Response-Guided Omission of Anthracycline in Patients with HER2-Positive Early Breast Cancer Treated with Neoadjuvant Taxane and Trastuzumab: 5-Year Follow-Up of Prognostic Study Using Propensity Score Matching.

BACKGROUND: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without fluorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). RESULTS: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. CONCLUSIONS: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.

Prognostic Factors in HER2-Positive Primary Breast Cancer Patients Treated Using Neoadjuvant Chemotherapy Plus Trastuzumab.

BACKGROUND: It is unclear for whom new anti-human epidermal growth factor receptor 2 (anti-HER2) agents, such as pertuzumab and T-DM1, should be considered. We investigated prognostic factors before neoadjuvant chemotherapy (NAC) among HER2-positive invasive breast cancer patients and those after NAC among patients who did not achieve pathological complete response (pCR) using conventional adjuvant trastuzumab. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and June 2017 at the Osaka Breast Clinic. Patients with distant metastasis or using NAC containing pertuzumab were excluded. The main outcome was disease-free survival (DFS). We investigated pre- and post-NAC prognostic factors using the log-rank test and Cox proportional hazards model. RESULTS: In total, 157 patients were included. Among the pre-NAC prognostic factors, younger age (under 40 years old) and positive clinical nodal status were significantly poorer prognostic factors (hazard ratio [HR] 3.47, 95% CI 1.06-10.12, p = 0.041 and HR 3.32, 95% CI 1.03-14.78, p = 0.045) by multivariate analysis. Among the post-NAC prognostic factors, patients with non-pCR (3-year DFS; 85 vs. 96%, p = 0.022) had a poorer DFS than patients with pCR. DFS was assessed for non-pCR patients (n = 64). High post-NAC Ki-67 status (≥20%; HR 6.73, 95% CI 1.82-31.93, p = 0.004) was a significant and large post-NAC tumor size (≥2 cm; HR 3.65, 95% CI 0.97-14.71, p = 0.056) was a marginally significant prognostic factor by multivariate analysis. After having combined them, high post-NAC Ki-67 status or large post-NAC tumor size was also a significant prognostic factor (HR 5.75, 95% CI 1.32-16.12, p = 0.017). CONCLUSIONS: Positive clinical nodal status and young age were found to be prognostic factors before NAC in HER2-postive invasive breast cancer patients. A high post-NAC Ki-67 status and large post-NAC tumor size were significant and marginally significant prognostic factors, respectively, after NAC in patients who did not achieve pCR. New anti-HER2 agents, such as pertuzumab and T-DM1, should be considered for the patients with those prognostic factors.

Pembrolizumab response in stage IV luminal-type breast cancer with high microsatellite instability: a case report.

BACKGROUND: Pembrolizumab (PEM), an immune checkpoint inhibitor (ICI), is often used for triple-negative breast cancer, but can also be used to treat solid tumors that exhibit high microsatellite instability (MSI-High). However, patients with breast cancer rarely have MSI-High, the use of PEM in such cases in clinical practice is uncertain due to lack of sufficient supporting data. Here, we report the case of a premenopausal woman in who received PEM for MSI-High luminal-type breast cancer. CASE PRESENTATION: A 40-year-old premenopausal Asian woman was diagnosed with stage IIA (T2N0M0) breast cancer and had an Oncotype DX recurrence score of 38. After surgery, she received 4 courses of chemotherapy with docetaxel and cyclophosphamide. After 3 months of tamoxifen therapy, the patient complained of abdominal pain due to right iliac metastasis, and biopsy of the metastatic lesion showed of luminal type; she was sequentially treated with fulvestrant, a CDK4/6 inhibitor, and an anticancer drug (TS1), but over the next year, metastasis to the bone and para-aortic lymph nodes increased. Tumor was MSI-High; PEM was started, and after three courses, bone metastases were reduced, para-aortic lymph node metastases resolved, opioids were discontinued, and the patient returned to society; PEM was administered for 1 year with no worsening of bone metastases on imaging. Asymptomatic brain metastasis less than 1 cm was detected and gamma knife was performed. Six months after completion of PEM, the patient is working with no new lesions. CONCLUSION: We report a case of luminal-type breast cancer with bone metastases and MSI-High, which was treated with PEM and showed a rapid therapeutic response.

