Follow-Up Strategies and Detection of Recurrent Breast Cancer in the Modern Era.

BACKGROUND: Regular history assessments and physical examination with annual breast imaging have been recommended as the standard surveillance protocol for breast cancer patients who underwent curative-intent therapy. Based on randomized studies conducted in the 2000s, surveillance with regular chest or abdominal imaging, chemistry panels, or tumor marker measurements does not improve survival in such patients. Given the remarkable recent improvements of systemic therapy, we hypothesized that more intensive surveillance may lead to early detection and improve treatment outcomes in the modern era. METHODS: We retrospectively evaluated the follow-up strategies and benefits of investigations used in usual practice. Breast cancer patients who had initial adjuvant therapy were recruited and classified according to the receipt of standard follow-up (history, physical examination, and annual breast imaging) or alternative follow-up (surveillance with at least annual chest or abdominal imaging or biannual liver function testing). The primary outcome was overall survival. Secondary outcomes included disease-free survival and the indicator of recurrence detection. RESULTS: Of 412 recruited patients, 213 (51.7%) and 199 patients (49.3%) were included in the standard follow-up group and alternative follow-up group, respectively. Among 90 patients (21%) with disease recurrence, the most frequent indicators of recurrence were newly reported symptoms or physical examination abnormalities (64%), followed by abnormal breast imaging (23%) and abnormal chest X-ray (10%). After a median follow-up of 85 months, approximately 90% of patients remained alive after 5 years in both groups. The mean overall survival was similar between the standard and alternative follow-up groups (154.5 months vs. 151.9 months, p = 0.54). There was no difference in terms of the proportion of interval visits, specific cancer treatment received, and disease-free survival. CONCLUSION: Standard follow-up with history assessments, physical examination, and annual breast imaging remains the recommended surveillance strategy in the modern era. Alternative follow-up strategy did not improve oncologic outcomes.

Outcomes of Patients With Breast Cancer Treated With or Without Internal Mammary Irradiation: A Single-Center, Retrospective Propensity Score-Matched Study.

Purpose: Internal mammary lymph node radiation therapy (IMN-RT) has unclear benefits. Historical data were based on only conventional (2-dimensional) radiation techniques. In this 3-dimensional radiation therapy era, we compared the distant metastasis-free survival (DMFS) rates of patients receiving IMN-RT with those who did not include coverage of the IMN (non-IMN-RT). This study aimed to determine the relationship between IMN-RT and distant metastasis control in patients with lymph node-positive breast cancer. Methods and Materials: This was a single-center retrospective cohort study. Patients were divided into 2 groups: IMN-RT and non-IMN-RT. The criterion of the IMN-RT group was that 80% of the prescribed dose covered ≥98% of the Clinical Target Volume of IMN. The primary outcome was 4-year DMFS, and the secondary outcomes were 4-year overall survival, 4-year disease-free survival, and cardiac toxicity. Results: From January 2012 to December 2018, 570 patients were evaluated (IMN-RT, 143 patients; non-IMN-RT, 427 patients). Propensity score matching decreased the number of patients in each group to 139. The median follow-up was 4.3 years. The 4-year DMFS rates were as follows: IMN-RT, 79.1% (95% confidence interval [CI], 70.1%-85.6%), and non-IMN-RT, 82.8% (95% CI, 74.2%-88.7%; P = .43). The groups' 4-year overall survival and disease-free survival rates did not differ. The 4-year overall survival rates were 84.3% (95% CI, 76.4%-89.8%) for IMN-RT and 88.1% (95% CI, 81.0%-92.7%; P = .39) for non-IMN-RT. The 4-year disease-free survival rates were 77.1% (95% CI, 68.1%-83.8%) for IMN-RT and 82.1% (95% CI, 73.6%-88.1%; P = .29) for non-IMN-RT. There was no significant difference in cardiac toxicity (IMN-RT, 1.4%; non-IMN-RT, 1.4%; P = 1.0). Conclusions: In the modern radiation technique era with real-world data, we could not find a benefit of internal mammary irradiation.

