Neoadjuvant Systemic Therapy in Early Breast Cancer: Results of a Prospective Observational Multicenter BRIDE Study.

To evaluate the rate of early breast cancer (EBC) patients treated with neoadjuvant systemic therapy (NAT) in Italy, criteria of patient selection and types of therapies delivered, an analysis of 1276 patients with stage I-II-III was conducted out of 1633 patients enrolled in the multicenter prospective observational BRIDE study. A total of 177 patients (13.9%) were treated with NAT and 1099 (85.9%) with surgery; in multivariate analysis, menopausal status, cT, cN, grade, HER2-positive and Triple negative (TN) subgroups were significantly associated with the decision to administer NAT. The type of NAT delivered was influenced by EBC subtype. NAT was administered to 53.2% of HER2+/HR-negative, 27.9% of HER2+/HR+, 7.1% of HER2-negative/HR+ and 30.3% of TN EBC patients. The pCR rates were similar to the ones reported in the literature: 74.2% in HER2+/HR-negative, 52.3% in HER2+/HR+, 17.2% in HER2-negative/HR+ and 37.9% in TN. In clinical practice, patient and tumor characteristics influenced oncologists in the decision to administer NAT in EBC and in the choice of the type of systemic therapy, according to ESMO and AIOM Guidelines. Currently, it is recommended always to evaluate the use of NAT in EBC, mainly in HER2+ and TN patients, considering that pCR is associated with significantly better survival of the patient and that effective therapies are now available for residual disease.

High-dose continuous-infusion ifosfamide in advanced thymic epithelial Tumors: A TYME network study.

BACKGROUND: We reported the efficacy and safety results of high-dose, continuous-infusion Ifosfamide,in patients with advanced thymoma (TM) and thymic carcinoma (TC). METHODS: This was a multicentric, prospective study in patients with advanced TM or TC, who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis or anti-PD(L)1 was allowed. Patients received Ifosfamide (1 g/m2/day) and sodium-2-mercaptoethanesulfonate (1 g/m2/day), as continuous infusion, via a portable pumps for 14 consecutive days. Treatment was administered every 4 weeks until progression or unacceptable toxicity, up to a maximum of 6 cycles. The primary endpoint was the overall response rate (ORR) assessed by RECIST1.1. Secondary endpoints included disease control rate (DCR), Progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Eighteen patients were enrolled from October 2020 to January 2022. Twelve patients had a TC, 5 a TM and 1 a mixed TM/TC. Sixty-one percent of patients (11/18) had stage IVB disease according to Masaoka-Koga, and 39% (7/18) had an ECOG-PS 2. The median number of previous lines of therapy was 2 (range:1-5), and 72% (13/18) and 61% (11/18) of patients were pretreated with an anti-angiogenesis drug and an anti-PD(L)1 drug respectively. The ORR and the disease control rate (DCR) were 28 % (95 %CI: 10 %-53 %) and 67 % (95 %CI: 41 %-86 %), respectively. The median follow-up for PFS was 17.3 months (95 %CI: 4.3-NA), and median PFS was 5.4 months (95 %CI: 2.9-6.4). The median duration of response and SD was respectively 19.6 months (95 %CI: 3.5-NA) and 6.0 months (95 % CI: 3.8-6.4). In patients with TC, the ORR and DCR were 15 % (95 % CI: 2 %-45 %) and 54 % (95 % CI: 25 %-81 %), respectively. In the subgroup of 5 patients with TM, 2 PR and 3 SD were observed. Most patients had only mild (grade 1-2) AEs, the most common being nausea and vomiting (39%; 7/18) and transaminases elevation (33%; 6/18). Twenty-two percent of patients (4/18) experienced an AEs of grade 3 and required ifosfamide dose reduction. No patients had severe AEs. CONCLUSION: High-dose continuous-infusion Ifosfamide can be considered as a valuable treatment option in patients with advanced thymic epithelial tumors.

Continuous sunitinib schedule in advanced platinum refractory thymic epithelial neoplasms: A retrospective analysis from the ThYmic MalignanciEs (TYME) Italian collaborative group.