High incidence of synchronous or metachronous breast cancer in patients with malignant and benign thyroid tumor or tumor-like disorders.

BACKGROUND: Although many reports indicated an association between thyroid diseases and breast cancer, such an association still remains controversial. The present study was aimed to clarify the association of thyroid diseases with the breast cancer incidence. In the patients with benign and malignant thyroid tumor or tumor-like disorders, the incidence of other malignancies was surveyed, and the frequency of thyroid cancer in patients with breast cancer was also surveyed. PATIENTS AND METHODS: Between 1982 and 2005, a total of 201 female patients received surgery for tumor or tumor-like disorders, including 65 carcinoma, 68 adenoma, 61 adenomatous goiter and 7 chronic thyroiditis cases. Their outcomes were surveyed in December 2006. Furthermore, during the same periods, 340 female patients underwent breast cancer surgery and their outcomes were also surveyed in December 2006. RESULTS: The overall incidence rate of breast cancer was 16.4% (33/201) in the patients, who received thyroid surgeries and was much higher than other malignancies: 2.0% gastric cancer, 1.0% uterine and colorectal cancer. The incidence rate of breast cancer in each disease was 13.8% for thyroid cancer, 16.2% for adenoma and 21.3% for adenomatous goiter, but no incidence for chronic thyroiditis. On the other hand, in the patients with breast cancer during the same period in our department, the frequency of thyroid cancer was only 2.1% (7/340). CONCLUSION: It appears that thyroid cancer, adenoma and adenomatous goiter were associated with the risk of breast cancer, but chronic thyroiditis was not related.

Cyclophosphamide augments the anti-tumor efficacy of uracil and tegafur by inhibiting dihydropyrimidine dehydrogenase.

The present study assesses the effects of neo-adjuvant chemotherapy (NAC) with uracil and tegafur (UFT) alone vs UFT plus cyclophosphamide (CPA), on the activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in breast cancer tissues. Breast cancer patients were randomly assigned to 3 groups; the control (no-treatment) group (n=13), the UFT (5-8 mg/kg/day) alone group (n=10) and the UFT plus CPA (1 mg/kg/one day interval) (UC) group (n=9), and they received NAC for 2-4 weeks. A total of 32 invasive ductal breast carcinomas were used to assay for TS and DPD activity. There were no statistically significant differences in tumor size or stage classification between the 3 groups. The DPD activity was inversely and significantly correlated with the tumor size and pT, but the TS activity was not correlated with these clinicopathological factors. The TS activity was decreased by NAC with UFT, and the addition of CPA resulted in an increased inhibition of TS activity. In contrast, DPD activity was increased by NAC with UFT administration, but its increased activity was significantly inhibited by the addition of CPA. Multiple regression analyses demonstrated that the total dose of UFT was a significant variable for inhibiting TS activity, and that CPA was a significant variable for inhibiting DPD activity. The DPD activity increased by UFT can be inhibited by CPA, and this may represent one of the possible mechanisms responsible for the anti-tumor activity of 5-FU or its derivatives as enhanced by CPA.

[Evaluation of therapeutic regimens for taxane-resistant recurrent/metastatic breast cancer].

Taxanes (TX) were administered to 246 of 292 patients with recurrent/metastatic breast cancer (MBC) who were treated in Hiei Hospital between January 2001 and May 2006. Recently, TX has been increasingly prescribed for preoperative treatment and postoperative adjuvant therapy. To improve the prognosis of MBC, regimens effective for TX-resistant cancer patients should be developed. In this study, with respect to hormone receptor (HR) and Her 2/neu (HER 2), we retrospectively investigated whether our series responded to the regimens used after TX resistance was acquired. As post TX-resistance therapy (trastuzumab was combined in HER2-positive patients), 387 treatment regimens were administered to 166 patients. The following regimens achieved a response rate (patients achieving PR or CR/patients who could be evaluated) of 10% or more: combination therapy with TX and capecitabine (11/61, 18%), CPT-11 (10/57, 17.5%), vinorelbine (5/46, 10.9%), MFL-P (continuous treatment with MTX, 5-FU, LV, and CDDP) (12/47, 25.5%), and DMpC (5'-DFUR, MPA, CPA p.o.) (5/16, 31.2%). The latter 2 regimens achieved a high response rate,and some HR (-) and HER 2 (-) patients also responded to these regimens. In HR (+) or HER 2 (+) patients who responded to TX, survival was longer than that of non-responders. However, there was no difference in the treatment responsiveness of post-TX regimens between TX-responders and non-responders, suggesting the survival-prolonging effect of TX.

