De novo versus recurrent metastatic breast cancer affects the extent of brain metastases.

PURPOSE: We aimed to identify factors associated with the extent of brain metastases in patients with breast cancer to help distinguish brain oligometastases (1-4 brain metastases) from extensive metastases (5 or more brain metastases). METHODS: This retrospective observational study included 100 female patients diagnosed with brain metastases from breast cancer at a single institution between January 2011 and April 2022. Patient demographics and tumor characteristics were compared between the brain oligometastases group and the extensive metastases group. Multivariable logistic regression analysis was performed to determine the independent factors, including age at initial diagnosis, initial stage, breast cancer subtype, detection time of brain metastases, and de novo or recurrent status of the metastatic disease. In a subgroup analysis of patients with brain oligometastases, demographic and tumor characteristics were compared between patients with single and two-four brain metastases. RESULTS: Of the 100 patients, 56 had brain oligometastases, while 44 had extensive brain metastases. The multivariable logistic regression analysis revealed that only the de novo/recurrent status of metastatic breast cancer was significantly associated with the extent of brain metastasis (p = 0.023). In the subgroup analysis of 56 patients with brain oligometastases, those diagnosed at an earlier stage were more likely to have a single brain metastasis (p = 0.008). CONCLUSION: Patients with de novo metastatic breast cancer are more likely to develop extensive brain metastases than those with recurrent metastatic breast cancer. This insight could influence the development of tailored approaches for monitoring and treating brain metastases, supporting the potential advantages of routine brain screening for patients newly diagnosed with stage IV breast cancer.

On-treatment derived neutrophil-to-lymphocyte ratio and survival with palbociclib and endocrine treatment: analysis of a multicenter retrospective cohort and the PALOMA-2/3 study with immune correlates.

BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been established as a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC); however, predictive biomarkers with translational relevance have not yet been elucidated. METHODS: Data from postmenopausal women who received the CDK4/6 inhibitor palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (N = 221; exploratory cohort). Pre- and on-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR; neutrophil/[leukocyte-neutrophil]) were correlated with survival outcomes. Data from the PALOMA-2 (NCT01740427) and PALOMA-3 studies (NCT01942135) involving patients treated with endocrine treatment with or without palbociclib were also analyzed (validation cohort). Prospectively enrolled patients (N = 20) were subjected to immunophenotyping with circulating immune cells to explore the biological implications of immune cell dynamics. RESULTS: In the exploratory cohort, palbociclib administration significantly reduced leukocyte, neutrophil, and lymphocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progression-free survival (PFS), higher on-treatment dNLRs were associated with worse PFS (hazard ratio = 3.337, P < 0.001). In the PALOMA-2 validation cohort, higher on-treatment dNLRs were associated with inferior PFS in patients treated with palbociclib and letrozole (hazard ratio = 1.498, P = 0.009), and reduction in the dNLR after treatment was predictive of a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbociclib and fulvestrant treatment in the PALOMA-3 validation cohort. Using flow cytometry analysis, we found that the CDK4/6 inhibitor prevented T cell exhaustion and diminished myeloid-derived suppressor cell frequency. CONCLUSIONS: On-treatment dNLR significantly predicted PFS in patients with HR-positive, HER2-negative ABC receiving palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment.

Resolution of Nonmass Enhancement Extension to the Nipple at Breast MRI after Neoadjuvant Chemotherapy: Pathologic Response and Feasibility for Nipple-sparing Mastectomy.

