Relapsing eosinophilic pneumonia in a patient with recurrent breast cancer receiving abemaciclib plus endocrine therapy.

This report presents the case of a 42-year-old Japanese woman with recurrent hormone receptor-positive breast cancer who developed eosinophilic pneumonia (EP) during treatment with abemaciclib combined with endocrine therapy. Seven years after a radical surgery and definite diagnosis of Stage I breast cancer, her cancer recurred with metastases to multiple organs. Initially treated with abemaciclib plus letrozole and goserelin for 3 months, she developed EP, which improved after the discontinuation of anti-cancer treatment and the administration of prednisolone. However, EP occurred again upon the reintroduction of endocrine therapy (i.e., letrozole and goserelin). It improved gradually with the suspension of endocrine therapy and the re-administration of prednisolone. This case underscores the need for further research into the prevention and management of EP in patients receiving abemaciclib with endocrine therapy for advanced breast cancer.

Preoperative Neutrophil-to-Lymphocyte Ratio in Postmenopausal Breast Cancer Patients.

INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR) has been recognized as a marker of systemic inflammation with a prognostic impact in patients with various cancers, including breast cancer. The aim of this study was to investigate the relationships between the preoperative NLR and breast cancer prognosis in the patients before and after menopausal age, and its relationship with other prognostic factors. METHODS: A total of 1868 patients with clinical Stage I-III primary breast cancer were enrolled. The associations between clinicopathological factors and the preoperative NLR were analyzed, and relapse-free survival (RFS) and overall survival (OS) were estimated. RESULTS: Statistical analyses stratified by the menopausal status revealed that a high NLR was significantly associated with worse RFS (P < 0.001) and OS (P = 0.001) in postmenopausal patients, but not in premenopausal patients. Although the postmenopausal patients with relapsed cancer tended to have higher NLR levels than those without relapse (P = 0.079), NLR levels of premenopausal patients with relapsed cancer were significantly lower than that of relapse-free patients (P = 0.024). In postmenopausal patients, a high NLR was only associated with worse RFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (P < 0.001), in those managed without adjuvant chemotherapy (P = 0.003); this association was not observed in patients who received adjuvant chemotherapy. CONCLUSIONS: The preoperative NLR can be a useful prognostic marker, especially in postmenopausal breast cancer patients. The relationships between the NLR and breast cancer prognosis may be more evident when patients are assessed according to their menopausal status.

[Comparative Safety Study of Original and Generic Docetaxel without Alcohol in the Treatment of Breast Cancer].

Docetaxel(DTX)is a key drug for breast cancer treatment; however, its formulation contains alcohol, which can cause several problems. We have been preparing original DTX without using its accompanying alcohol-solubilizing solution since 2013 and switched to generic DTX without alcohol in 2015. In this study, we compared adverse events between the original and generic DTX, both of which did not contain alcohol. We retrospectively investigated the occurrence of adverse events in breast cancer patients who were treated with DTX(75 mg/m2)as neoadjuvant or adjuvant chemotherapy from January 2013 to December 2017. 201 patients participated in the study(75/126 in the original/generic groups). The incidence of febrile neutropenia, hypersensitivity reactions, and skin toxicities did not differ between the groups(p=0.620, 0.066, 0.205). The severity of edema and peripheral neuropathy was significantly worse in the patients receiving the generic DTX (p<0.01, <0.01). The findings suggest a difference in the incidence of edema and peripheral neuropathy following treatment with the original and generic DTX, regardless of the inclusion of alcohol.

