Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial.

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.

Immunohistochemistry-based molecular subtyping of triple-negative breast cancer and its prognostic significance.

Background: Immunohistochemistry (IHC)-based protein markers representing molecular subtypes are of great value for routine use. This study aimed to evaluate the frequency distributions of the molecular subtypes of triple-negative breast cancer (TNBC) using IHC-based surrogate markers and examined their prognostic value. Methods: Patients with TNBC treated at a university hospital in Southern Thailand were included in this study. Expression levels of androgen receptor, CD8, Forkhead box transcription factor C1, and Doublecortin-like kinase 1 were detected in tumor tissue to classify them into luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immunosuppressed (BLIS), mesenchymal-like (MES), and unclassifiable (UC) subtypes. The association between variables and disease-free survival (DFS) and overall survival (OS) was analyzed using Cox proportional hazards regression. Results: Among the 195 cases of TNBC, the frequency distribution of the IHC-based subtype was as follows: BLIS, 52.8%; LAR, 19.0%; IM, 17.4%; MES, 0.5%; and un-classifiable, 10.3%. BLIS subtype was significantly found in younger ages (mean: 49.6 years) than other subtypes (mean: 51-57.7 years). LAR and BLIS subtypes were significantly associated with poorer OS compared to the IM subtype in univariate analysis, however, only BLIS was significant in multivariate analysis (HR: 3.29, 95% CI: 1.01-10.72). IHC-based subtype was not found to be associated with DFS. Conclusion: This study revealed the differences in the proportion frequency of IHC-based TNBC subtypes in Thai patients compared to other populations. IHC-based molecular subtyping may be beneficial for prognosis. However further refinement of the molecular classification of TNBC is needed for better clinical relevance.

A Clinical Prediction Model for Breast Cancer in Women Having Their First Mammogram.

BACKGROUND: Digital mammography is the most efficient screening and diagnostic modality for breast cancer (BC). However, the technology is not widely available in rural areas. This study aimed to construct a prediction model for BC in women scheduled for their first mammography at a breast center to prioritize patients on waiting lists. METHODS: This retrospective cohort study analyzed breast clinic data from January 2013 to December 2017. Clinical parameters that were significantly associated with a BC diagnosis were used to construct predictive models using stepwise multiple logistic regression. The models' discriminative capabilities were compared using receiver operating characteristic curves (AUCs). RESULTS: Data from 822 women were selected for analysis using an inverse probability weighting method. Significant risk factors were age, body mass index (BMI), family history of BC, and indicated symptoms (mass and/or nipple discharge). When these factors were used to construct a model, the model performance according to the Akaike criterion was 1387.9, and the AUC was 0.82 (95% confidence interval: 0.76-0.87). CONCLUSION: In a resource-limited setting, the priority for a first mammogram should be patients with mass and/or nipple discharge, asymptomatic patients who are older or have high BMI, and women with a family history of BC.

Intraoperative Molecular Analysis of Total Tumor Load in Sentinel Lymph Node: A Predictor of Axillary Status in Early Breast Cancer.

BACKGROUND: Axillary lymph node dissection (ALND) remains the standard of care in breast cancer patients with positive sentinel lymph node (SLN). However, approximately 40-60% of patients with positive SLNs have not developed to non-SLN metastasis and ALND seems to be an overtreatment. The purpose of this study was to analyze predictors and define a specific cut-off of total tumor load (TTL) of CK19 that can be used as a predictive factor of non-SLN metastasis in early breast cancer patients. MATERIALS AND METHODS: The records of 238 patients with cT1-3N0 breast cancer who had an intraoperative SLN evaluation performed through One-Step nucleic acid (OSNA) assay at Songklanagarind Hospital between 1 January 2015 and 31 December 2019 were examined. Univariate and Multivariate analysis was used to identify clinicopathologic features in SLN-positive patients that predict metastasis to non-SLNs. Finally, receiver operative characteristics (ROC) curves were used to choose an optimal TTL cut-off value. RESULTS: Of a total of 110 patients who had a positive SLN, only 48 (43.64%) were found to have positive nodes in non-SLN. Multivariate analysis revealed that lymphovascular invasion, type of SLN metastasis and SLN TTL (copies/µL) were independent predictors of positive non-SLNs.  TTL cut-off value was 19,000 copies/µL, with an AUC of 0.838 with 72.7% sensitivity and 84.7% specificity to predict non-SLN metastasis. CONCLUSIONS: The likelihood of positive non-SLNs in patients who showed a positive SLN correlates with lymphovascular invasion, type of SLN metastasis and SLN TTL (copies/µL). Our result revealed that the patients with a SLN TTL ≥19,000 copies/µl continue to attract the recommendation to proceed with ALND. This cut-off value can then help clinicians to assess which patients would benefit from ALND.

Laparoscopic trans-hiatal approach in a rare case of double giant epiphrenic diverticula: A case report.