Background Nipple-sparing mastectomy (NSM) is usually contraindicated in patients with nonmass enhancement (NME) extension to the nipple at breast MRI. However, little is known about the feasibility of NSM when NME extension to the nipple resolves after neoadjuvant chemotherapy (NAC). Purpose To evaluate whether NSM is an appropriate surgical procedure for patients in whom NME extension to the nipple resolves after NAC. Materials and Methods This retrospective study included 383 women with NME at baseline MRI who underwent NAC followed by mastectomy between January 2007 and March 2022 at a single institution. NME extension to the nipple was assessed using breast MRI before NAC (hereafter, pre-NAC) and after NAC (hereafter, post-NAC). In 326 women who underwent mastectomy with removal of the nipple-areolar complex, the rate of pathologic analysis-confirmed tumor invasion of the nipple compared with NME extension to the nipple at post-NAC breast MRI was evaluated. Tumor involvement of the nipple was also assessed in those with complete pathologic response at posttreatment MRI. Furthermore, the outcomes in 57 women undergoing NSM were investigated, particularly in patients with NME extension to the nipple at initial diagnosis. Results Of the 326 women who underwent mastectomy with removal of the nipple-areolar complex (mean age, 49 years ± 9.4 [SD]), 217 patients (67%) showed NME extension to the nipple on pre-NAC MRI scans. Among the 153 women (70%) in whom the NME extension to the nipple resolved after NAC, the rate of pathologic analysis-confirmed tumor invasion of the nipple was 2.6% (four of 153 women; 95% CI: 0, 6.5). No pathologic analysis-confirmed tumor invasion of the nipple was detected in 31 women with complete response at MRI. Of the 57 women who underwent NSM, 12 (21%) with resolution of NME extension to the nipple after NAC had no relapse during the median follow-up of 31 months (range, 11-80 months). Conclusion Pathologic analysis-confirmed tumor invasion of the nipple was rare in women with resolution of nonmass enhancement extension to the nipple after neoadjuvant chemotherapy (NAC). Therefore, nipple-sparing mastectomy could be feasible in this population, especially in those with complete MRI response to NAC. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Lee in this issue.

PD-L1 tumour expression is predictive of pazopanib response in soft tissue sarcoma.

BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy. METHODS: Tumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%. RESULTS: Among the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8-5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1-9% (n = 3, 4.5%), 10-49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45-5.56, P = 0.006). CONCLUSION: We identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.

Correction to: Palbociclib use with grade 3 neutropenia in hormone receptor-positive metastatic breast cancer.

In the original publication of the article, under the Results section, subheading "Patient survival", the second sentence that reads as "The 6-month PFS was 92.4%, 81.8%, and 93.3% and the one-year PFS was 72.0%, 88.9%, and 78.9% in Groups 1-3, respectively." should read as "The 6-month PFS was 82.8%, 75.0%, and 68.0% and the one-year PFS was 77.0%, 62.0%, and 63.8% in Groups 1-3, respectively.".

Palbociclib use with grade 3 neutropenia in hormone receptor-positive metastatic breast cancer.

PURPOSE: Neutropenia is the most common toxicity of CDK4/6 inhibitors, causing frequent dose interruptions. However, CDK4/6 inhibitor-induced neutropenia shows a benign clinical course in contrast to that caused by chemotherapy. Here, we investigated the safety of a new dose scheme for palbociclib, which avoids dose delays or reductions due to afebrile grade 3 neutropenia. METHODS: A consecutive cohort of ER( +)/HER2( -) advanced breast cancer patients who received palbociclib between 2017 and 2018 was analyzed. The patients were classified into Group 1 (patients who maintained palbociclib dose with afebrile grade 3 neutropenia), Group 2 (patients who experienced any dose modification with afebrile grade 3 neutropenia), and Group 3 (patients without afebrile grade 3 neutropenia). The primary endpoint was febrile neutropenia incidence; other toxicities were compared with those of the PALOMA-2 trial. RESULTS: Among the 107 patients, 54.2%, 22.4%, and 23.4% were classified into Groups 1, 2, and 3, respectively. There was no febrile neutropenia in Groups 1 and 2 during palbociclib treatment. Group 1 showed higher incidence of thrombocytopenia (all-grade, 32.8%; grade 3-4, 8.6%) than Group 2 and the PALOMA-2 data, but there was no bleeding related to thrombocytopenia. Group 1 showed higher incidence of all-grade non-hematologic adverse events than Group 2; only one grade 3 non-hematologic toxicity was observed in Group 1. There were no treatment-related hospitalizations or deaths in Group 1. CONCLUSIONS: Thus, omitting palbociclib dose modification with afebrile grade 3 neutropenia is safe and tolerable without febrile neutropenia events. This scheme could be useful to avoid unnecessary reductions in palbociclib doses in future practice.

