Recently, phase I studies with novel antibody drug conjugates targeting HER2 suggested benefit in HER2-low patients -defined as immunohistochemistry(IHC) +1 or +2 FISH/ISH non-amplified, with advanced breast cancer(BC). Data on the prognostic value of HER2-low in early stage disease is scarce. The purpose of this study was to evaluate the impact of HER2-low status on response to neoadjuvant chemotherapy(NACT) and survival outcomes in early stage HER2negative BC. MethodsRecords from all BC patients treated with NACT from January 2007 to December 2018 in a single cancer center were retrospectively reviewed. Primary objective was to compare differences between pathologic complete response(pCR) and relapse free survival(RFS) in luminal HER2-low/HER2-0 and triple negative(TNBC) HER2-low/HER2-0. Results855 non-HER2-positive patients were identified. Median follow-up was 59 months. 542 had luminal BC (63.4%) and 313 TNBC (36.6%). 285 (33.3%) were HER2-low. Among luminal tumors, 145 had HER2 IHC+1 (26.8%) and 91 IHC+2/ISH non-amplified (16.8%). In TNBC, only 36 had HER2 IHC+1 (11.5%) and 13 IHC+2/ISH non-amplified (4.2%). Among luminal/HER2-low and luminal/HER2-0 population, there was a high proportion of clinical T3/4 (61.5% vs 69.2%, p=0.053), node positive (74.2% vs 66.3%, p=0.27) and stage III tumors (63.1% vs 65%, p=0.51). The same was true TNBC/HER-low as compared to TNBC/HER2-0, despite a non-statistically significant higher cT4 among TNBC/HER-low (32.7% vs. 19.3%, p=0.17). pCR was 13% in luminal/HER2-low versus 9.5% in luminal/HER2-0 (p=0.27), and 51% in TNBC/HER2-low versus 47% in TNBC/HER2-0 (p=0.64). 5y RFS was 72.1% in luminal/HER2-low and 71.7% in luminal/HER2-0 (p=0.47), and 75.6% in TNBC/HER2-low versus 70.8% in TNBC/HER2-0 (p=0.23). HER2-low status was not associated with RFS in multivariate analysis (HR 0.83, 95%CI 0.6-1.11, p=0.21). ConclusionOur data does not support HER2-low as a biologically distinct BC subtype, with no predictive effect on pCR after NACT nor prognostic value on survival outcomes.
Background Triple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer. In this study, we investigated how the cell composition of the immune cell infiltrated modifies the survival of patients with resected TNBC. Methods Retrospectively, we collected data from 76 patients diagnosed with non-metastatic TNBC with available tissue blocks for tissue micro-array (TMA) construction. The TMA was constructed using two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phospho-STAT1 was determined by immunohistochemistry. Results We observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+). PD-L1 expression in the stroma was associated with the percentage of TILs (p = 0.018) as, PD-L1 expression in the tumor was associated with the percentage of TILs (p = 0.049). We found a correlation between TILs and PD-L1 expression in stroma cells (p = 0.020) and in tumor cells (p = 0.027). In our cohort, we observed a trend for improved survival associated with higher CD8+ (p = 0.054) and CD4 + (p = 0.082) cell counts, but the results were not statistically significant. Conversely, the expression of PTEN in tumor cells and a low number of FOXP3+ cells in tumor stroma were both associated with improved OS. The CD8 to FOXP3 ratio and the CD4 to FOXP3 ratio were associated with better OS as well, however, only the CD8 to FOXP3 ratio had its prognostic impact confirmed in the METABRIC TNBC cohort. There was no association between PD-L1 expression and OS. Conclusion TNBC tumor microenvironment is enriched for lymphocytes and macrophages. FOXP3 expression and the CD8 to FOXP3 ratio in the tumor stroma as well as the loss of PTEN expression in tumor cells are prognostic factors in non-metastatic TNBC.