The transthoracic approach for esophageal diverticulectomy saves dissection but limits the amount of antireflux surgery that can be done. However, the laparoscopic trans-hiatal approach usually limits access to large diverticula located at the mid-thoracic level. We describe a 67-year-old Thai man who had two giant epiphrenic diverticula (ED) (11 × 7.6 cm and 3.2 × 3.4 cm). The highest part of the fundus of the larger ED was 12.6 cm above the hiatus. Preoperative esophageal manometry and an upper gastrointestinal study showed no obvious features of motility disorder. In addition, the clinical evaluation of the esophagogastroduodenoscopy revealed a hiatal hernia. Laparoscopic trans-hiatal esophageal diverticulectomy with intraoperative assessment by endoscopy was carried out. A partial wrap using Dor fundoplication was constructed without myotomy. There were no postoperative related complications. We believe that tailor-made operations in unusual cases can be safe using combined techniques to reduce postoperative morbidity.

Pathum Raksa Project: Addressing Disparity in Breast Cancer Care Through National Innovation in Thailand.

PURPOSE: Breast cancer is a growing public health challenge in Thailand. Pathum Raksa project was launched in 2015, as a result of higher than expected rate of triple-negative breast cancers in Thai women. The purpose of this project was to identify the cause(s) and address the issue(s), hence improving the quality of breast cancer biomarker testing in Thailand. MATERIALS AND METHODS: Nineteen hospitals across the country, with 902 breast cancer patients were enrolled in this study during 2015-2020. The pre- and post-data from Pathum Raksa initiative was only available for Khon Kaen University (KKU) and Udonthani hospitals in Northeast Thailand. We developed a resource-stratified strategic plan that included designing a unique specimen container, forming multidisciplinary teams from the Surgery and Pathology Departments, and employing locally developed innovative technologies to optimize the entire process of breast cancer diagnostics and biomarker testing. RESULTS: The rate of triple-negative breast cancers in KKU and Udonthani decreased 52.8% (p = 0.02) and 28.9% (p = 0.48), respectively. The rate of ER+ breast cancers in both hospitals increased 5% post-Pathum Raksa implementation. The rate of HER2-neu+ (score 3+) also increased in both hospitals (particularly an increased 65% rate in KKU). Luminal A/B cancers were the most common subtype in both KKU and Udonthani hospitals. CONCLUSION: Pathum Raksa project has significantly improved breast cancer biomarker testing in Thailand. As a result of this national innovation, false-negative rates of breast biomarkers have significantly decreased, resulting in improving prognosis, treatment, and survival of breast cancer women in Thailand.

Prediction for Breast Cancer in BI-RADS Category 4 Lesion Categorized by Age and Breast Composition of Women in Songklanagarind Hospital.

BACKGROUND: Older age and dense breast are the important risk factors for breast cancer. The ACR BI-RADS lexicon 5th edition does not mention how patient age and breast density may affect the category assessment. The aim of this study was to investigate whether patient age and breast density influence the positive predictive value (PPV) of mammographic and ultrasonographic findings categorized as BI-RADS category 4 and subcategories 4a, 4b, and 4c among female patients. MATERIALS AND METHODS: A retrospective study was conducted in Songklanagarind Hospital between January 1, 2016 and December 31, 2017 in female patients older than 18 years who had breast lesions categorized as BI-RADS category 4 and subcategories 4a, 4b, 4c. A total of 961 breast lesions consisted of 772 (80.33%) benign lesions and 189 (19.67%) malignant lesions. Categorization was done in each lesion based on age ranges of ≤35 years, >35 to 60 years, and >60 years and breast density according to mammographic breast composition. The PPV for each BI-RADS category was calculated based on the pathological diagnoses and were compared using the chi-square test. RESULTS: The overall PPV in each subcategory was in the reference range. The PPV increased with increasing age: 4% vs. 22.63% vs. 36.67% for category 4 (p-value=0.01); 0% vs. 5.81% vs. 6.88% for subcategory 4a (p-value=0.002); 6.67% vs. 26.62% vs. 51.35% for subcategory 4b (p-value=0.001); and 33.33% vs. 76.92% vs. 81.82% for subcategory 4c (p-value=0.02). An association was not found between PPV and breast density. CONCLUSION: A significantly positive association was found between PPV and age in patients in BI-RADS subcategories 4a, 4b, and 4c. This study could not determine that mammographic breast composition according to the ACR BI-RADS 5th edition was associated with PPV due to improper sample distribution.

Efficacy, Safety, and Tolerability of Pertuzumab, Trastuzumab, and Docetaxel for Patients With Early or Locally Advanced ERBB2-Positive Breast Cancer in Asia: The PEONY Phase 3 Randomized Clinical Trial.

