Naoko Matsuda

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

ABSTRACT Introduction: Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.

Risk factors for locoregional disease recurrence after breast-conserving therapy in patients with breast cancer treated with neoadjuvant chemotherapy: An international collaboration and individual patient meta-analysis: Recurrence After Neoadjuvant Chemotherapy

Several studies have reported a high risk of local disease recurrence (LR) and locoregional disease recurrence (LRR) in patients with breast cancer after neoadjuvant chemotherapy (NCT) and breast‐conserving therapy (BCT). The objective of the current study was to identify potential risk factors for LR and LRR after NCT and BCT.

Safety and Efficacy of Panitumumab Plus Neoadjuvant Chemotherapy in Patients With Primary HER2-Negative Inflammatory Breast Cancer

Importance Combining conventional chemotherapy with targeted therapy has been proposed to improve the pathologic complete response (pCR) rate in patients with inflammatory breast cancer (IBC). Epidermal growth factor receptor (EGFR) expression is an independent predictor of low overall survival in patients with IBC. Objective To evaluate the safety and efficacy of the anti-EGFR antibody panitumumab plus neoadjuvant chemotherapy in patients with primary human epidermal growth factor receptor 2 (HER2)-negative IBC. Design, Setting, and Participants Women with primary HER2-negative IBC were enrolled from 2010 to 2015 and received panitumumab plus neoadjuvant chemotherapy. Median follow-up time was 19.3 months. Tumor tissues collected before and after the first dose of panitumumab were subjected to immunohistochemical staining and RNA sequencing analysis to identify biomarkers predictive of pCR. Intervention Patients received 1 dose of panitumumab (2.5 mg/kg) followed by 4 cycles of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m2), and carboplatin weekly and then 4 cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks. Main Outcomes and Measures The primary end point was pCR rate; the secondary end point was safety. The exploratory objective was to identify biomarkers predictive of pCR. Results Forty-seven patients were accrued; 7 were ineligible. The 40 enrolled women had a median age of 57 (range, 23-68) years; 29 (72%) were postmenopausal. Three patients did not complete therapy because of toxic effects (n = 2) or distant metastasis (n = 1). Nineteen patients had triple-negative and 21 had hormone receptor–positive IBC. The pCR and pCR rates were overall, 11 of 40 (28%; 95% CI, 15%-44%); triple-negative IBC, 8 of 19 (42%; 95% CI, 20%-66%); and hormone receptor–positive/HER2-negative IBC, 3 of 21 (14%; 95% CI, 3%-36%). During treatment with panitumumab, nab-paclitaxel, and carboplatin, 10 patients were hospitalized for treatment-related toxic effects, including 5 with neutropenia-related events. There were no treatment-related deaths. The most frequent nonhematologic adverse event was skin rash. Several potential predictors of pCR were identified, including pEGFR expression and COX-2 expression. Conclusions and Relevance This combination of panitumumab and chemotherapy showed the highest pCR rate ever reported in triple-negative IBC. A randomized phase 2 study is ongoing to determine the role of panitumumab in patients with triple-negative IBC and to further validate predictive biomarkers. Trial Registration ClinicalTrials.gov Identifier: NCT01036087

The Prognostic Effect of Changes in Tumor Stage and Nodal Status After Neoadjuvant Chemotherapy in Each Primary Breast Cancer Subtype

Background: Although the prognostic value of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) depends on the intrinsic subtype of breast cancer, it is not clear whether chemosensitivity itself, shown by a decreasing tumor burden after NAC, contributes to improved prognosis in primary breast cancer patients, especially in patients with non‐pCR. The aim of this study was to assess the prognostic effect of changes in tumor stage or nodal status after NAC in each primary breast cancer subtype. Patients and Methods: We assessed 719 consecutive patients with primary breast cancer who underwent surgical resection after NAC between 2001 and 2010. The patients were divided into 5 subtypes according to their hormone receptor (HR) status, HER2 status, and nuclear grade (NG; 1/2 = low, and 3 = high). Results: In patients with HR‐positive (HR+)/HER2−/NG‐low tumors, regardless of change in tumor size, the loss of node positivity after NAC significantly improved disease‐free survival (DFS). In patients with HR+/HER2−/NG‐high tumors, achievement of tumor downstaging as well as the loss of node positivity improved their DFS. In patients with HR−/HER2− tumors, tumor downstaging and the loss of node positivity significantly improved DFS, despite a non‐pCR. In contrast, in patients with HER2+ tumors, changes in tumor stage or nodal status were not associated with prognosis unless pCR was achieved. Conclusion: Our results revealed that changes in tumor stage and nodal status after NAC might be prognostic markers in patients with HR+/HER2−/NG‐high tumors or HR−/HER2− tumors, even if there are residual tumors in the breast.

