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.

Feasibility, accuracy and acceptability of self-sampled human papillomavirus testing using careHPV in Cambodia: a cross-sectional study.

OBJECTIVE: Self-sampled human papillomavirus (HPV) testing is a potential option for cervical cancer screening, but research is scarce in Cambodia. We evaluated the feasibility, accuracy, and acceptability of self-sampled HPV testing using careHPV. METHODS: A cross-sectional study including women aged 20-49 years attending 2 national hospitals in the capital city was conducted. Women underwent both self-sampling and clinician-sampling of specimens, and were then asked to complete an acceptability questionnaire. The paired samples were analyzed for high-risk HPV by careHPV and genotyped by polymerase chain reaction (PCR). RESULTS: A total of 375 women were eligible for inclusion. Based on PCR, 78.9% were negative for HPV in both self and clinician-samples, 9.9% had a complete HPV type match, and 6.1% had all HPV types in clinician-samples also detected in self-samples. In 5.1%, one or more HPV types identified in the clinician-samples were missed in self-samples. When using careHPV, the overall agreement between the 2 sampling methods was 95.7% (95% confidence interval [CI]=95.8-95.6) with good concordance (κ=0.66, 95% CI=0.56-0.76). Nearly 90% of the women preferred clinician-sampling over self-sampling, citing greater comfort, ease, and speed. CONCLUSION: Self-sampled HPV testing using careHPV could be an option for cervical cancer screening in Cambodia; however, it requires periodic quality control of handling procedures. In addition, women's health education regarding the accuracy of self-sampled HPV testing and the importance of follow-up in cases of positive results is needed.

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.

A Review of the Implementation Status of and National Plans on HPV Vaccination in 17 Middle-Income Countries of the WHO Western Pacific Region.

The World Health Organization's Western Pacific Region is responsible for one-fourth of the global cervical cancer burden, and nearly 90% of that burden is concentrated in middle-income countries (MICs). Applying a conceptual model of implementation of population-based interventions, we synthesized the current implementation status of human papillomavirus (HPV) vaccination and national plans that form the basis of its implementation in 17 MICs. We gathered information from a range of governmental documents, published studies, and global databases. For all available national cancer-related plans and immunization plans, we examined the description of HPV vaccination. We found that, as of July 2021, only four countries (24%) had a mature HPV vaccination program with a high first-dose coverage; three (18%) had introduced HPV vaccination, but needed further efforts to scale it up, seven (41%) had not been able to introduce it after conducting demonstration projects, and three (18%) did not have any experience in HPV vaccination. In the national plans, most of the countries recognized the importance of HPV vaccination, but only 10 (59%) provided an implementation strategy on how it would be introduced or scaled up. Countries with a mature program were more likely to have their implementation strategy detailed in their national cancer control plan. Successful implementation of HPV vaccination requires overcoming known challenges and having a clear national plan. Positioning HPV vaccination clearly in the overall national cancer control plan may be key to accelerating its nationwide implementation.

The current situation of health services for hydatidiform mole in Cambodia.

AIM: Management of hydatidiform mole is important to reduce the mortality and morbidity of choriocarcinoma. This study aims to understand the existing health services for hydatidiform mole and to estimate the incidence of gestational trophoblastic disease (GTD) in Cambodia. METHODS: A questionnaire was used to collect information on the existing health services for pregnancy and hydatidiform mole at health facilities from attendants of the 16th Annual Conference of the Cambodian Society of Gynecology and Obstetrics in 2017. The incidence of GTD in 2014-2017 was estimated using Health Information System data. RESULTS: A total of 126 attendants, who were from all provinces except three provinces, answered the questionnaire. The work places were national hospitals (n = 29), provincial hospitals (n = 42), district hospitals (n = 20), health centers (n = 6), and others (n = 29). The answers of participants from the public sector suggested the following: Ultrasonography is available at all hospitals but not health centers; Human chorionic gonadotropin (hCG) measurement is only available at national hospitals; Treatment of hydatidiform mole is performed at national hospitals and provincial hospitals; and Treatment of gestational trophoblastic neoplasia (GTN) is provided at national hospitals. The incidence of hydatidiform mole and GTN at health facilities in the public sector in 2014-2017 was 0.95 per 1000 deliveries and 6.58 per 100 000 deliveries, respectively. CONCLUSIONS: The results suggest that provincial hospitals are important to detect suspected invasive mole and refer to national hospitals for diagnosis and treatment. Further studies on the management of GTD and development of the guidelines of GTD are needed.

What is the current status of Japan's efforts to meet global goals and targets to eliminate cervical cancer?