Impact of serum vitamin D on the response and prognosis in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Several studies have recently reported that the relationships between serum vitamin D and the prognosis or the pathological response to neoadjuvant chemotherapy (NAC) in breast cancer. However, there are no data regarding the clinical impacts of the vitamin D in Japanese breast cancer patients so far. PATIENTS AND METHODS: In the present study, a total of 250 patients with clinical Stage I-III primary breast cancer who were treated with NAC and subsequently underwent definitive surgery were included. Serum 25-hydroxvitamin D (25(OH)D) levels were evaluated using blood samples obtained before NAC. RESULTS: The serum 25(OH)D was positively associated with age, and the serum 25(OH)D was significantly higher in postmenopausal women than that in pre/peri-menopausal women. Serum 25(OH)D level was not associated with the achievement of pathological complete response (pCR) in this cohort. The low 25(OH)D levels were significantly associated with shorter time to distant recurrence (TTDR). According to the univariate analysis, high clinical stage before NAC (cStage III) and low serum 25(OH)D level were significantly associated with the shorter TTDR, and pCR was significantly associated with the longer TTDR. According to a multivariate analysis, low serum 25(OH)D level were independent poor prognostic factors for TTDR. CONCLUSIONS: The low 25(OH)D levels were significantly associated with poorer prognosis in Japanese women with operable breast cancer patients treated with NAC.

The clinical usefulness of the CTS5 in the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer.

BACKGROUND: Clinical Treatment Score post-5 years (CTS5) is a promising prognostic tool to evaluate late distant recurrence (DR) risk for breast cancer after 5-year adjuvant endocrine therapy. PATIENTS AND METHODS: Among 560 postmenopausal women with pathological stage I-III estrogen receptor-positive (ER+) primary breast cancer, 383 women who had received 5-year adjuvant endocrine therapy without any recurrence at 5 years after surgery were included in this study. The CTS5 was calculated for each patient using a previously published formula, and the patients were stratified by their CTS5 values into the low-, intermediate- and high-CTS5 risk groups. RESULTS: According to the CTS5, 205 (53.5%), 106 (27.7%) and 72 (18.8%) patients were classified into the low-, intermediate-, and high-CTS5 risk groups, respectively. A higher ER expression level was significantly associated with the low CTS5. The increased administration of adjuvant chemotherapy was significantly associated with a high CTS5. The occurrence of DR was higher in the intermediate and high CTS5 groups than in the low CTS5 group. The DRFS in the low CTS5 risk group was significantly better than that in the intermediate- or high-risk groups. In the ER-high or HER2-negative (HER2-) group, the DRFS in the low-risk group was significantly better than that of the intermediate- or high-risk groups. However, in the low-ER or HER2-positive group, there was no significant difference in DRFS among the three risk groups. CONCLUSIONS: In postmenopausal women with ER+ breast cancer, low CTS5 was considered to be associated with a very low risk of late DR. Thus, extended endocrine therapy may be unnecessary for patients with low CTS5 scores. Extended endocrine therapy should be offered for patients with intermediate or high CTS5 scores, especially those with high-ER and HER2- breast cancer.

Efficacy of Adjuvant Combination Therapy With Trastuzumab and Chemotherapy in HER2-positive Early Breast Cancer: A Single Institutional Cohort Study from Clinical Practice.

BACKGROUND/AIM: To evaluate the improvement in the prognosis by adjuvant trastuzumab in clinical practice and the risk factors for distant recurrence, we retrospectively investigated the prognosis of HER2-positive early breast cancer in our department before and after the introduction of adjuvant trastuzumab. PATIENTS AND METHODS: Cohorts A and B included 161 and 182 cases, respectively, who underwent surgery before (2000-2007) and after (2008-2015) the introduction of adjuvant trastuzumab. RESULTS: The rates of relapse-free and distant metastasis-free survival were significantly better in cohort B than in cohort A. The risk factors of distant recurrence found in cohort A, such as the presence of lymph node metastasis, lymphatic invasion, and a low histological grade, did not increase the risk in cohort B. CONCLUSION: Many risk factors seemed to have been negated by adjuvant trastuzumab administration. Therefore, further escalation of adjuvant treatment should be carefully considered.

The comparison of the anatomic stage and pathological prognostic stage according to the AJCC 8th edition for the prognosis in Japanese breast cancer patients: data from a single institution.