BACKGROUND: Thymic epithelial tumors (TETs) are rare diseases, with diverse clinical behaviour and prognosis. Intermittent dosing sunitinib represents the gold-standard systemic treatment following platinum-based chemotherapy. To ensure more homogeneous drug exposure, continuous daily dosing (CDD) sunitinib is utilised in other malignancies; however, no data exist in patients with TETs. METHODS: We retrospectively examined data from patients with platinum-resistant TETs receiving CDD sunitinib 37.5 mg between 1 May 2017 and 31 May 2022 within the Italian collaborative group for ThYmic MalignanciEs. Primary end-points were median progression-free survival, overall response rate (ORR), median duration of response and major treatment-related adverse events. RESULTS: A total of 20 consecutive patients (12 thymic carcinoma [TC], 6 B3, and 2 B2 thymoma) were evaluated. Among the 19 patients evaluable for response, ORR was 31.6% (95% CI, 12.5%-56.5%). Among patients with TC, one complete response, four partial responses, and four stable diseases were observed (ORR 41%).The overall median progression-free survival was 7.3 months (95% CI, 4.5-10.3): 7.3 months (95% CI, 4.4-NA) within patients with thymoma and 6.8 months (95% CI, 2.8-10.3) in patients with TC; median duration of response was 10.3 months (95% CI, 2.8-NA). CDD was associated with a manageable toxicity profile. Six patients (30%) experienced >G2 toxicity, nine required dose reduction and three discontinued treatment due to adverse events. CONCLUSIONS: CDD sunitinib showed a relevant antitumor activity and confirmed a good toxicity profile. Similar effectiveness and a better toxicity profile as compared with intermittent dosing historical data suggest that this schedule should be considered.

Predictors of fulvestrant long-term benefit in hormone receptor-positive/HER2 negative advanced breast cancer.

We retrospectively investigated in women treated with fulvestrant for HR+/HER2 negative advanced breast cancer clinical, pathological and molecular features associated with long-term benefit from treatment defined as being progression-free at 18 months. Specifically, we analyzed on formalin-fixed paraffin-embedded tumor samples ESR1 and PI3KCA mutations and miRNAs profiles. 59 patients were evaluable (median age of 67 years, range 32-92). 18-month PFS rate was 27%; the lack of visceral metastases significantly predicted the likelihood of being progression-free at 18 months, while PI3KCA mutations, found in 36% of patients, were not associated with 18-month PFS. As of miRNAs, miR-549a, miR-644a, miR-16-5p were negatively while let-7c-5p was positively associated with 18-month PFS. In addition, miR-520d-3p and miR-548g-3p values were significantly lower while miR-603, miR-181a-5p and miR-199a-miR-199b-3p values were significantly higher in patients achieving 18-month PFS. In silico analysis of targets modulated by these two latter groups of miRNAs show that in patients achieving 18-month PFS the Hippo and Wnt signaling pathways were predicted to be upregulated while endocrine resistance was potentially repressed by miR-603, miR-181a-5p and miR-199a-miR-199b-3p. Our results provide additional clues on the molecular mechanisms involved in fulvestrant activity and resistance. Underlying pathways should be further elucidated and confirmed in larger cohorts.

Clinicopathological and Immunohistochemical Characteristics in Male Breast Cancer: A Retrospective Case Series.

BACKGROUND: Due to its rarity, male breast cancer (mBC) remains an inadequately characterized disease, and current evidence for treatment derives from female breast cancer (FBC). METHODS: We retrospectively analyzed the clinicopathological characteristics, treatment patterns, and outcomes of mBCs treated from 2000 to 2013. RESULTS: From a total of 97 patients with mBC, 6 (6.2%) with ductal in situ carcinoma were excluded, and 91 patients with invasive carcinoma were analyzed. Median age was 65 years (range: 25-87 years). Estrogen receptors were positive in 88 patients (96.7%), and progesterone receptors were positive in 84 patients (92.3%). HER-2 was overexpressed in 13 of 85 patients (16%). Median follow-up was 51.5 months (range: 0.5-219.3 months). Five-year progression-free survival (PFS) was 50%, whereas overall survival (OS) was 68.1%. Patients with grades 1 and 2 presented 5-year PFS of 71% versus 22.5% for patients with grade 3 disease; 5-year OS was 85.7% for patients with grades 1 and 2 versus 53.3% of patients with grade 3. Ki-67 score >20% and adjuvant chemotherapy were also statistically significant for OS on univariate analyses. Twenty-six of 87 patients (29.8%) experienced recurrent disease and 16 of 91 patients (17.6%) developed a second neoplasia. CONCLUSION: Male breast cancer shows different biological patterns compared with FBC, with higher positive hormone-receptor status and lower HER-2 overexpression. Grade 3 and Ki-67 >20% were associated with shorter OS. IMPLICATIONS FOR PRACTICE: There is little evidence that prognostic features established in female breast cancer, such as grading and Ki-67 labeling index, could be applied to male breast cancer as well. This study found that grade 3 was associated with shorter overall survival and a trend for Ki-67 >20%; this could help in choosing the best treatment option in the adjuvant setting. Many questions remain regarding the impact of HER-2 positivity on survival and treatment with adjuvant anti-HER-2 therapy. Regarding metastatic male breast cancer, the results suggest that common regimens of chemo-, endocrine and immunotherapy used in female breast cancer are safe and effective for men. Male breast cancer patients show a higher incidence of second primary tumors, especially prostate and colon cancers and should therefore be carefully monitored.