Intermediate HER2 expression is associated with poor prognosis in estrogen receptor-positive breast cancer patients aged 55 years and older.

PURPOSE: An antibody-drug conjugate targeting HER2, DS8201, has shown clinical activity against breast cancer with low-level HER2 expression. We aimed to evaluate the prognostic impact of intermediate HER2 expression in estrogen receptor (ER)+ early breast cancer (EBC) and metastatic breast cancer (MBC) cohorts. METHODS: We analyzed prospectively collected data from EBC and MBC cohorts at Yonsei Cancer Center. Patients with HER2 immunohistochemistry (IHC) 0 ~ 1+ were assigned to the HER2-negative group, and patients with IHC 2+ and in situ hybridization (ISH)-negativity were assigned to the HER2-intermediate group. After the exclusion of HER2 IHC 3+ or ISH+ patients, a total of 2657 EBC and 535 MBC patients were analyzed. RESULTS: In total, 654 (24.6%) EBC and 166 (31.0%) MBC patients were classified in the HER2-intermediate group. The HER2-intermediate patients more frequently tended to have progesterone receptor (PR)-negativity and higher nuclear grade in the EBC cohort, and showed a higher proportion of patients aged ≥ 55 years compared with the HER2-negative group in the MBC cohort. The HER2-intermediate patients showed significantly poorer recurrence-free survival (RFS) compared to the HER2-negative patients in the EBC cohort (p = 0.044). Notably, intermediate HER2 expression predicted poorer RFS in EBC patients aged ≥ 55 years (hazard ratio 1.95; p = 0.042) in multivariate Cox analysis but did not affect RFS in those aged < 55 years. In line with the EBC cohort results, intermediate HER2 expression predicted poorer overall survival (OS) in MBC patients aged ≥ 55 (hazard ratio 1.45; p = 0.044) without affecting OS of those aged < 55 years. CONCLUSION: Intermediate HER2 expression is an independent predictor of poor prognosis in both ER+ EBC and MBC patients aged ≥ 55 years. The clinical efficacy of new HER2-targeting antibody-drug conjugates needs to be validated in this high-risk subset of ER+ breast cancer patients.

Differences in the Efficacies of Pazopanib and Gemcitabine/Docetaxel as Second-Line Treatments for Metastatic Soft Tissue Sarcoma.

BACKGROUND: We retrospectively investigated the treatment outcomes of second-line treatment with pazopanib or gemcitabine/docetaxel in patients with advanced soft tissue sarcoma (STS). METHODS: Ninety-one patients who were treated with pazopanib or gemcitabine/docetaxel for advanced STS between 1995 and 2015 were analyzed. RESULTS: Forty-six and 45 patients received pazopanib and gemcitabine/docetaxel, respectively. The median progression-free survival for the group treated with pazopanib was 4.5 months compared with 3.0 months for the gemcitabine/docetaxel group (p = 0.593). The median overall survival for the group treated with pazopanib was 12.6 months compared with 14.2 months for the gemcitabine/docetaxel group (p = 0.362). The overall response rates (ORRs) were 6.5 and 26.7% in the pazopanib and gemcitabine/docetaxel groups, respectively. The following parameters had ORRs favoring gemcitabine/docetaxel: age ≥50 years (31.6 vs. 2.9%, p = 0.006), histologic grade 1-2 (40.9 vs. 0%, p = 0.001), and poor first-line treatment response (23.3 vs. 3.0%, p = 0.022). Gemcitabine/docetaxel was associated with better ORRs for the following histologic subtypes: leiomyosarcoma (p = 0.624), malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (p = 0.055), and angiosarcoma (p = 0.182). However, the ORR of synovial sarcoma favored pazopanib (p = 0.99). CONCLUSIONS: The efficacies of pazopanib and gemcitabine/docetaxel as second-line treatments after doxorubicin or ifosfamide failure differed among clinical and histologic subgroups and appeared to facilitate a more personalized treatment approach for advanced STS.