Disparities in Access to Systemic Treatment for Breast Cancer in Thailand and Major Asian Territories.

PURPOSE: Breast cancer (BC) treatment has shifted from chemotherapy to targeted therapy. Several targeted agents have demonstrated an improvement in survival. Given that national healthcare resources were correlated with the cancer mortality-to-incidence ratio, we compared access to BC drugs in Thailand with that in other Asian countries. METHODS: BC experts involved in the Breast International Group (BIG)-Asia in six representative groups for countries or special administrative region (SAR) in Asia (Hong Kong SAR, Japan, Korea, Taiwan, Thailand, and Singapore) were invited to participate in the survey. The questionnaire addressed national health reimbursement schemes, molecular testing for early BC (EBC), availability and accessibility of BC drugs. Accessibility and reimbursement of the drugs were reported based on their listing as essential medicines in the World Health Organization Model List of Essential Medicines (WHO-EML) and their nomination as effective drugs in the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). The study was approved by all participating BIG-Asia organizations in November 2021. RESULTS: Genomic tests for EBC were non-reimbursable in all surveyed territories. Reimbursement and co-payment of BC drugs vary between and within these regions (particularly Thailand). Most drugs in the WHO-EML and ESMO-MCBS (A/B for EBC and 4/5 for advanced BC) were accessible in all surveyed territories. However, the accessibility of effective but costly WHO-EML and ESMO-MCBS drugs was not uniform in Thailand. There was an evident disparity for individuals covered by the Thai Social Security/Universal Health Coverage schemes. CONCLUSION: Essential BC drugs are generally accessible in selected BIG-Asia countries or SAR. There is a disparity in accessing high-cost drugs in Thailand compared with other Asian territories.

Patterns and outcomes of immune-related adverse events in solid tumor patients treated with immune checkpoint inhibitors in Thailand: a multicenter analysis.

BACKGROUND: Most immune-related adverse event (irAE) patterns and treatment guidelines are based on western clinical data. We evaluated the incidence and patterns of irAEs in patients treated with immune-checkpoint inhibitors (ICI) in Thailand. METHODS: All solid tumor patients treated with ICIs were retrospectively reviewed in a multicenter analysis. The study aims to evaluate the incidence of irAEs and their characteristics, treatments, outcomes, and impact on survival. All irAEs were graded using the CTCAE version 4.0. Characteristics of irAEs including time to onset, duration of irAEs, specific treatments, and outcomes of irAEs were reviewed. The Chi-square or Fisher's exact test was used to compare variables. Overall survival (OS) was estimated by the Kaplan-Meier method, and compared by the log-rank test. A p-value < 0.05 was considered statistically significant. RESULTS: irAEs of any grade were observed in 98 of 414 patients (24%), whereas grades 3-4 irAEs were observed in 5.6%. The majority of patients (78%) were treated with monotherapy ICI (anti-PD1/PD-L1 92%). The most common all-grade irAEs were hypothyroidism (7.5%), hepatitis (6.5%), and rash (4.8%). Median onset of overall irAEs was 63 days. Pancreatitis and pneumonitis had the earliest onset at 30 and 34 days, respectively. ICIs were rechallenged in 68 of 98 patients with irAE. Eleven of sixty-eight patients (11.2%) with initial irAE had reoccurrence after ICI rechallenge. Based on a multivariate analysis, pre-existing hypothyroidism, ICI used in a clinical trial setting, and combinations of ICI/ICI were independent factors predicting irAE occurrence. Patients with irAE had a statistically significant longer overall survival (OS) when compared to patients without irAE (p = 0.019). A multivariate analysis revealed that occurrence of irAE was an independent prognostic factor for OS (HR 0.70, 95% CI 0.51-0.96; p = 0.028). CONCLUSION: irAE was commonly observed in Thai cancer patients treated with ICIs. Most irAEs were low-grade and manageable. Re-occurrence of irAE after re-challenging ICI was not uncommonly observed. Patients who experienced irAEs might have significantly longer OS compared to patients without irAEs. However, OS in this study should be interpreted with caution since it might be affected by various tumor types, treatment settings, dosing schedule, and ICI combinations.