Level of HER2/neu amplification in primary tumours and metastases in HER2-positive breast cancer and survival after trastuzumab therapy.

BACKGROUND: The level of HER2/neu amplification may vary widely in breast cancers with HER2/neu alteration. The clinical significance of this phenomenon is still unclear. This study was aimed to explore the level of HER2/neu amplification in primary tumours and metastases in HER2-positive metastatic breast cancer (MBC) and its potential impact on survival after a trastuzumab-containing therapy. METHODS: We retrospectively identified MBC patients treated with a trastuzumab-containing therapy and performed dual-colour FISH on tumour samples from either primary tumour and/or metastasis in a central laboratory. RESULTS: We retrieved 110 tumour samples from 91 patients and included 79 tumour samples (primary = 56; metastasis = 23) from 63 patients in the final analysis. We found higher level of HER2/neu amplification in the metastases than in the primary tumours (median HER2/CEP17 ratio: 10.5 vs. 7.0, respectively). In 69% of patients (n = 16) with two tumour samples, the level of HER2/neu amplification was higher in the metastasis than in the paired primary tumour (median HER2/CEP17 ratio: 10.9 vs. 8.3, respectively, p = 0.004). The incremental gain in level of HER2/neu amplification was associated with significantly shorter OS after trastuzumab-containing therapy (p = 0.023, HR 1.014, CI95%: 1.002-1.025). CONCLUSIONS: The level of HER2/neu amplification tends to increase from the primary tumour to the paired metastases in a significant proportion of patients with HER2-positive MBC. This phenomenon, although still not completely understood, could lead to a shorter OS after trastuzumab therapy.

Level of HER2/neu gene amplification as a predictive factor of response to trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer.

To explore the clinical significance of the level of HER2/neu gene amplification in a homogenous cohort of 33 patients with HER2-positive metastatic breast cancer (MBC) and available tumor samples treated with a trastuzumab-based regimen, we retrospectively performed dual-color fluorescence in-situ hybridization test and correlated them for each patient with time-to-progression (TTP) and overall survival (OS). We obtained values of HER2/chromosome 17 centromere (CEP17) ratio ranging from 2.5 to 21 (median 7.2). At the Cox model there is indication that patients whose tumors have high-level HER2/CEP17 ratio have shorter TTP and OS than those with lower ratio, when treated with a trastuzumab-based regimen. Correlations do not reach the limits of statistical significance but no formal sample size calculation was performed due to the explorative nature of the study. If confirmed in larger cohorts of patients, HER2/CEP17 ratio could represent a reliable and economical predictor of response to trastuzumab-based therapy in MBC.

Unexpected low efficacy of stealth liposomal doxorubicin (Caelyx) and vinorelbine in metastatic breast cancer.

In this phase II study, 23 patients with metastatic breast cancer were treated with a combination of Caelyx (40 mg/m2 on day 1) and vinorelbine (20 mg/m2 on days 1 and 8) every 4 weeks. According to the statistical design, enrollment was closed after the first stage due to the low response rate observed (four partial remissions, 12 stabilizations). Toxicity was acceptable, however, grade 3-4 neutropenia was not negligible. Our study does not support the development of this combination in advanced breast cancer.