Importance: Prospective assessment of treatments known to benefit patients in global clinical trials in specific racial groups is essential. Objective: To compare the efficacy, safety, and tolerability of adding pertuzumab to trastuzumab and docetaxel vs placebo, trastuzumab, and docetaxel in Asian patients with ERBB2-positive early or locally advanced breast cancer. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled phase 3 trial enrolled 329 women with ERBB2-positive early (T2-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) and primary tumor larger than 2 cm from March 14, 2016, to March 13, 2017. Analysis of the primary end point was performed on an intention-to-treat basis. Interventions: Before surgery, patients received 4 cycles of intravenous pertuzumab (840-mg loading dose and 420-mg maintenance doses), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), and docetaxel (75 mg/m2) or intravenous placebo, trastuzumab, and docetaxel every 3 weeks. After surgery, patients received 3 cycles of intravenous fluorouracil, epirubicin, and cyclophosphamide followed by 13 cycles of the same intravenous anti-ERBB2 therapy (pertuzumab and trastuzumab or placebo and trastuzumab) for up to 1 year. Main Outcomes and Measures: The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by disease category and hormone receptor status, was used to compare rates between treatment groups. Results: In total, 329 female patients were randomized (pertuzumab, 219; and placebo, 110; mean [SD] age, 48.8 [9.5] years). In the intention-to-treat population, total pathologic complete response rates were 39.3% (86 of 219) in the pertuzumab group and 21.8% (24 of 110) in the placebo group (difference, 17.5% [95% CI, 6.9%-28.0%]; P = .001). Of the most common grade 3 or higher adverse events, there was a higher incidence of neutropenia in the pertuzumab group (83 of 218 [38.1%] vs 36 of 110 [32.7%]). Serious adverse events were reported in 10.1% of patients (22 of 218) in the pertuzumab group and 8.2% of patients (9 of 110) in the placebo group. Conclusions and Relevance: Treatment with pertuzumab, trastuzumab, and docetaxel resulted in a statistically significant improvement in the total pathologic complete response rate vs placebo, trastuzumab, and docetaxel for the neoadjuvant treatment of ERBB2-positive early or locally advanced breast cancer in Asian patients. Safety data were in line with the known pertuzumab safety profile and generally comparable between treatment groups. The PEONY trial adds to the totality of data showing the benefit of the pertuzumab regimen. Trial Registration: ClinicalTrials.gov identifier: NCT02586025.

Ethnic disparity in breast cancer survival in southern Thai women.

BACKGROUND: Breast cancer has the highest incidence in women of all cancers and its burden is expected to continue to increase worldwide, especially in middle-income countries such as Thailand. The southern region of Thailand is unique in that it is comprised of 30% Muslims, whereas the rest of Thailand is 95% Buddhist. Breast cancer incidence and survival differ between these religious groups, but the association between clinical subtype of breast cancer and survival has not yet been assessed. METHODS: Here we characterized differences in breast cancer survival with consideration to clinical subtype by religious group (Muslim Thai and Buddhist Thai women). We compared distributions of age, stage and clinical subtype and assessed overall survival by religion. RESULTS: Our findings show that Muslim Thai women with breast cancer are diagnosed at a younger age, at later stages and have shorter overall survival times compared to Buddhist Thai women with breast cancer. We also observe a higher proportion of triple negative tumors characterized in Muslim Thai women. CONCLUSIONS: Our findings confirm previous studies that have shown lower survival rates in Muslim Thai women compared to Buddhist women with breast cancer and offer novel information on subtype distribution. To date, this is the first study assessing clinical subtypes in southern Thailand by religious status. IMPACT: Our findings are critical in providing information on the role of clinical subtype in cancer disparities and provide evidence from the Southeast Asian region for global studies on breast cancer survival.

The Pre-Treatment Neutrophil-Lymphocyte Ratio: a Useful Tool in Predicting Non-Sentinel Lymph Node Metastasis in Breast Cancer Cases

Background: The sentinel lymph node (SLN) biopsy is a highly accurate predictor of overall axillary nodal status in early breast cancer patients. There is however, still a debate on which patients with a positive SLN can benefit from axillary lymph node dissection (ALND). Numerous studies have been designed to identify variables that are predictive of non-SLN metastasis to avoid a complete ALND. The aim of this study was to determine whether the pre-treatment neutrophil-lymphocyte ratio (NLR) can be a predictive factor of non-SLN metastasis in early breast cancer patients. Materials and Methods: The records of 214 consecutive patients with cT1-3N0 invasive breast cancer who had undergone intraoperative SLN evaluation at Songklanagarind Hospital between the 1stof March 2011 and the 30thof May 2016 were examined. Data on patient demographics, tumor variables and NLR were collected and factors for non-SLN metastasis were analyzed using multivariate logistic regression. The power of the NLR was quantified with receiver operating characteristics (ROC) curves as measured by the areas under curves (AUC). Results: Multivariate analysis established presence of lymphovascular invasion (OR 8.4, 95%CI 2.3-31.3, p=0.002), macrometastasis (OR 6.6, 95%CI 1.8-24.7, p=0.005), and NLR (OR 2.3, 95%CI 1.1-4.8, p=0.033) as predictive factors of non-SLN metastasis with statistical significance. The AUC for NLR was 0.7 (95%CI 0.6-0.8) with an optimal cut-off of 2.6 giving a sensitivity of 62%, a specificity of 83.8%, a positive predictive value of 77.3% and a negative predictive value of 70.5%. Conclusion: Pre-treatment NLR is a useful diagnostic aid for predicting additional non-SLN metastasis.