with this short protocol and in the corresponding surgical specimens processed routinely with a 24 h formalin fixation time-i.e., within the guidelines interval time.

CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer: implication for a potential clinical relevance in trastuzumab treatment.

The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2) in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P = .007). Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P = .005). Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3-kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P = .018 for the metastatic cohort and P = .021 for the neoadjuvant cohort). Our findings highlight a link between HER2 and CDC25A that positively modulates HER2-targeted therapy response, suggesting that, in HER2-positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity.

MR-guided stereotactic breast biopsy using a mixed ferromagnetic-nonmagnetic coaxial system with 12- to 18-gauge needles: clinical experience and long-term outcome.

PURPOSE: This study investigated the clinical application of a magnetic-resonance (MR)-guided breast biopsy (MRBB) system consisting of a nonmagnetic coaxial needle and a ferromagnetic core biopsy needle. MATERIALS AND METHODS: MRBB was performed on 70 breast lesions. The biopsy device consisted of a nonmagnetic 14- to 16-gauge coaxial needle and a ferromagnetic 16- to 18-gauge biopsy needle. RESULTS: Of the 70 lesions, 29 were malignant and 41 nonmalignant. All 29 malignant lesions underwent surgery and were confirmed as malignant at final histology. Of the 41 nonmalignant lesions, 35 underwent follow-up breast MR imaging (mean, 26 ± 19 months), which demonstrated no lesions changes; six lesions underwent surgery because of poor radiological-pathological correlation; of these 6 lesions, 3 were nonmalignant, one was borderline (lobular carcinoma in situ) and two were malignant (well-differentiated tubular carcinoma and infiltrating ductal carcinoma). Sensitivity, specificity, positive and negative predictive values and diagnostic accuracy were, respectively, 93.5%, 100%, 100%, 95.1% and 97.1% if the lobular carcinoma in situ was considered a nonmalignant histological result, and 90.6%, 100%, 100%, 92.7% and 95.7% if the lobular carcinoma in situ was considered malignant. CONCLUSIONS: MRBB with a ferromagnetic-nonmagnetic coaxial system represented an easy way to perform a biopsy procedure and was easily applicable in the routine clinical setting.

Unexplained neonatal respiratory distress due to congenital surfactant deficiency.

Genetic abnormalities of pulmonary surfactant were identified by DNA sequence analysis in 14 (12 full-term, 2 preterm) of 17 newborn infants with fatal respiratory distress of unknown etiology. Deficiency of adenosine triphosphate-binding cassette protein, member A3 (n = 12) was a more frequent cause of this phenotype than deficiency of surfactant protein B (n = 2).

[Genetic basis in chronic interstitial familial pneumopathy. Familial study of SFTPC]. / Basi genetiche della pneumopatia cronica interstiziale familiare. Studio familiare dell'SFTPC.

Mutations in the gene encoding surfactant protein C (SP-C) SFTPC have been found to be associated with chronic interstitial lung disease. A 5-year-old girl oxygen dependent from birth and affected by interstitial lung disease (ILD) is heterozygous for a T to C change in exon 3 resulting in the substitution of threonine for isoleucine at codon 73 (173T), already described in association with ILD. We studied 25 members of her family where the 173T mutation in the SP-C gene is associated to chronic pulmonary diseases. Five members in the mother's family showed respiratory diseases with great diversity in clinical features: her mother was affected by restrictive pneumopathy and emphysema, her grand-mother by asthma and recurrent pneumonia, 2 uncles underwent lung transplantation in the adult age, an aunt was clinically diagnosed having pulmonary fibrosis. All the family members affected by pulmonary diseases and one with no clinical symptoms showed the presence of the mutation 173T. Among the other family members the mutation was found in six subjects for whom no clinical data were available, yet. Our results confirm that heterozygosity for the mutation 173T may cause chronic inflammation of the lung or progressive pulmonary fibrosis. In addition, the possibility to study a large pedigree allowed us to perform a genotype-phenotype correlation indicating a marked phenotypic variability. The diversity in symptoms, age at onset, clinical course, duration of lung disease in the relatives sharing this mutation indicates an incomplete penetrance of the mutation. This might be due to the influence of other genetic factors thus indicating that the phenotype may be complicated by additional components.

Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer.

The feasibility and toxicity of allogeneic stem cell transplantation after nonmyeloablative conditioning including thiotepa, fludarabine, and cyclophosphamide have been investigated in 6 patients with breast cancer and 7 patients with renal cell cancer. The program included the use of escalating doses of donor lymphocyte infusions (DLI) and/or interferon alpha (IFNalpha) for patients showing no tumor response and no graft-versus-host disease (GVHD). Patients were at high risk of transplant-related mortality (TRM) because of age, advanced stage, and previous treatments. We observed a partial remission in 4 renal cancer and in 2 breast cancer patients (one at the molecular level in the bone marrow), occurring after cyclosporine withdrawal or after DLI and/or IFNalpha. All the responses were accompanied by the occurrence of acute GVHD. We conclude that reduced-intensity allogeneic stem cell transplantation is a feasible procedure in renal and breast cancer, and that the exploitation of graft-versus-tumor effect after DLI is a promising finding.