BACKGROUND: The TNM system, which reflects the anatomical extent of disease, was used for stage definition. In the recently published AJCC 8th edition, the new staging system of the clinical and pathological prognostic stage, which incorporates biological factors, is introduced. PATIENTS AND METHODS: A total of 2622 patients with primary breast cancer at stage I-III were included in this study. The anatomic stage (aStage) and the pathological prognostic stage (ppStage) for each case were determined according to the definition of the AJCC 8th edition, and the influence of these stages on the prognosis was compared. RESULTS: The stage distributions of aStage and ppStage were as follows: aStage, stage IA (54.8%), IB (1.1%), IIA (26.1%), IIB (9.2%), IIIA (5.6%), IIIB (0.1%), and IIIC (3.1%); and ppStage, stage IA (66.6%), IB (13.1%), IIA (11.1%), IIB (3.2%), IIIA (3.3%), IIIB (1.4%), and IIIC (1.2%). Compared with the aStage, the ppStage stayed the same in 1710 patients (65.2%), was downstaged in 778 patients (29.7%), and was upstaged in 134 patients. The pathological tumor size (pT2) and lymph node metastasis (pN1) were associated with downstaging, and histological grade 3 was associated with upstaging. ER positivity, PgR positivity, and HER2-positivity were significantly associated with downstaging, and the TN subtype was associated with upstaging. Both the aStage and ppStage were significantly associated with the prognosis; however, the Kaplan-Meier curves for the relapse-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival were better stratified by the ppStage. CONCLUSION: The ppStage reflects the prognosis of patients with early breast cancer more accurately than the aStage.

CD44v9 as a poor prognostic factor of triple-negative breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard therapeutic strategy for triple-negative breast cancer (TNBC). TNBC patients with residual disease after NAC have a significantly worse survival than those with pathological complete response (pCR); however, there is no apparent prognostic factor for non-pCR patients. Cancer stemness or epithelial-mesenchymal transition (EMT) might influence the sensitivity to chemotherapy. PATIENTS AND METHODS: Forty-eight patients with TNBC who were treated with NAC were available were included in this study. The expressions of stemness marker CD44v9, EMT marker vimentin and BRCA1, and basal phenotype were evaluated with immunohistochemistry. The relationships between the expression of these proteins and the pCR rate and the prognosis, especially in the patients with residual tumors, were investigated. RESULTS: Among the 48 patients, pCR was achieved in 14 cases. High nuclear grade and basal phenotype in the pre-NAC samples were significantly correlated with pCR (p = 0.0458 and 0.0343). There were no significant relationships between the pCR rate and the expression of CD44v9, vimentin, or BRCA1. Achieving pCR was significantly correlated with longer distant metastasis-free survival (DMFS) (p = 0.0206). High CD44v9 expression was significantly associated with shorter DMFS (p = 0.0291). Among the patients in whom pCR was not achieved, high grade in the residual tumor cells, poor pathological response and high CD44v9 expression in the pre-treatment CNB samples were significantly correlated with a poor DMFS (p = 0.0433, 0.0406 and p = 0.0333). In addition, high grade in the residual tumor cells was significantly associated with high CD44v9 expression in the pre-treatment CNB (p = 0.0389). CONCLUSIONS: High CD44v9 expression in pre-NAC samples was associated with poor prognosis in TNBC patients treated with NAC, especially for those in whom pCR was not achieved.

Impact of Visceral Metastasis on Efficacy of Fulvestrant in Patients with Hormone Receptor-positive Recurrent Breast Cancer.

BACKGROUND: Previous studies have suggested that the presence of visceral metastasis is a parameter useful in predicting the treatment efficacy of fulvestrant in patients with advanced breast cancer. PATIENTS AND METHODS: We retrospectively examined the association between treatment efficacy and presence of visceral metastasis in 75 patients with hormone receptor-positive recurrent breast cancer who were treated with fulvestrant or no more than five lines of other endocrine monotherapy after recurrence. RESULTS: Nineteen patients received fulvestrant, 10 of whom had visceral metastasis. The median time to progression was 4 months for the overall study population; it was significantly longer for patients with non-visceral metastasis (5.4 months; 95% confidence interval=3.7-11.2 months) than for those with visceral metastasis (3.3 months; 95% confidence interval, 0.4-5.3 months; p=0.01). No differences in time to progression were found between the groups of patients with visceral metastasis and non-visceral metastasis who underwent other endocrine therapies. CONCLUSION: Fulvestrant is more effective for patients with non-visceral metastasis of recurrent breast cancer with than for those with visceral metastasis.