Marked Loss of Muscle, Visceral Fat, or Subcutaneous Fat After Gastrectomy Predicts Poor Survival in Advanced Gastric Cancer: Single-Center Study from the CLASSIC Trial.

BACKGROUND: There is increasing interest in the influence of body composition on oncological outcomes. We evaluated the role of skeletal muscle and fat among patients with gastric cancer (GC) who underwent gastrectomy with or without adjuvant chemotherapy, as well as those changes' associations with survival outcomes. METHODS: The present study evaluated 136 patients with GC who were enrolled in the CLASSIC Trial at Yonsei Cancer Center. Baseline body compositions including skeletal muscle area, Hounsfield units (HU), visceral fat area, and subcutaneous fat area were measured by preoperative computed tomography (CT). CT before and after the gastrectomy were used to determine the 6-month relative changes in body composition parameters. Continuous variables were dichotomized according to the best cutoff values by Contal and O'Quigley method. RESULTS: Seventy-three patients (53.7%) underwent surgery alone, and 63 patients (46.3%) underwent surgery followed by adjuvant chemotherapy. The baseline body composition parameters were not associated with disease-free survival (DFS) or overall survival (OS). Except for the HU, the marked loss of muscle, visceral fat, or subcutaneous fat significantly predicted shorter DFS and OS. Patients with a marked loss in at least one significant body composition parameter had significantly shorter DFS (hazard ratio 2.9, 95% confidence interval 1.7-4.8, P < 0.001) and OS (hazard ratio 2.9, 95% confidence interval 1.7-5.0, P < 0.001). CONCLUSIONS: Marked loss in body composition parameters significantly predicted shorter DFS and OS among patients with GC who underwent gastrectomy. Postoperative nutrition and active healthcare interventions could improve the prognosis of these GC patients.

Preoperative Serum Carcinoembryonic Antigen Level as a Prognostic Factor for Recurrence and Survival After Curative Resection Followed by Adjuvant Chemotherapy in Stage III Colon Cancer.

BACKGROUND: Carcinoembryonic antigen (CEA) is the most widely used tumor marker in colon cancer; however, there has been controversy regarding the significance of preoperative serum CEA level as a prognostic factor for recurrence. In this study, we evaluated the optimal cutoff value and prognostic significance of preoperative serum CEA level in stage III colon cancer. METHODS: Based on a retrospective cohort of 965 patients with stage III colon cancer who underwent elective curative surgery and adjuvant chemotherapy with fluoropyrimidine and oxaliplatin (training set), we determined the optimal cutoff value of CEA for recurrence using the Contal and O'Quigley method. We assessed the prognostic value of this cutoff value in terms of disease-free survival (DFS) and overall survival (OS) in a prospective cohort of 268 patients with stage III colon cancer (validation set). A Cox proportional hazards model was used to explore the association of prognostic variables with DFS and OS. RESULTS: The statistically determined best cutoff value for CEA was 3 ng/mL in the training set. A high CEA level (≥3 ng/mL) was associated with inferior DFS (hazard ratio [HR] 4.609, 95 % confidence interval [CI] 2.028-10.474) and OS (HR 3.956, 95 % CI 1.127-13.882) in the validation set, while multivariate analysis showed that a high CEA level was an independent risk factor for DFS and OS in both study subsets. CONCLUSION: Preoperative serum CEA level is an independent prognostic factor for DFS and OS in patients with stage III colon cancer after curative resection and adjuvant chemotherapy.

Role of adjuvant chemotherapy in locally advanced rectal cancer with ypT0-3N0 after preoperative chemoradiation therapy and surgery.