Predictive significance of cancer related-inflammatory markers in locally advanced rectal cancer.

BACKGROUND: Locally advanced rectal cancer is treated using neoadjuvant chemoradiation (nCRT), followed by total mesorectal excision (TME). Tumor regression and pathological post-treatment stage are prognostic for oncological outcomes. There is a significant correlation between markers representing cancer-related inflammation, including high neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte (MLR) and unfavorable oncological outcomes. However, the predictive role of these markers on the effect of chemoradiation is unknown. AIM: To evaluate the predictive roles of NLR, MLR, and PLR in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiation. METHODS: Patients (n = 111) with locally advanced rectal cancer who underwent nCRT followed by TME at the Minimally Invasive Surgery Unit, Siriraj Hospital between 2012 and 2018 were retrospectively analyzed. The associations between post-treatment pathological stages, neoadjuvant rectal (NAR) score and the pretreatment ratios of markers of inflammation (NLR, MLR, and PLR) were analyzed. RESULTS: Clinical stages determined using computed tomography, magnetic resonance imaging, or both were T4 (n = 16), T3 (n = 94), and T2 (n = 1). The NAR scores were categorized as high (score > 16) in 23.4%, intermediate (score 8-16) in 41.4%, and low (score < 8) in 35.2%. The mean values of the NLR, PLR, and MLR correlated with pathological tumor staging (ypT) and the NAR score. The values of NLR, PLR and MLR were higher in patients with advanced pathological stage and high NAR scores, but not statistically significant. CONCLUSION: In patients with locally advanced rectal cancer, pretreatment NLR, MLR and PLR are higher in those with advanced pathological stage but the differences are not significantly different.

Randomized, double-blind, placebo-controlled study of aprepitant versus two dosages of olanzapine with ondansetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving high-emetogenic chemotherapy.

PURPOSE: We assessed the efficacy of aprepitant (APR) or 10 or 5 mg OLN (OLN10 or OLN5) plus ondansetron and dexamethasone for chemotherapy-induced nausea/vomiting (CINV) prophylaxis in patients receiving high-emetogenic chemotherapy (HEC). METHODS: Patients who received doxorubicin + cyclophosphamide or cisplatin were given intravenous ondansetron and dexamethasone prior to chemotherapy and oral dexamethasone on days 2-4 and randomized 1:1:1 to receive APR125 on day 1 and APR80 on days 2-3 or OLN10 or OLN5 on days 1-4. Matched placebo controls were used. The primary endpoint was no nausea in ≤ 120 h. Secondary endpoints included CINV severity, complete response (CR) rate, adverse effects (AE), and quality of life. RESULTS: Of 141 patients, 104 received AC and 37 received cisplatin. The no-nausea rates were 33% (APR), 43.2% (OLN10; p = 0.24), and 37% (OLN5; p = 0.87). Grades 2-4 nausea were experienced by fewer patients for OLN10 than for APR (24-120 h, 8.7% vs. 27.7%, respectively; p = 0.02; overall period, 19.6% vs. 40.4%, respectively; p = 0.03). The median visual analog scale nausea score from 24 to 120 h was significantly lower for OLN10 (2.3) than for APR (1.2, p = 0.03). The degrees of vomiting, CR, and AE were similar between the APR and OLN10 groups. CINV was similar between the OLN5 and APR groups. CONCLUSIONS: Nausea was less severe for OLN10 than for APR in patients receiving HEC, but other measures were similar. CINV prevention efficacy was comparable between OLN5 and APR.