Chemotherapy-induced amenorrhea and the resumption of menstruation in premenopausal women with hormone receptor-positive early breast cancer.

BACKGROUND: For premenopausal women with breast cancer, information on the effects of chemotherapy and the risk of infertility is important. In this study, the effect of chemotherapy on the ovarian function in premenopausal women with hormone receptor-positive breast cancer was investigated, with an age-stratified analysis of the appearance of amenorrhea and the resumption of menstruation after the use of chemotherapy with anthracyclines or taxanes. PATIENTS AND METHODS: Premenopausal women diagnosed with operable Stage I-III hormone receptor-positive breast cancer and underwent neoadjuvant or adjuvant chemotherapy with the standard regimen of anthracyclines and/or taxanes were included. The patients were classified into age groups in 5-year increments, and the rates of chemotherapy-induced amenorrhea (CIA), resumption of menstruation, and duration of CIA after chemotherapy were analyzed. RESULTS: The subjects consisted of 101 patients (median age 45 years). CIA occurred in 97 (96%) patients and 40 patients resumed menstruation. In all patients aged ≤39 years menstruation restarted, whereas in all patients aged ≥50 years, menstruation did not restart. For the patients who resumed menstruation, the younger the patients, the sooner menstruation tended to restart. The resumption of menstruation occurred within 1 year for younger patients aged around 30 years, but for those aged ≥35 years, 60% of cases took around 2-3 years for resumption. CONCLUSIONS: The incidence of CIA, the resumption of menstruation and duration of CIA after chemotherapy depend greatly on the patient's age.

[High incidence-rate of oral mucositis in breast cancer patients receiving anthracycline-based chemotherapy (FEC100)].

BACKGROUND: Oral mucositis is a frequent complication, but is poorly studied among patients with solid tumors. The purpose of this study is to clarify the incidence rate of oral mucositis in Japanese breast cancer patients receiving anthracycline-based chemotherapy(FEC100). METHODS: From June 2007 to July 2008, 61 breast cancer patients eligible for this study received anthracycline-based chemotherapy(FEC100: 5-FU 500mg/m / / 2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)at National Kyushu Cancer Center and Iwate Medical University Hospital. The incidence rate and grade of oral mucositis were evaluated in these patients. RESULTS: The cumulative incidence of oral mucositis was about 50%. Episodes of oral mucositis were more common during courses with febrile neutropenia than during courses without it(75. 0% vs 44. 9%, p=0. 12). The reduction of oral mucositis was only 13. 6% after administering the steroidal ointment and/or mouthwash, including sodium azulene sulfonate. CONCLUSIONS: New methods are needed to prevent and treat oral mucositis in patients receiving anthracycline- based chemotherapy(FEC100).

Can patients with metastatic breast cancer be cured after introduction of newer and more effective agents?

Unlike early stage breast cancer, metastatic breast cancer (MBC) is generally considered incurable except for a small number of patients with oligometastatic disease. The goal of treatment of MBC should be the prolongation of life and improvement of symptoms and quality of life. The prognoses of patients with MBC, however, have been improved with the introduction of newer, more effective agents. Therefore, the clinical question arises whether MBC patients can be cured with these new therapeutic agents. However, there are a couple of problems in tackling this question, including the duration of follow-up and the presence of strong adjuvant therapy. Firstly, most trials in MBC have a relatively short follow-up; long-term surveillance (>3-5 years) is exceptional, so little is known about the definitive outcome and the exact proportion of long-term survivors. Secondly, most of the patients have received pre- or postoperative adjuvant therapy. The cancer cells at metastatic sites are considered to be relatively resistant to the agents used in metastatic settings. Promisingly, a number of novel therapeutic agents including antibody-drug conjugates, irreversible small molecule HER2-tyrosine inhibitors, and HER2 dimerization inhibitors show promise in the treatment of HER2-overexpressing MBC, as well as PARP-1 [poly(ADP-ribose) polymerase-1] inhibitors for triple-negative breast cancer.