BACKGROUND: We aimed to explore the clinical benefit of adjuvant chemotherapy (AC) with fluoropyrimidine in patients with ypT0-3N0 rectal cancer after preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME). METHODS: Patients with ypT0-3N0 rectal cancer after preoperative CRT and TME were included using prospectively collected tumor registry cohort between January 2001 and December 2013. Patients were categorized into two groups according to the receipt of AC. Disease-free survival (DFS) and overall survival (OS) were compared between the adjuvant and observation groups. To control for potential confounding factors, we also calculated propensity scores and performed propensity score-matched analysis for DFS and OS. RESULTS: Of the 339 evaluated patients, 87 patients (25.7%) did not receive AC. There were no differences in DFS (hazard ratio [HR], 0.921; 95% confidence interval [CI], 0.562-1.507; P = 0.742) and OS (HR, 0.835; 95% CI, 0.423-1.648; P = 0.603) between the adjuvant and observation groups. After propensity score matching, DFS (HR, 1.129; 95% CI, 0.626-2.035; P = 0.688) and OS (HR, 1.200; 95% CI, 0.539-2.669; P = 0.655) did not differ between the adjuvant and observation groups. Advanced T stage and positive resection margin were independently associated with inferior DFS and OS on multivariate analysis. CONCLUSIONS: AC did not improve DFS and OS for patients with ypT0-3N0 rectal cancer after preoperative CRT followed by TME in this cohort study. The confirmative role of AC in locally advanced rectal cancer should be evaluated in prospective randomized trials with a larger sample size.

Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers.

BACKGROUND: Among colorectal cancers (CRCs), high-frequency microsatellite instability (MSI-H) is associated with a better prognosis, compared with low-frequency MSI or microsatellite stability (MSI-L/MSS). However, it is unclear whether MSI affects the prognosis of recurrent CRCs. METHODS: This study included 2940 patients with stage I-III CRC who underwent complete resection. The associations of MSI status with recurrence patterns, disease-free survival (DFS), overall survival from diagnosis to death (OS1), and overall survival from recurrence to death (OS2) were analysed. RESULTS: A total of 261 patients (8.9%) had MSI-H CRC. Patients with MSI-H CRC had better DFS, compared to patients with MSI-L/MSS CRC (hazard ratio (HR): 0.619, P<0.001). High-frequency microsatellite instability CRC was associated with more frequent local recurrence (30.0% vs 12.0%, P=0.032) or peritoneal metastasis (40.0% vs 12.3%, P=0.003), and less frequent lung (10.0% vs 42.5%, P=0.004) or liver metastases (15.0% vs 44.7%, P=0.01). Recurrent MSI-H CRC was associated with worse OS1 (HR: 1.363, P=0.035) and OS2 (HR: 2.667, P<0.001). An analysis of patients with colon cancer yielded similar results. CONCLUSIONS: Recurrence patterns differed between MSI-H CRC and MSI-L/MSS CRC, and recurrent MSI-H CRCs had a worse prognosis.

Assessment of Adrenal Function and Health-Related Quality of Life in Advanced Gastric Cancer Patients Who Received First-Line Chemotherapy.

OBJECTIVE: We performed this prospective study to identify both the incidence of adrenal insufficiency (AI) and health-related quality of life (HRQOL) in advanced gastric cancer (AGC) patients who were treated with the S-1 plus cisplatin (SP) regimen as a first-line palliative chemotherapy. METHODS: We assessed adverse events (AEs) observed in 52 patients who received the SP regimen for AGC between January 2009 and June 2010 using the Common Toxicity Criteria Adverse Events (CTCAE) version 3.0. Adrenal function was assessed at baseline and 12 weeks after chemotherapy using the low-dose adrenocorticotropic hormone stimulation test. HRQOL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC-QLQ C30). RESULTS: The incidence of AI was 30.8% (n = 16) and of AE observed 55% (n = 29) among 52 patients after 12 weeks of chemotherapy. Of 29 patients with AE, 34.4% (n = 10) were diagnosed with AI, and of 23 patients without AE, 26.1% (n = 6) were diagnosed with AI. CONCLUSION: The incidence of secondary AI in AGC patients was not rare and was not correlated with the presence of nonspecific AEs. Although patients diagnosed with AI did not show any related symptoms, they are at risk of potentially life-threatening consequences. Thus, the evaluation of AI could be suggested for patients who received chemotherapy.