Association between dietary patterns and disease recurrence in Thai colorectal cancer patients.

Beside established anti-cancer treatment, dietary modification is one of the most promising approaches for reducing the probability of colorectal cancer (CRC) recurrence. Many Western studies showed a relationship between shortened survival and increased amounts of Western diet (meat and processed meat). Given that Thai food is dissimilar to Western diet, we aimed to explore the association between dietary patterns and disease recurrence among Thai CRC patients.Early-stage CRC patients who were disease-free at the end of a 2-year period or patients with disease recurrence within 2 years were enrolled. Patients were administered a food frequency questionnaire to evaluate their dietary lifestyle. Quantitative comparison within individual food groups among patients who were disease-free and among those with recurrence was performed. Proportion of patients with recurrence and disease-free survival was compared between patients who had consumed the lowest and highest tertile of each dietary pattern.A total of 225 CRC patients were enrolled (151 disease-free and 74 recurrence). There were no significant differences in demographic or tumor parameters between patients with or without disease recurrence. From the questionnaire, 45 food items were assigned to 1 of 12 food groups according to similarity in nutritional profile. Patients who consumed high amounts of pickled fish or chili-paste had significantly lower recurrence rates compared to patients who had never eaten those foods (P < .01). From the factor analysis, meat/wheat, vegetarian, and fast-food/processed fruit patterns were identified as the major dietary patterns. There was no significant association between intakes of individual dietary patterns and CRC recurrence.Among CRC patients with Thai dietary lifestyles there was no association between meat/wheat, fast-food/processed fruit, or vegetarian dietary patterns and CRC recurrence. Greater consumption of some unique Thai foods, such as chili-paste or pickled fish, may relate to better outcomes for CRC patients.

From presentation to paper: Gender disparities in oncological research.

Gender disparities in scientific publications have been identified in oncological research. Oral research presentations at major conferences enhance visibility of presenters. The share of women presenting at such podia is unknown. We aim to identify gender-based differences in contributions to presentations at two major oncological conferences. Abstracts presented at plenary sessions of the American Society of Clinical Oncology (ASCO) Annual Meetings and European Society for Medical Oncology (ESMO) Congresses were collected. Trend analyses were used to analyze female contribution over time. The association between presenter's sex, study outcome (positive/negative) and journals' impact factors (IFs) of subsequently published papers was assessed using Chi-square and Mann-Whitney U tests. Of 166 consecutive abstracts presented at ASCO in 2011-2018 (n = 34) and ESMO in 2008-2018 (n = 132), 21% had female presenters, all originating from Northern America (n = 17) or Europe (n = 18). The distribution of presenter's sex was similar over time (p = 0.70). Of 2,425 contributing authors to these presented abstracts, 28% were women. The proportion of female abstract authors increased over time (p < 0.05) and was higher in abstracts with female (34%) compared to male presenters (26%; p < 0.01). Presenter's sex was not associated with study outcome (p = 0.82). Median journals' IFs were lower in papers with a female first author (p < 0.05). In conclusion, there is a clear gender disparity in research presentations at two major oncological conferences, with 28% of authors and 21% of presenters of these studies being female. Lack of visibility of female presenters could impair acknowledgement for their research, opportunities in their academic career and even hamper heterogeneity in research.

Post-Operative Concurrent Chemoradiation for Patients with Non-Squamous Cell Carcinoma of Head and Neck: A Retrospective Cohort of the Uncommon Cancers.