Abstract P2-02-11: Accuracy of MRI and ultrasonography in predicting pathologic complete response in breast cancer patients treated with neoadjuvant chemotherapy

Background: Surgical treatment could be omitted if we could predict pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in primary breast cancer patients by radiological findings accurately. The aim of this study is to assess the accuracy of MRI and ultrasonography (US) in predicting pathologic complete response in breast cancer patients treated with NAC. Methods: Five hundred sixty nine primary breast cancer patients who underwent breast conserving surgery after NAC between 2004 and 2008 were reviewed. Sensitivity and specificity of clinical complete response (cCR) by MRI alone and in combination with US were retrospectively assessed. pCR in primary tumor was defined as no residual invasive carcinoma. Spotted, linear or trabecular lesions without vascularity detected by US and/or enhanced on late phase of MRI findings were suspected to be residual in situ carcinoma. Results: The median age of the 569 patients analyzed was 50 years (range, 26-76 years). Of the patients, 86 (15.1%) had pCR. Of 79 patients who were diagnosed cCR by MRI alone, 72 patients (91.1%) were accurately predicted. Of 490 patients who were diagnosed to have residual invasive carcinoma, 14 patients (2.9%) had pCR. Of 75 patients who were diagnosed cCR by MRI in combination with US, 68 patients (90.7%) was accurately predicted. Of the 494 patients who were diagnosed to have residual invasive carcinoma, 18 patients (3.6%) had pCR. The combination of MRI and US had a sensitivity of 79.1%, specificity of 98.6%. For 85 patients who were diagnosed cCR by MRI and/or US, positive predictive value was 89.4% in ER-positive breast cancer, 100% in ER-negative/HER2-positive breast cancer, and 81.5% in triple negative breast cancer. In terms of prediction of residual in situ carcinoma, of the 86 patients with pCR, 43 (50%) had residual in situ carcinoma. The median size of residual tumor was 2.0 cm (range, 0.01-8.0 cm). Twenty five of 37 patients (67.6%) who are diagnosed cCR without any residual in situ carcinoma by both MRI and US were accurately predicted. Twelve of the 37 patients (31.6%) had residual carcinoma (in situ carcinoma, n = 10, and invasive carcinoma, n = 2) on surgical specimen. Twenty one of 38 patients (55.3%) who are diagnosed cCR with residual in situ carcinoma by both MRI and US had pCR with residual in situ carcinoma accurately. Twelve of the 38 patients (31.6%) had pCR without any in situ carcinoma and 5 (13.2%) had residual invasive carcinoma on surgical specimen. Conclusions: Our results indicated that MRI in combination with US was highly useful to predict pCR in breast cancer patients treated with NAC, although it was hard to predict a presence of residual in situ carcinoma. Pathological intervention using a vacuum-assisted breast biopsy in addition to these radiological modalities is expected for higher accuracy of predicting pCR. We are going to conduct a prospective multi-institutional study to assess predictive value of the method. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-02-11.

Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis

Background: Bone is the most common site of metastasis of breast cancer. Biological mechanisms of metastasis to bone may be different from mechanisms of metastasis to non-bone sites, and identification of distinct signaling pathways and somatic mutations may provide insights on biology and rational targets for treatment and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone-only versus non-bone sites of first metastasis. Methods: Primary tumor samples were collected before treatment from 389 patients with untreated primary breast cancer and distant metastasis at diagnosis. In each sample, 46 or 50 cancer-related genes were analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. Fishers exact test was used to identify somatic mutations associated with bone-only first metastasis. Logistic regression models were used to identify differences in detected somatic mutations, clinicopathologic characteristics, and survival between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only (“other-only first metastasis”). Results: Among the 389 patients, 72 (18.5%) had bone-only first metastasis, 223 (57.3%) had other-only first metastasis, and 94 (24.2%) had first metastasis in both bone and non-bone sites. The most commonly mutated genes were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and lower grade (grade 1 or 2; Nottingham grading system) (all three comparisons, p<0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma (p=0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1%-62.9%]; p=0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis (p=0.49 and p=0.68, respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p=0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis (p=0.54) but was significantly associated with hormone-receptor-negative disease (p<0.001). Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis tend to have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer.