Oral UFT (uracil plus futrafur) for neoadjuvant chemotherapy of gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy has become one of the topics of interest in chemotherapy of gastric cancer; the present study assessed the clinical benefits of neoadjuvant chemotherapy with oral uracil and futrafur (UFT) for gastric cancer.METHODS: Between 1991 and 1997, 82 patients with gastric cancer (36 with early and 46 with advanced cancers) received UFT at 300-600 mg/day orally for 1-6 weeks before surgery. Objective responses, histological effects, and postsurgical survival rates were assessed.RESULTS: In 69 of the 82 patients, the objective responses of the primary lesions were assessed by endoscopy or upper gastrointestinal series examination, and 2 complete responses (CR)s, 25 partial responses (PRs), and 42 no changes (NCs) were seen (39.1% response). Histological effects were evaluated in 82 patients, and 2 grade 3, 11 grade 2, 11 grade 1b, 27 grade 1a, and 31 grade 0 effects were seen. A longer period of UFT administration was associated with a CR or PR. However, the objective responses did not correlate with the histological effects. All the patients underwent gastrectomy, and during the median follow-up period of 41 months, 3-year survival rates were 97.1% for pTNM stage 1, 75% for stage 2, 86.7% for stage 3, and 41.6% for stage 4. The survival rates of stage 3 and stage 4 patients were higher than those of the historical controls in our department. However, CR or PR did not correlate with the improvement in survival. Side effects before surgery were not serious; they included slight myelotoxicity, liver dysfunction, and anorexia; however, 3 patients (3.7%) had suture insufficiency, 3 patients (3.7%) had methicillin-resistant Staphylococcus aureus (MRSA) enteritis, and 7 patients (8.5%) had liver dysfunction.CONCLUSIONS: Preoperative chemotherapy for gastric cancer with oral UFT was safe and resulted in a good local response (macro- and microscopically) which may indicate the possibility of improved survival with neoadjuvant chemotherapy with UFT. Furthermore, preoperative chemotherapy with oral UFT is easy and patients can receive this treatment on an outpatient basis.

Ductal carcinoma in situ arising within a benign phyllodes tumor: A case report with a review of the literature.

Phyllodes tumor (PT) is a rare type of breast tumor that rarely occurs with breast carcinoma. This study evaluated a 53-year-old female patient with a benign PT with ductal carcinoma in situ (DCIS) within the tumor. A firm, painless, well-demarcated tumor measuring 4-5 cm was noted in the left breast. Over the course of the previous 14 years, the patient underwent excision of a breast tumor four times at the same site in the left breast. The pathological diagnosis of the first tumor was a fibroadenoma (FA), and those of the following three were benign PTs. The tumor was the 5th one noted over the course of the previous 14 years, following the previously recorded surgeries. A firm tumor with a diameter of 3.5 cm was located beneath the scar from the previous surgery, just above the nipple of the left breast. Mammography revealed a high-density irregularly shaped mass with a clear margin. An ultrasound showed low but heterogeneous echogenicity. A computed tomography scan revealed a well-defined enhanced tumor. These image examinations were compatible with recurrent PT. Fine-needle aspiration cytology revealed that the tumor was likely a benign FA. The patient underwent a partial mastectomy with a 1.0 cm margin from the tumor edge, and the firm, attached scar tissue was also resected. Macroscopic examination showed a hard elastic mass, which was encapsulated by thin fibrous tissue and which adhered firmly to the adjacent scar tissue. Microscopic examination showed a 5 mm in diameter DCIS of the cribiform type in a section of the PT epithelial component with an apparently benign stroma. The DCIS cells were strongly positive for estrogen and progesterone receptors, but HER2 expression was negative (score 0). The patient received local irradiation following surgery and no evidence of recurrence or metastasis was detected in the 2 years following surgery. This was a noteworthy case of a DCIS arising in benign PT. To the best of our knowledge, a total of 28 breast carcinomas were previously reported to arise in PT. In this case report, a female patient who presented with a PT was evaluated. A review of the literature is also discussed.