Five-Fraction High-Conformal Ultrahypofractionated Radiotherapy for Primary Tumors in Metastatic Breast Cancer.

PURPOSE: To report on the local control and toxicity of 5-fraction, high-conformal ultrafractionated radiation therapy (RT) for primary tumors in patients with metastatic breast cancer (MBC) who did not undergo planned surgical intervention. METHODS: We retrospectively reviewed 27 patients with MBC who underwent 5-fraction high-dose ultrafractionated intensity-modulated RT for their primary tumors between 2017 and 2022 at our institution. A median dose of 66.8 Gy (range, 51.8-83.6 Gy) was prescribed to the gross tumor, calculated in 2-Gy equivalents using an α/ß ratio of 3.5, along with a simultaneous integrated boost of 81.5%. The primary endpoint of this study was local control. RESULTS: The median tumor size and volume were 5.1 cm and 112.4 cm3, respectively. Treatment was generally well tolerated, with only 15% of the patients experiencing mild acute skin toxicity, which resolved spontaneously. The best infield response rate was 82%, with the objective response observed at a median time of 10.8 months post-RT (range, 1.4-29.2), until local progression or the last follow-up. At a median follow-up of 18.3 months, the 2-year local control rate was 77%. A higher number of prior lines of systemic therapy was significantly associated with poorer 2-year local control (one-two lines, 94% vs three or more lines, 34%; p = 0.004). Post-RT, 67% of the patients transitioned to the next line of systemic therapy, and the median duration of maintaining the same systemic therapy post-RT was 16.3 months (range, 1.9-40.3). CONCLUSION: In our small dataset, 5-fraction, high-conformal ultrahypofractionated breast RT offered promising 2-year local control with minimal toxicity. Further studies are warranted to investigate the optimal dose and role in this setting.

Feasibility of Intraoperative Radiotherapy Tumor Bed Boost in Patients with Breast Cancer after Neoadjuvant Chemotherapy.

PURPOSE: This study aimed to assess the feasibility and safety of administering intraoperative radiotherapy (IORT) as a boost during breast-conserving surgery (BCS) following neoadjuvant chemotherapy for patients at high risk of breast cancer recurrence. MATERIALS AND METHODS: Patients who underwent neoadjuvant chemotherapy received a single 20-Gy dose of IORT during BCS, followed by external beam radiotherapy 4-6 weeks after surgery. RESULTS: The median follow-up duration was 31.0 months (range, 18.0-59.0 months). Initial tumor sizes had a median of 2.6 cm (range: 0.8-5.3 cm), reducing to 0.3 cm (range: 0-4.0 cm) after neoadjuvant chemotherapy. The most common neoadjuvant chemotherapy regimen was doxorubicin and cyclophosphamide, followed by paclitaxel (n=42, 73.7%). Among 57 patients who received neoadjuvant chemotherapy before BCS and IORT, 2 patients (3.5%) required secondary surgery to achieve negative resection margins due to initially positive margins. Regional lymph node irradiation was performed in 37 (64.9%) patients. There was no grade 3 or higher adverse events, with 4 patients (7.0%) experiencing grade 2 acute radiation dermatitis and 3 (5.3%) having less than grade 2 breast edema. Binary correlation analysis did not reveal statistically significant associations between applicator size or radiation therapy modality and the risk of treatment-related toxicity. Furthermore, chi-square analysis showed that the grade of treatment-related toxicity was not associated with the fractionated regimen (p=0.375). CONCLUSION: Most patients successfully received IORT as a tumor bed boost after neoadjuvant chemotherapy. Thus, IORT may be a safe and feasible option for patients with advanced-stage breast cancer receiving neoadjuvant chemotherapy.

Tumor-Infiltrating Lymphocyte Level Consistently Correlates with Lower Stiffness Measured by Shear-Wave Elastography: Subtype-Specific Analysis of Its Implication in Breast Cancer.