Abstract P3-14-10: Conversion to node-negative after neoadjuvant chemotherapy is a surrogate prognostic marker in patients with hormone receptor-positive breast cancer

Background: While pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) improves patients’ survival with HER2-positive and triple-negative (TN) breast cancers, it has been reported not to be the same for patients with hormone receptor (HR)-positive breast cancer. However, it is not well known whether chemosensitivity presented by change in tumor stage or nodal status after NAC contributes to improve the prognosis with HR-positive breast cancer. The aim of this study was to evaluate the impact of change in tumor stage or nodal status after NAC on prognosis in patients with primary breast cancer. Patients and Methods: We assessed retrospectively 599 consecutive patients with primary breast cancer (a median age of 49 years, ranging 26-79 years) who underwent surgical resection after NAC between 2001 and 2008. HR (ER and PR) statuses were determined by immunohistochemistory (IHC). HER2 status was determined by IHC and/or fluorescent in situ hybridization assays. ER-positive and PR-positive patients were 426 (71.1%) and 353 patients (58.9%), respectively. HER2 status was positive in 130 patients (21.7%). HR-positive subtype was defined as ER and/or PR-positive and HER2 negative. We compared the patients with respect to disease-free survival (DFS) and overall survival (OS) based on change in tumor stage and nodal status after NAC. pCR was defined as no residual invasive tumor and ypN0. Results : After NAC, 84 (14.0%) patients had pCR. Two hundred ninety one (48.6%) decreased tumor stage and 308 (51.4%) did not decrease tumor stage. Regarding nodal status, 190 (31.7%) had cN0 and 409 (68.3%) had cN+ before NAC, and 286 had ypN0 (47.7%) and 313 had ypN+ (52.2%). For patients with TN breast cancer, patients with pCR had excellent prognosis compared to those with residual tumor in either the breast or lymph node (non-pCR) (DFS, p<0.01, and OS, p = 0.035, respectively). Among the non-pCR group, patients with ypN0 also have longer DFS and OS than patients with ypN+ (p<0.01, and p = 0.031, respectively). However, for ypN0 patients with TN breast cancer, patients with residual primary tumor had significantly shorter DFS and OS than patients with ypT0. For HR-positive breast cancer patients, there was a trend that patients with pCR had better DFS than patients with non-pCR (p = 0.069). In terms of OS, there was no significant difference between pCR and non-pCR (p = 0.285). Patients with ypN0 had significantly longer DFS and OS than those with ypN+ regardless of residual tumor stage (p< 0.001 and p = 0.01, respectively). Change in tumor stage itself did not contribute to improve patients’ survival. Conclusions: Our results revealed that HR-positive breast cancer patients with conversion to lymph nodes metastasis after NAC have a good prognosis even if they have residual tumor in the breast, while TN breast cancer patients require pCR to have a good prognosis. It indicated that conversion to node-negative after neoadjuvant chemotherapy might be a surrogate prognostic marker in patients with HR-positive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-10.

Abstract P5-16-04: Predictive biomarkers for invasion on final pathology in patients with preoperative diagnosis of ductal carcinoma in situ of the breast by needle biopsy

Background Predictors of synchronous invasive breast cancer in patients diagnosed with only ductal carcinoma in situ (DCIS) in pre-operative needle biopsies have not been well-defined. Establishing such predictors of invasion has potential to significantly alter management by identifying those patients for whom surgery may be avoidable en lieu of conservative management. This study aims to identify clinicopathologic factors from pre-operative needle biopsies that are predictive of invasive cancer on subsequent surgical excision. Methods The study population consisted of 69 breasts from 67 patients initially diagnosed with only DCIS on needle biopsy (core needle or mammotome) at St. Luke9s International Hospital, Japan from 2006 until 2008. Parameters analyzed included presenting clinical features, DCIS nuclear grade and morphologic pattern, and immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor-2 (HER2), Ki-67 antigen, p16, p53 and cyclooxygenase-2 (COX2) in biopsy specimens. These immunohistochemical markers were previously identified to foretell invasive carcinoma subsequent to DCIS (Kerlikowske, JNCI 2010). Associations between clinical, pathological, and immunohistochemical findings in initial biopsy specimens and the presence of invasive cancer on subsequent excision were analyzed for significance using univariate and multivariate analysis. Results Of 69 breasts with only DCIS on initial needle biopsy, subsequent surgical excision revealed pure DCIS in 46 (66.7%), microinvasive carcinoma in 4 (5.8%), and invasive carcinoma in 19 (27.5%) cases. Sentinel node biopsy was performed in 57 (82.6%) of 69 cases, and 53 (93.0%) of these showed no evidence of lymph node metastases. All 4 cases with lymph node metastases revealed invasive carcinoma in surgical excisions. By univariate analysis, pre-operative factors significantly associated with invasion on surgical excision included detection of a lump by palpation (p Conclusion If confirmed in a larger sample, predictive clinical and biomarker parameters can help identify those patients diagnosed with only DCIS in needle biopsy who are at high risk of harboring unsampled invasive cancer on final pathology. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-16-04.