Placement of an expandable metallic stent improves the efficacy of chemoradiotherapy for pancreatic cancer with malignant portal vein stenosis or obstruction.

BACKGROUND: Advanced or recurrent pancreatic cancer can sometimes cause obstruction or stenosis of the portal vein (PV), resulting in various symptoms of portal hypertension (PH), such as ascites, pancytopenia, hemorrhagic tendencies and liver dysfunction. We placed an expandable metallic stent into the PV to improve PH-associated complications and liver function. The placement of the PV stent was beneficial for administering chemotherapeutic agents and radiotherapy (RT) safely, and resulted in an improved response rate (RR) and survival. PATIENTS AND METHODS: In the present study, 14 patients with malignant portal obstruction due to advanced or recurrent pancreatic cancer received PV stent placement to manage their PH-associated symptoms. After a mini-laparotomy at the ileocecal region, the ileocecal vein was cut and an expandable metallic stent (6-8 mm in diameter and 6-8 cm in length) was inserted into the PV under image roentgenography. After placement of the PV stent, the patients received anti-coagulation treatment with heparin and biaspirin for 1-3 months. All patients received chemotherapy with UFT, cyclophosphamide (CPA) and gemcitabine (GEM), and 11 patients also received RT. RESULTS: The RR was 43% (3 complete (CR), 3 partial (PR), 3 stable disease (SD), and 5 progressive disease (PD)), and the mean survival times (MST) after the initiation of therapy or placement of the PV-stent were 12.6 and 9.5 months, respectively, while the 1-year survival rates were 54.5% and 35.1%, respectively. In the 3 CR patients, 2 died of carcinomatous ascites 13 and 21 months later, and 1 is still disease free. In the PR and SD patients, pain and PH-associated symptoms such as ascites and hyperglycemia were also improved. CONCLUSION: The placement of a PV stent is beneficial for improving PH-associated symptoms as well as facilitating chemo-RT and the efficacy of therapy.

Heterogeneic expression of estrogen receptor between the primary tumor and the corresponding involved lymph nodes in patients with node-positive breast cancer and its implications in patient outcome.

BACKGROUND AND OBJECTIVES: The estrogen-receptor (ER) status of breast cancers has typically been evaluated in primary tumors (PTs), and the influence of ER expression in the involved lymph nodes (LNs) on prognosis of the patients with node-positive breast cancer remains unclear. The expression of ER was compared between PT and corresponding involved LNs in patients with node-positive breast cancer. METHODS: Eighty-seven patients with node-positive breast cancer were immunohistochemically assessed to measure the expression of ER in PT and involved LN with anti-ER monoclonal antibody. RESULTS: Thirty-five (40.2%) of PTs and 26 (29.9%) of involved LNs were evaluated as ER(+). The ER expression in PTs was significantly correlated with that in involved LNs (P < 0.0001), and the ER expression was almost the same in both the PT and corresponding involved LN in 66 cases (75.9%): both (+), 20 (23.0%); and both (-), 46 (52.9%). However, ER expression differed in 21 cases (24.1%) between involved LN and the corresponding PT: PT-ER(+)/LN-ER(-), 15 (17.2%); and PT-ER(-)/LN-ER(+), 6 (6.9%). The survival of patients with ER(+)-PT was significantly better than that of ER(-)-PT patients (P = 0.0086), but ER expression in involved LN did not have any significant effect on patient survival. Furthermore, when survival periods were grouped by coexpression of ER in the PT and involved LN, the best survival was seen in the PT-ER(+)/LN-ER(-) group (P < 0.001 vs. others). In the patients, who received adjuvant endocrine therapy, the survival of the PT-ER(+) group was significantly better than that of PT-ER(-) group (P = 0.0145), but LN-ER expression did not show any significant influence on the survival rate. Multivariate analysis demonstrated that clinical stage and ER-expression in the PT were significant variables, but ER expression in the involved LN was not. CONCLUSIONS: The ER expression was discordant between PT and involved LN in about 24% of the breast cancers evaluated, and ER expression in involved LNs had less influence on patient prognosis than ER expression in the corresponding PT.