Background: Non-squamous cell carcinoma of the head and neck (HNnSCCA) is a rare tumor. Surgery is the standard treatment for resectable non-metastatic patients. Post-operative radiation (RT) is indicated for high-risk patients. No data from the randomized controlled trial utilizing post-operative concurrent chemoradiation (CCRT) is available. This study was aimed to determine the benefit of post-operative CCRT in the patients with resectable non-metastatic HNnSCCA. Methods: We retrospectively reviewed data of 139 patients with HNnSCCA (excluding nasopharyngeal, neuroendocrine, and skin cancers) who underwent surgery and post-operative radiation (RT) at Siriraj Hospital from 2009­2015. Results: Ninety-nine of the 139 patients had RT alone and 40 had CCRT. More patients receiving CCRT had ≥ one high-risk feature (80% CCRT vs. 57.6% RT; p=0.018). Five-year disease-free survival (DFS) and overall survival (OS) did not differ between the groups (58.6% CCRT vs. 68.2% RT; p=0.35 and 81.7% CCRT vs. 81.0% RT; p=0.35, respectively). Interestingly, post-operative CCRT was independently associated with significantly superior DFS (hazard ratio, HR 0.29; 95% confidence interval, CI 0.10 to 0.86; p=0.02) and OS (HR 0.08; 95% CI 0.01 to 0.43; p=0.003) according to multivariable analyses. Conclusion: Post-operative CCRT was associated with better survival in high-risk patients with resectable non-metastatic HNnSCCA comparing with post-operative RT alone. Post-operative CCRT might be considered as a treatment option for these patients.

Cutaneous toxicities of epidermal growth factor receptor inhibitors: A prospective study in 60 Asian patients.

BACKGROUND: Several prospective studies have been conducted in epidermal growth factor receptor (EGFR) inhibitor-related cutaneous reactions in Caucasian patients, but prospective studies in Asian populations are scarce. OBJECTIVE: To investigate the cutaneous side effects of EGFR inhibitors in Asian cancer patients and to assess tumor response to dermatologic manifestations. METHODS: Sixty patients with lung or colorectal cancer who were receiving EGFR inhibitors were prospectively followed for at least one year by oncologists and dermatologists. RESULTS: Of 60 patients (33 males, 27 females), 46 lung cancer patients received erlotinib (n=29) and gefitinib (n=17). Cetuximab was prescribed in 14 colorectal cancer patients. Fifty-eight patients (58/60, 96.7%) developed cutaneous reactions. The most common reactions were xerosis (82.8%), acne (79.3%), and skin desquamation (62.1%). Most reactions were mild and well-tolerated. Of 14 patients who had severe reactions, temporary treatment interruption was necessary in 3 patients and a decreasing dose was required in another 3 patients. There were no statistically significant differences in type, severity, or number of cutaneous reactions between responders (29/58) and non-responders (29/58) to EGFR inhibitors. At median follow-up time of 11.92±1.08 months, no patient died from cutaneous toxicities. Nine patients died from cancer and 11 patients lost to follow-up. CONCLUSION: In this Asian population, almost all patients (96.7%) developed cutaneous toxicities of EGFR inhibitors. Xerosis, acne, and desquamation were common in Asian cancer patients. Most reactions were mild and well tolerated. Due to limited number of patients, this study did not show significant associations between cutaneous toxicities and tumor response.

Compound A attenuates toll-like receptor 4-mediated paclitaxel resistance in breast cancer and melanoma through suppression of IL-8.