Background: Recent studies suggest that the percentage of TILs is a predictive factor for response to NAC and a prognostic factor associated with long-term disease control in hormone receptor-negative breast cancer. The TILs working group's current recommendation is to evaluate stromal TILs as the principal parameter in future studies. The term lymphocyte-predominant breast cancer (LPBC) can be used as a descriptive term for tumors that contain more lymphocytes than carcinoma cells. Typically, the threshold of stromal lymphocytes for LPBC is around 50% of the stromal surface area. It is unclear if this cutoff will be used in the future as such an intense TIL infiltration in tumors has been reported to be infrequent (∼10%). Studies with TNBC have demonstrated increasingly better overall survival (OS) and disease-free survival (DFS) associated with continuous scores of TIL in patients treated with adjuvant chemotherapy. In patients treated with NAC, TILs predicted pathological complete response (pCR). Our goal was to evaluate the impact of TIL on OS in TNBC patients treated with NAC. Methods: Data from patients with histologically confirmed TNBC treated with NAC from a single institution (A. C. Camargo Cancer Center - ACCCC), between July 2002 and November 2013, were retrospectively collected using electronic medical records. Patients with metastatic disease or in situ carcinoma at diagnosis were excluded. The density of TILs was evaluated in full-face hematoxylin and eosin-stained (HE) slides. Three blinded pathologists made the assessment of each slide, and a consensus on the TIL percentage was achieved. A cut-off of 10% for TIL percentage was employed for OS and DFS calculations, based on technical statistical maximizing log-rank test. We use this cut-off to test the association with pathological pCR rate as well. For pCR rate, we also used a cut-off of 50% (LPBC). We used Chi-square test to evaluate the association with pCR. A p-value<0,05 was considered statistically significant for all tests. Results: We identified 78 patients that fulfilled all inclusion and exclusion criteria. The median age was 42 years (range 17-70), and the clinical stage distribution was IIA (14%), IIB (22%), IIIA (19%), IIIB (33%) and IIIC (11%). 58 patients had archival FFPE blocks available and suitable for pathological analysis. Median follow-up was 4,1 years. Overall survival in 5 years in this subgroup was 62% (median not reached). 23 (39.7%) tumors had TIL> 10%, however only 10 had TIL > 50%. TIL >10% was associated with improved OS (HR 0.33, 95% CI, 1.0 to 0.11; p = 0.04). The same cut-off was associated with better DFS, although not statistically significant (HR 0.46, 95% CI, 1.1 to 0.18; p = 0.1). The overall pCR rate was 39.6% (48% for patients with TIL > 10% and 34% for patients with TIL <or = 10%; p = 0.3). LPBC had similar pCR rate (40% for LPBC vs. 39% for non-LPBC), probably due to the small number of samples analyzed. pCR was associated with a decreased risk of death (HR 0.06, 95% CI, 0.008 to 0.47; p<0.01). Conclusion: We observed improved OS associated with TIL>10% in TNBC patients treated with NAC. pCR was also associated with better OS. Citation Format: Sampaio CdDAT, de Lima VCC, de Andrade VP, Neotti T, Tavares MC, Sessa VA, Calsavara VF, Zenun GR, Giongo AA, da Costa AABA. Tumor-infiltrating lymphocytes (TILs) is associated with improved overall survival in triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy (NAC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-44.
Introduction: The axillary lymph node status is one of the most important prognostic factors in breast cancer. For locally advanced tumors, neoadjuvant chemotherapy favors higher rates of breast lumpectomy and downstaging tumor burden of axilla. The aim of this study was to evaluate the use of a standardized image-guided protocol after neoadjuvant chemotherapy to enable sentinel node dissection in patients with axillary downstaging, avoiding axillary dissection. Methods: Retrospective cohort study of data collected from medical records of patients who underwent neoadjuvant chemotherapy in a single center, from January 2014 to December 2018. The protocol comprises the placement of a metal clip in positive axillary lymph node, in patients with up to two clinically abnormal lymph nodes presented on imaging. After neoadjuvant chemotherapy, and once a radiologic complete response was achieved, sentinel node dissection was performed using blue dye and radiotracer. Axillary dissection were avoided in patients whose clipped sentinel node were negative for metastasis and in patients with three identified and negative sentinel node dissection. Results: A total of 471 patients were analyzed for this study: 303 before and 165 after the implementation of the protocol; 3 cases were excluded. The rate of sentinel node dissection in clinical nodes positive patients was statistically higher in this group when compared to patients treated before the protocol implementation (22.8% vs. 40.8%; p=0.001). Patients with triple negative and HER2-positive tumors underwent sentinel node dissection more frequently when compared to luminal tumors (p=0.03). After multivariate analysis, the variables that were associated with a greater chance of performing sentinel node dissection were clinical staging, type of surgery performed and implementation of the axillary assessment protocol. Conclusions: The results showed that the use of an easily and accessible image-guided protocol can improve sentinel node dissection in selected patients, even if the lymph node was positive previously to neoadjuvant treatment.