Background: We aimed to elucidate the clinical significance of tumor stiffness across breast cancer subtypes and establish its correlation with the tumor-infiltrating lymphocyte (TIL) levels using shear-wave elastography (SWE). Methods: SWE was used to measure tumor stiffness in breast cancer patients from January 2016 to August 2020. The association of tumor stiffness and clinicopathologic parameters, including the TIL levels, was analyzed in three breast cancer subtypes. Results: A total of 803 patients were evaluated. Maximal elasticity (Emax) showed a consistent positive association with an invasive size and the pT stage in all cases, while it negatively correlated with the TIL level. A subgroup-specific analysis revealed that the already known parameters for high stiffness (lymphovascular invasion, lymph node metastasis, Ki67 levels) were significant only in hormone receptor-positive and HER2-negative breast cancer (HR + HER2-BC). In the multivariate logistic regression, an invasive size and low TIL levels were significantly associated with Emax in HR + HER2-BC and HER2 + BC. In triple-negative breast cancer, only TIL levels were significantly associated with low Emax. Linear regression confirmed a consistent negative correlation between TIL and Emax in all subtypes. Conclusions: Breast cancer stiffness presents varying clinical implications dependent on the tumor subtype. Elevated stiffness indicates a more aggressive tumor biology in HR + HER2-BC, but is less significant in other subtypes. High TIL levels consistently correlate with lower tumor stiffness across all subtypes.

Predictive Markers of Treatment Response to Neoadjuvant Systemic Therapy with Dual HER2-Blockade.

In patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, achievement of pathologic complete response (pCR) is a known prognostic indicator after neoadjuvant systemic therapy (NAST). We investigated the clinicopathological factors associated with pCR in patients with HER2-positive breast cancer treated with dual HER2-blockade. In this retrospective study, 348 patients with HER2-positive breast cancer who received NAST with docetaxel and carboplatin, combined with trastuzumab and pertuzumab (TCHP), were included. Of the 348 patients with HER2 protein expression data, 278 (79.9%) had HER2 immunochemistry (IHC) 3+. Data on tumor-infiltrating lymphocyte (TIL) levels were available for 305 patients, showing a median TIL level of 20% (IQR 5-50), among which 121 (39.7%) had high TIL levels (≥30%). Estrogen receptor (ER) status (77.9% in ER-negative vs. 47.5% in ER-positive; p < 0.001), HER2 protein expression (71.6% in IHC 3+ vs. 34.3% in IHC 2+; p < 0.001), and TIL levels (71.9% in high vs. 57.6% in low; p = 0.011) were significantly associated with the pCR rate. In addition, we observed a significant link between numerical TIL levels (per 10% increment) and the pCR rate. After adjusting other clinicopathologic factors, ER status (low expression [defined as 1-9% expression] or negative), HER2 IHC 3+ and numerical TIL levels (per 10% increment), and high TIL levels (≥30%) were found to be independent predictors of pCR. Notably, in ER-negative breast cancer, the treatment response was excellent, irrespective of HER2 expression and TIL levels. Conversely, in ER-positive cases, low ER expression, HER2 IHC 3+, and numerical TIL levels or high TIL levels emerged as independent predictors of pCR. Our results suggest that ER expression, HER2 protein expression, and TIL levels serve as valuable predictors of the treatment response to neoadjuvant TCHP.

Elasticity Values as a Predictive Modality for Response to Neoadjuvant Chemotherapy in Breast Cancer.