BACKGROUND: Paclitaxel (PTX) is a potent anti-cancer drug commonly used for the treatment of advanced breast cancer (BCA) and melanoma. Toll-like receptor 4 (TLR4) promotes the production of pro-inflammatory cytokines associated with cancer chemoresistance. This study aims to explore the effect of TLR4 in PTX resistance in triple-negative BCA and advanced melanoma and the effect of compound A (CpdA) to attenuate this resistance. METHODS: BCA and melanoma cell lines were checked for the response to PTX by cytotoxic assay. The response to PTX of TLR4-transient knockdown cells by siRNA transfection was evaluated compared to the control cells. Levels of pro-inflammatory cytokines, IL-6 and IL-8, and anti-apoptotic protein, XIAP were measured by real-time PCR whereas the secreted IL-8 was quantitated by ELISA in TLR4-transient knockdown cancer cells with or without CpdA treatment. The apoptotic cells after adding PTX alone or in combination with CpdA were detected by caspase-3/7 assay. RESULTS: PTX could markedly induce TLR4 expression in both MDA-MB-231 BCA and MDA-MB-435 melanoma cell lines having a basal level of TLR4 whereas no significant induction in TLR4-transient knockdown cells occurred. The siTLR4-treated BCA cells revealed more dead cells after PTX treatment than that of mock control cells. IL-6, IL-8 and XIAP showed increased expressions in PTX-treated cells and this over-production effect was inhibited in TLR4-transient knockdown cells. Apoptotic cells were detected higher when PTX and CpdA were combined than PTX treatment alone. Isobologram exhibited the synergistic effect of CpdA and PTX. CpdA could significantly decrease expressions of IL-6, XIAP and IL-8, as well as excreted IL-8 levels together with reduced cancer viability after PTX treatment. CONCLUSIONS: The acquired TLR4-mediated PTX resistance in BCA and melanoma is explained partly by the paracrine effect of IL-6 and IL-8 released into the tumor microenvironment and over-production of anti-apoptotic protein, XIAP, in BCA cells and importantly CpdA could reduce this effect and sensitize PTX-induced apoptosis in a synergistic manner. In conclusion, the possible impact of TLR4-dependent signaling pathway in PTX resistance in BCA and melanoma is proposed and using PTX in combination with CpdA may attenuate TLR4-mediated PTX resistance in the treatment of the patients.

Risk Factors for Chemotherapy-Related Toxicity and Adverse Events in Elderly Thai Cancer Patients: A Prospective Study.

OBJECTIVES: To assess factors predisposing to severe chemotherapy-related toxicity and adverse events (AEs) and dose modification in aging cancer patients. METHODS: Cancer patients aged ≥70 years scheduled to receive the first cycle of a new chemotherapy regimen were enrolled. On the day of starting chemotherapy, demographic data, performance status (PS), and geriatric parameters were recorded. AEs and chemotherapy modification were recorded. Quality of life (QOL) was assessed at baseline and 3 months after starting chemotherapy or at the end of chemotherapy. RESULTS: We included 151 patients (mean age, 76.4 years) with gastrointestinal (47%), lung (24%), breast (9%), or genitourinary (6%) cancer. All-grade and severe AEs occurred in 83 and 42% of patients, respectively; 51.6% of patients required chemotherapy modification due to toxicities. A higher incidence of severe AEs (71% vs. 39%, p = 0.01) and poorer QOL was found in patients with PS 2 than in those with PS 0-1. Patients with PS 2 or who received palliative-intent chemotherapy or had multiple comorbidities were more likely to discontinue chemotherapy because of toxicity. CONCLUSIONS: PS remains a key predictor of chemotherapy-related toxicity in elderly patients. PS 2 was correlated with higher incidence of severe AEs, premature treatment discontinuation, and worsening QOL after treatment.

Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin-cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study.

PURPOSE: The purpose of this study is to determine the efficacy of ginger for reducing chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients receiving adriamycin and cyclophosphamide (AC) regimens. METHODS: We enrolled breast cancer patients receiving AC who experienced moderate to severe nausea or vomiting during the first chemotherapy cycle. Subjects were randomized to receive a 500-mg ginger capsule or placebo twice a day for 5 days starting on the first day of the second AC cycle and were switched to the other treatment in the third cycle. All participants also received ondansetron and dexamethasone for CINV prophylaxis. Nausea severity was recorded once a day during the first 5 days of each cycle. The primary outcome was reduction in nausea score. RESULTS: Thirty-four subjects (68 cycles of AC) were enrolled. Mean (range) maximum nausea score in the first AC cycle was 58 (40-90). Thirty-three subjects (97 %) received the same AC doses in the second as in the third cycle. Mean (±standard error) maximum nausea scores in patients receiving ginger and placebo were 35.36 (±4.43) and 32.17 (±3.71), respectively. The difference in mean maximum nausea scores was 3 (95 % confidence interval, -3 to 9; P = 0.3). There were no significant differences between ginger and placebo in terms of vomiting incidence and severity, rescue medication use, chemotherapy compliance, and adverse events. CONCLUSIONS: Ginger (500 mg) twice daily was safe, but conferred no additional benefit in terms of reducing nausea severity in breast cancer patients receiving AC and ondansetron and dexamethasone for CINV prophylaxis.