Background: Axillary lymph node status is one of the most important prognostic factors in breast cancer (BC). Neoadjuvant Chemotherapy (NACT) has been indicated for locally advanced tumors, and for HER2-positive and triple negative tumors larger than 2.0 and 1.0 cm, respectively, regardless of axillary status. This approach allows to assess biological response of the tumor, predicting prognosis and may permit more conservative surgeries in breast and axilla. However, there is no consensus about the best approach on management of axilla after NACT. Objective: To evaluate the rate of axillary downstaging after NACT in BC patients using a standardized protocol with a clip marker placement on positive lymph nodes prior to chemotherapy at a Cancer Center. Methods: This single-center, Institutional Review Board (IRB)-approved, retrospective study evaluated 471 BC patients who underwent NACT from January/2014 to December/2018. All included patients were evaluated for histological type, clinical T and N stages before NACT, modality of breast surgery (mastectomy vs. lumpectomy), type of axillary dissection (Axillary Lymph Node Dissection [ALND], sentinel lymph node biopsy [SLNB], or SLNB followed by ALND), placement or not of a clip marker in axillary lymph nodes before NACT, reason for the ALND and the pathological response by residual cancer burden (RCB) criteria. Patients were divided in two groups, before and after institution of a standardized protocol for axillary management after NACT in January/2017, which consists of: (1) biopsy of clinically suspect axillary lymph nodes before NACT, and placement of a clip marker in one positive lymph node in patients with 1-2 suspected lymph nodes (N1); (2) SLNB after NACT using blue dye and radioactive isotope injection; (3A) in the presence of clip marker in an axillary lymph node, confirmation of its extraction is performed through radiography of the surgical specimen and, (3B) in the absence of clip markers on axillary lymph nodes, removal of at least 03 sentinel lymph nodes should be performed; (4) no further axillary dissection is performed if all SLN are negative on frozen section analysis; any residual lymph node disease and/or absence of previously placed clip marker on SLNB specimen indicate ALND.Results: Patients’ mean age was 47 years (range 24-87 years), 67.2% (n=316) were cT2-T3, 83.5% (n=393) cN+ (N1 and N2), 62.6% (n = 295) had mastectomy. ALND was performed in 64.7% (n=303) patients, SLNB in 33.3% (n=156) and SLNB followed by ALND in 1.9% (n=9). In the subgroup of N+ patients (n=385), it was possible to perform SNB in 25.6% (n=98). 165 of 471 patients (35%) were included in standardized protocol for axillary management; the rate of SLNB in N+ patients was statistically higher in this group when compared to patients treated before the implementation of the protocol (34.4% vs. 22.8%; p=0.025).Conclusion: The results of the present study demonstrate a significant increase in sparing ALND after the implementation of a standardized protocol for management of axilla after NACT. However, further multi-institutional studies are still needed to support its widely adoption, as well as clinical trials to assess overall and disease-free survival in those patients who had omitted ALND after NACT. Citation Format: Marina de Paula Canal, Caroline Rocha, Marina Sonagli, Almir Bitencourt, Solange Sanches, Monique Tavares, Cynthia Osório, Fabiana Baroni Makdissi. Impact of a standardized protocol for management of axilla after neoadjuvant chemotherapy in breast cancer patients at a cancer center [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-44.
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