Significant survival improvement of patients with recurrent breast cancer in the periods 2001-2008 vs. 1992-2000.

BACKGROUND: It is unclear whether individualized treatments based on biological factors have improved the prognosis of recurrent breast cancer. The purpose of this study is to evaluate the survival improvement of patients with recurrent breast cancer after the introduction of third generation aromatase inhibitors (AIs) and trastuzumab. METHODS: A total of 407 patients who received first diagnosis of recurrent breast cancer and treatment at National Kyushu Cancer Center between 1992 and 2008 were retrospectively evaluated. As AIs and trastuzumab were approved for clinical use in Japan in 2001, the patients were divided into two time cohorts depending on whether the cancer recurred before or after 2001. Cohort A: 170 patients who were diagnosed between 1992 and 2000. Cohort B: 237 patients who were diagnosed between 2001 and 2008. Tumor characteristics, treatments, and outcome were compared. RESULTS: Fourteen percent of cohort A and 76% of cohort B received AIs and/or trastuzumab (P < 0.001). The median overall survival (OS) times after breast cancer recurrence were 1.7 years and 4.2 years for these respective cohorts (P < 0.001). Both the time period and treatment of AIs and/or trastuzumab for recurrent disease were significant prognostic factors in multivariate analysis (cohort B vs. cohort A: HR = 0.70, P = 0.01; AIs and/or trastuzumab for recurrent disease: yes vs. no: HR = 0.46, P < 0.001). When patients were categorized into 4 subgroups by the expression of hormone receptor (HR) and HER-2 status, the median OS times of the HR-positive/HER-2-negative, HR-positive/HER-2-positive, HR-negative/HER-2-positive, and HR-negative/HER-2-negative subtypes were 2.2, 2.4, 1.6, and 1.0 years in cohort A and 4.5, 5.1, 5.0, and 1.4 years in cohort B. CONCLUSIONS: The prognosis of patients with recurrent breast cancer was improved over time following the introduction of AIs and trastuzumab and the survival improvement was apparent in HR- and/or HER-2-positive tumors.

A case of HER-2-positive advanced inflammatory breast cancer with invasive micropapillary component showing a clinically complete response to concurrent trastuzumab and paclitaxel treatment.

We report a case of HER-2-positive advanced inflammatory breast cancer with invasive micropapillary component showing a complete response to trastuzumab and paclitaxel treatment. A 37-year-old woman was referred to our hospital for right breast swelling with broad skin redness and right axillary tumor. Ipsilateral infraclavicular and contralateral axillary lymph nodes swelling were also recognized. The histopathological findings of core-needle biopsy specimens from primary breast tumor and ipsilateral axillary lymph node were invasive ductal carcinoma with a micropapillary component. Immunohistochemical examination gave a negative result for estrogen receptor (ER)/progesterone receptor (PgR), and overexpression of HER-2 (Hercep Test 3+). Advanced inflammatory breast cancer with an invasive micropapillary component was diagnosed (T4d N3 M1 (LYM), stage IV). The patient was treated with combination chemotherapy using weekly paclitaxel and trastuzumab. After administration of three courses, the breast swelling, skin redness, and lymph node swelling disappeared completely. She maintained complete remission of disease for 12 months and was judged to have a clinically complete response by the RECIST criteria. Invasive micropapillary carcinoma is known to be an aggressive histological type associated with a high incidence of lymph node metastasis and poor prognosis. This is the first reported case of advanced inflammatory breast cancer with an invasive micropapillary component showing a clinically complete response to trastuzumab-containing treatment. This report suggests trastuzumab-containing chemotherapy is a promising therapy for HER-2-positive advanced invasive micropapillary carcinoma.