Shear-wave elastography (SWE) is an effective tool in discriminating malignant lesions of breast and axillary lymph node metastasis in patients with breast cancer. However, the association between the baseline elasticity value of breast cancer and the treatment response of neoadjuvant chemotherapy is yet to be elucidated. Baseline SWE measured mean stiffness (E-mean) and maximum stiffness (E-max) in 830 patients who underwent neoadjuvant chemotherapy and surgery from January 2012 to December 2022. Association of elasticity values with breast pCR (defined as ypTis/T0), pCR (defined as ypTis/T0, N0), and tumor-infiltrating lymphocytes (TILs) was analyzed. Of 830 patients, 356 (42.9%) achieved breast pCR, and 324 (39.0%) achieved pCR. The patients with low elasticity values had higher breast pCR and pCR rates than those with high elasticity values. A low E-mean (adjusted odds ratio (OR): 0.620; 95% confidence interval (CI): 0.437 to 0.878; p = 0.007) and low E-max (adjusted OR: 0.701; 95% CI: 0.494 to 0.996; p = 0.047) were independent predictive factors for breast pCR. Low elasticity values were significantly correlated with high TILs. Pretreatment elasticity values measured using SWE were significantly associated with treatment response and inversely correlated with TILs, particularly in HR+HER2- breast cancer and TNBC.

Comparison of Programmed Cell Death Ligand 1 Status between Core Needle Biopsy and Surgical Specimens of Triple-Negative Breast Cancer.

PURPOSE: Pembrolizumab is currently used to treat advanced triple-negative breast cancer (TNBC) and high-risk early TNBC with neoadjuvant chemotherapy (NAC). The tumor-infiltrating lymphocyte (TIL) level and programmed cell death ligand 1 (PD-L1) status are predictors of response to NAC and immune checkpoint inhibitor treatment. We aimed to investigate whether the PD-L1 status in core needle biopsies (CNBs) could represent the whole tumor in TNBC. MATERIALS AND METHODS: A total of 49 patients diagnosed with TNBC who received upfront surgery without NAC between January 2018 and March 2021 were included. The PD-L1 expression (SP142 and 22C3 clones) and TIL were evaluated in paired CNBs and resected specimens. The concordance PD-L1 status and TIL levels between CNBs and resected specimens were analyzed. RESULTS: PD-L1 positivity was more frequently observed in resected specimens. The overall reliability of TIL level in the CNB was good [intraclass correlation coefficient (ICC)=0.847, p<0.001]. The agreements of PD-L1 status were good and fair, respectively (SP142, κ=0.503, p<0.001; 22C3, κ=0.380, p=0.010). As the core number of CNB increased, the reliability and agreement also improved, especially from five tumor cores (TIL, ICC=0.911, p<0.001; PD-L1 [22C3], κ=0.750, p=0.028). Regarding PD-L1 (SP142), no further improvement was observed with ≥5 tumor cores (κ=0.600, p=0.058). CONCLUSION: CNBs with ≥5 tumor cores were sufficient to represent the TIL level and PD-L1 (22C3) status in TNBC.

YAP1 Expression in HR+HER2- Breast Cancer: 21-Gene Recurrence Score Analysis and Public Dataset Validation.

BACKGROUND: YAP1, an oncogene in numerous cancers, is a downstream transcription factor of the Hippo pathway. This study focuses on its relationship with the Oncotype Dx (ODX) test risk score (RS) in patients with hormone-receptor-positive, HER2-negative (HR+HER2-) breast cancer. METHODS: We retrospectively analyzed 401 HR+HER2- breast cancer patients from Gangnam Severance Hospital who underwent ODX tests (May 2014-April 2020). YAP1 nuclear localization was evaluated via immunohistochemical staining and its clinical correlation with clinicopathological parameters, including RS, was analyzed. Public datasets TCGA-BRCA and METABRIC validated clinical outcomes. RESULTS: YAP1 expression negatively correlated with ODX RS (OR 0.373, p = 0.002). Elevated YAP1 mRNA levels corresponded to better clinical outcomes, specifically in ER-positive patients, with significant results in METABRIC and TCGA-BRCA datasets (p < 0.0001 OS in METABRIC, p = 0.00085 RFS in METABRIC, p = 0.040 DFS in TCGA-BRCA). In subsets with varying ESR1 mRNA expression and pronounced YAP1 expression, superior survival outcomes were consistently observed. CONCLUSION: YAP1 may be a valuable prognostic marker and potential therapeutic target in HR+HER2- breast cancer patients.