Does Extending the Waiting Time of Low-Rectal Cancer Surgery after Neoadjuvant Chemoradiation Increase the Perioperative Complications?

Background. Traditionally, rectal cancer surgery is recommended 6 to 8 weeks after completing neoadjuvant chemoradiation. Extending the waiting time may increase the tumor response rate. However, the perioperative complication rate may increase. The purpose of this study was to determine the association between extending the waiting time of surgery after neoadjuvant chemoradiation and perioperative outcomes. Methods. Sixty patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiation followed by radical resection at Siriraj hospital between June 2012 and January 2015 were retrospectively analyzed. Demographic data and perioperative outcomes were compared between the two groups. Results. The two groups were comparable in term of demographic parameters. The mean time interval from neoadjuvant chemoradiation to surgery was 6.4 weeks in Group A and 11.7 weeks in Group B. The perioperative outcomes were not significantly different between Groups A and B. Pathologic examination showed a significantly higher rate of circumferential margin positivity in Group A than in Group B (30% versus 9.3%, resp.; P = 0.04). Conclusions. Extending the waiting to >8 weeks from neoadjuvant chemoradiation to surgery did not increase perioperative complications, whereas the rate of circumferential margin positivity decreased.

Factors that predict recurrence later than 5 years after initial treatment in operable breast cancer.

BACKGROUND: Occasionally, breast cancer relapses more than 5 years after initial treatment, sometimes with highly aggressive disease in such late-recurring patients. This study investigated predictors of recurrence after more than 5 years in operable breast cancer. METHODS: We retrospectively analyzed data from patients with recurrent breast cancer treated at Siriraj Hospital. Patients were divided into those whose relapse times were longer or shorter than 5 years. Factors that predicted late recurrence were analyzed in both the overall population and the luminal subgroup. Patterns of relapse, changes in biomarkers, and time to disease progression after first relapse were also recorded. RESULTS: We included 300 women whose breast cancers recurred between 2005 and 2013, of whom 180 had recurrence within 5 years of diagnosis and 120 later than 5 years (median time to recurrence: 45.43 months; range: 4.4-250.3 months). Tumors larger than 2 cm, lymph node metastasis, and high nuclear grade were related with early recurrence. Estrogen receptor-positive, progesterone receptor-positive, and HER2(-) disease predicted late recurrence. Almost all late-relapsing patients with luminal tumors had high estrogen receptor (ER(+)) titers (≥50 %) and HER2(-) disease. Liver and brain were the most common early recurrence sites. Biomarkers did not significantly change by time of recurrence. CONCLUSIONS: ER(+)/PR(+) and HER2(-) patients have higher risk of recurrence later than 5 years, especially in patients with high ER titer and low nuclear grade. Larger and node-positive tumors had higher risk of early recurrence.

A phase II study of the combination of gemcitabine plus carboplatin as the neoadjuvant treatment in locally advanced breast cancer.