Following the global call to action by the World Health Organization (WHO), the world is currently moving to eliminate cervical cancer as a public health problem. To eliminate the cancer within this century, which is defined as an age-adjusted cervical cancer incidence rate (ASIR) below 4 per 100,000 women, WHO recommends all countries to achieve "90-70-90" targets for human papilloma virus (HPV) vaccination, cervical cancer screening, and treatment of precancer and cancer by 2030. In Japan, ASIR has been rising since the late 1990s to 11.1 per 100,000 women, and this rise is particularly prominent in women of reproductive age. HPV vaccination coverage is as low as 0.3%, largely due to the Governments ongoing suspension of proactive recommendations for the vaccine. Given the absence of centralized, population-based cervical cancer screening program and a nationwide surveillance system for systematic monitoring, the exact screening participation rate and treatment rate are difficult to estimate. A national survey suggested that only around 40% of women between the ages of 20 and 69 years underwent cervical cancer screening within the last two years. National policies and systems for HPV vaccination and screening should be updated in a more efficient way as new evidence and innovations become available. In the wake of powerful global momentum, actions must be taken now to further enhance cervical cancer control and ensure that Japanese girls and women are no longer left behind.

The cooperation between professional societies contributes to the capacity building and system development for prevention and control of cancer in low- and middle-income countries: the practice of Cervical Cancer Prevention and Control Project in Cambodia.

Globally, an estimated 570,000 women are newly diagnosed with cervical cancer, and 311,000 women die every year, with approximately 90% of the cases occurring in low- and middle-income countries (LMICs). Cervical cancer is the most common cancer in women in Cambodia, with age-standard incidence rate of 13.5/100,000 and mortality rate of 10.1/100,000. This paper introduces the educational and managerial interventions of Cambodia Cervical Cancer Project 2015-2018 by two professional societies of Cambodia and Japan. It can be categorized into three phases: health education and screening; diagnosis and treatment of precancerous lesions; and pathology service. Human papillomavirus test-based cancer screening and treatment of precancerous lesions were successfully initiated. Key factors contributed to optimal outcomes are partnership between two professional societies with strong commitment, and a comprehensive and stepwise quality-focused approach. A complementary role and joint society initiatives is a novel approach and substantial in sustainability for developing a system of cervical cancer management. This effort might serve as a good example how professional societies can contribute to capacity building and system development for prevention and control of cancer in LMICs.

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.

Development and evaluation of a cervical cancer screening system in Cambodia: A collaborative project of the Cambodian Society of Gynecology and Obstetrics and Japan Society of Obstetrics and Gynecology.

AIM: In Cambodia, the Japan Society of Obstetrics and Gynecology and the Cambodian Society of Gynecology and Obstetrics have an on-going project, started in 2015, for cervical cancer prevention and treatment. The project, currently aimed at factory workers, includes a women's health education program that leads into cervical cancer prevention by establishment of a system for early detection and treatment. It begins by health education, screening for human papillomavirus (HPV), followed by colposcopy and quicker treatment of earlier precursor lesions. METHODS: Rates for participant screening, HPV test positivity, cervical intraepithelial neoplasia (CIN) detection and distribution of HPV types were compared between two screening programs, factory-based and hospital-based. Some HPV test samples were divided into two, one of which was sent to Japan for a quality-control check of the Cambodian testing. RESULTS: The factory-based participant screening rate was 19% (128/681). HPV was detected more frequently in the factory-based program participants (12%) than in the hospital-based program participants (5%). Unfortunately, however, the rate of receiving proper secondary colposcopy screening among the HPV-positive females was significantly higher in the hospital-based program (94%) than the factory-based program (40%) (P < 0.001). The Cambodian laboratory HPV testing accuracy was 92.6%. HPV types demonstrated no significant difference between the two prevention programs. CONCLUSION: We could successfully introduce HPV-based screening, starting from health education. However, low rate of screening, especially secondary screening for HPV positive factory workers was identified. Also, HPV testing could be further improved for accuracy through close monitoring.

How can we strengthen pathology services in Cambodia?

Rapid economic growth and a changing disease burden have increased the demand for pathology services in Cambodia. This paper describes the status of pathological services and international support for pathology professionals in Cambodia, and discusses future needs for strengthening pathology services. In 2016, there were only four pathologists and 18 pathology technologists in Cambodia. A postgraduate course in pathology was created in 2015, and five residents became certified in 2018. Besides multinational support with lectures and practice for pathologists, the Japanese team provides on-the-job training for pathology technologists to improve slide preparation for diagnosis. A clinicopathological conference was introduced to strengthen the communication among pathologists, pathology technologists, and gynecologists. Although there is a long way to go to reach high quality pathological services, coordination among international partners needs to continue, as does the balance between human resource development for pathology professionals, to provide a higher level of care to local citizens.

Methylated DNA and high total DNA levels in the serum of patients with breast cancer following neoadjuvant chemotherapy are predictive of a poor prognosis.

In a previous study, we established a one-step methylation-specific polymerase chain reaction (OS-MSP) assay for the detection of methylated DNA (met-DNA) and total DNA levels in serum. For the present study, this OS-MSP assay was used for patients with breast cancer treated with neoadjuvant chemotherapy (NAC) in order to investigate the prognostic significance of met-DNA and total DNA levels. Following treatment with NAC and prior to surgery, serum samples obtained from 120 patients with stage II/III breast cancer were subjected to the OS-MSP assay for analysis of the glutathione S-transferase pi 1, Ras association (RalGDS/AF-6) domain family member 1 and retinoic acid receptor ß2 genes. The detection of methylation in a minimum of one of these genes indicated a positive outcome of the assay. The total DNA content of the serum was also determined. Of the 120 stage II/III patients, seven (6%) were positive for met-DNA in serum and showed a significantly worse overall survival (OS) time compared with patients negative for met-DNA (n=113) (5-year OS, 43 vs. 85%; P=0.002). The patients with high total DNA levels in serum (n=40) also showed a significantly worse OS compared with those with low total DNA levels (n=80) (65 vs. 91%; P<0.001). The presence of met-DNA and high total DNA levels in the serum were found to be significant prognostic factors that are independent of a pathological complete response by multivariate analysis. Following NAC, met-DNA and high total DNA levels in the serum detected with the OS-MSP assay constitute novel prognostic factors for patients with breast cancer; this may be clinically useful for the prognosis prediction for patients who do not achieve a pathological complete response following NAC.

Methylated DNA and total DNA in serum detected by one-step methylation-specific PCR is predictive of poor prognosis for breast cancer patients.

PURPOSE: We recently developed the one-step methylation-specific PCR (OS-MSP) assay which can detect methylated DNA (met-DNA) in serum with high sensitivity. To examine its prognostic value, we applied this new assay to the detection of met-DNA in serum of breast cancer patients. METHODS: Serum samples taken before surgery from 336 primary invasive breast cancer patients were subjected to the OS-MSP assay for the promoter regions of GSTP1, RASSF1A, and RARß2. The assay outcome was considered positive when methylation was detected in at least one of these three genes. Total DNA content in serum was also determined. RESULTS: Of the 336 stage I/II patients, 33 (10%) were positive for met-DNA in serum and showed a significantly worse overall survival (OS) rate at 100 months (78 vs. 95%; p = 0.002) than those with negative findings (n = 303). Patients with high total DNA in serum (n = 112) also showed a significantly worse OS rate at 100 months (86 vs. 97%; p = 0.001) than those with low total DNA in serum (n = 224). Moreover, patients both positive for met-DNA and with high total DNA in serum (n = 18) showed a much worse OS rate at 100 months (65 vs. 94%; p < 0.001) than the others (n = 318). CONCLUSIONS: Met-DNA in serum detected with the OS-MSP assay constitutes a significant and independent prognostic factor, and its combination with total DNA in serum seems to be even more effective for prediction of prognosis for breast cancer patients.

[Evaluation of 31 cases treated with bevacizumab-based chemotherapy].

The combination of bevacizumab and standard chemotherapy prolongs progression-free survival and improves response rates in advanced nonsquamous non-small-cell lung cancer(NSCLC). We evaluated the efficacy and safety of bevacizumab based chemotherapy in 31 cases of NSCLC. Adverse events occurred in all patients. Grade≥3 hematotoxicities were seen in 27 patients(87. 0%). Grade≥3 non-hematotoxicities were seen in 13 patients(41. 9%). Bevacizumab-related adverse events included epistaxis(74. 2%), hypertension(22. 6%), and proteinuria(22. 6%). Hemoptysis was reported in 9 patients( 29. 0%), but there was no pulmonary hemorrhage or severe hemoptysis. The treatment results of the 18 patients were evaluated as followes: partial response(PR)10, stable disease(SD)7, and progressive disease(PD)1 patient. The response rate(CR+PR)and disease control rate(CR+PR+SD)were 55. 6%and 94. 4%, respectively. The response rates were 66. 7%, 50. 0%, and 57. 1% for 1st-line(6 patients), 2nd-line and later(12 patients), and postoperative recurrence(7 patients all after 2nd-line)patients, respectively. Bevacizumab-based chemotherapy is an efficacious and safe treatment for advanced nonsquamous NSCLC.

Leiomyosarcoma of the breast: a case report and review of the literature about therapeutic management.

We experienced a leiomyosarcoma of the breast in an 18-year-old female. No specific treatment has been established. In order to clarify appropriate therapeutic management methods, the limited data available from our and previous case reports were assessed. A leiomyosarcoma of the breast must be excised with a negative margin. If the tumor size is large and an adequate margin, greater than 3-cm margin around the excised tumor, is not achieved due to anatomical constraints, radiotherapy may be indicated.