OBJECTIVE: Although anthracycline-based regimen is standard neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC), there is some concern over its toxicities such as alopecia and cardiotoxicity. Gemcitabine is another active agent in metastatic breast cancer after failure to anthracycline with less toxicity. The objective of the present study is to evaluate the efficacy and safety of the combination of gemcitabine and carboplatin as NAC in LABC. MATERIAL AND METHOD: Patients with histologically confirmed LABC (T3, T4 or N2 and M0) were included. Patients were scheduled to receive 3 cycles of neoadjuvant GC (gemcitabine 1,000 mg/m2 D1, D8 and carboplatin AUC x 5 D1) every 21 days. Patients with clinical response underwent surgery and additional 3 cycles of adjuvant GC. Primary endpoint was clinical response rate whereas secondary endpoints included pathological response, DFS, OS and toxicity. RESULTS: Between 2004 and 2007, 40 LABC patients were enrolled. Of 40 patients, 35 were evaluable for efficacy and 40 for toxicity. Twenty-three out of 35 patients (65%) obtained cPR. Among 22 patients who had clinical response and who underwent surgery, overall pathological response rate was 51.5% with 1-pCR (2.9%) and 17-pPR (48.5%). All 7 triple-negative patients had pathological response (1-pCR, 6-pPR). At median follow-up of 59 months, median DFS and OS were not reached. Five-year OS and DFS were 67% and 62%, respectively Major adverse effect was myelosuppression without fatal complications. CONCLUSION: The combination GC was feasible and well-tolerated for LABC in neoadjuvant setting. Triple-negative subgroup seems to have high response to GC.

Pituitary metastasis from renal cell carcinoma: a case report with literature review.

A 52-year-old man suffered from visual disturbance for 5 months. He then developed malaise, constipation and anorexia with significant weight loss. Physical examination showed noticeable signs of hypothyroidism, such as slurred speech, dry skin, macroglossia, myoedema and slow relaxation of ankle reflexes. In addition, eye exam showed abnormal visual acuity with left homonymous hemianopia. A large mass was found at right scapular region. Endocrinologic investigation results were compatible with secondary hypothyroidism with adrenal insufficiency. Subsequent CT brain revealed an enhancing mass at pituitary gland and also a mass at right occipital lobe with surrounding edema. CT of chest demonstrated multiple lung nodules, right scapular mass and incidentally revealed 8.7-cm hypervascular mass at left kidney. The final diagnosis was renal cell carcinoma with bone, lung, brain and pituitary metastasis. He received hormone replacement therapy as well as bisphosphonate and brain radiation. Following treatments, he was able to return to work with recovery of visual impairment. Pituitary metastasis is a rare condition. Our patient presented with symptoms of hypothyroidism which may mimic pituitary adenoma, but had other clues of malignancy such as significant weight loss and scapular mass. The most common cancers that occasionally metastasize to pituitary gland are breast and lung cancer. Previously, renal cell carcinoma with pituitary metastasis has been reported. Unlike ourpatient, most of these cases developed metachronous pituitary metastasis.

HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab.

Although current breast cancer treatment guidelines limit the use of HER2-blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ER(+)), HER2(-) luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from patients with breast cancer as compared with matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by receptor activator of NF-κB (RANK)-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC targeting agents are administered in the adjuvant setting. Cancer Res; 73(5); 1635-46. ©2012 AACR.

Treatment of locally advanced rectal cancer: controversies and questions.

Rectal cancers extending through the rectal wall, or involving locoregional lymph nodes (T3/4 or N1/2), have been more difficult to cure. The confines of the bony pelvis and the necessity of preserving the autonomic nerves makes surgical extirpation challenging, which accounts for the high rates of local and distant relapse in this setting. Combined multimodality treatment for rectal cancer stage II and III was recommended from National Institute of Health consensus. Neoadjuvant chemoradiation using fluoropyrimidine-based regimen prior to surgical resection has emerged as the standard of care in the United States. Optimal time of surgery after neoadjuvant treatment remained unclear and prospective randomized controlled trial is ongoing. Traditionally, 6-8 wk waiting period was commonly used. The accuracy of studies attempting to determine tumor complete response remains problematic. Currently, surgery remains the standard of care for rectal cancer patients following neoadjuvant chemoradiation, whereas observational management is still investigational. In this article, we outline trends and controversies associated with optimal pre-treatment staging, neoadjuvant therapies, surgery, and adjuvant therapy.

Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population.

Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance.