bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Child-Pugh score to assess perioperative outcome in epithelial ovarian cancer patients
Authors: Pua T. , Novetsky A. P. , Blank S. V.
Published: August 2020

5571

Background: The Child-Pugh score was designed to predict surgical outcome for patients with liver cirrhosis. This score is comprised of five variables (ascites, bilirubin, albumin, prothrombin time and encephalopathy) that were thought to determine prognosis. Epithelial ovarian cancer (EOC) and cirrhosis share manifestations of increased abdominal girth, ascites, malnutrition and abnormal laboratory findings. In this study, we evaluate the application of the Child-Pugh score to assess EOC outcome. Methods: A review of EOC patients (pts) undergoing primary cytoreductive surgery at our institution from 2003 to 2008 was performed. Pts without preoperative serum bilirubin, albumin, prothrombin time or documentation of ascitic volume were excluded. Women were divided into either Child class A (Child score <6) or Child class B/C (>6). Estimated blood loss, ICU admission, minor (infection, transfusion, ileus/bowel obstruction) and major complications (re-operation, peri-operative death, hospital stay >14 days) and survival analysis were evaluated using chi square and Cox proportional hazards model, respectively. Results: A total of 105 patients were evaluated, 29 with early stage (I/II) and 76 with late stage (III/IV) disease. Estimated blood loss was not significantly different between Child class A vs B/C groups (469 ml vs 628 ml, p = 0.45). Optimal cytoreduction was achieved in 92.3% vs 65.8%, respectively (p = 0.001). Post-operative ICU admission (4.8% vs 23.7%, p = 0.004) and minor complication (35% vs 66%, p = 0.003) rates were also significantly lower in the Child A vs B/C group. Of note there were 4 peri-operative deaths, all in the B/C group (p = 0.01). Length of hospital stay between the two groups were 4 vs 8.4 days, respectively (p = 0.008). Women in Child class B/C had a hazard ratio of 12.4 (95% CI 1.5 - 100.7) for death as compared to those in Child class A. Conclusions: Application of the Child classification to women with ovarian cancer revealed increased rates of suboptimal cytoreduction and peri-operative complications including ICU admission, infection, transfusion and death. EOC patients with higher Child score prior to surgery may consider neoadjuvant chemotherapy to decrease morbidity of surgery.

No significant financial relationships to disclose.
Prognostic factors of patients with advanced stage serous borderline tumors of the ovary
Authors: Morice P. , Uzan C. , Kane A. , Rey A. , Gouy S. , Pautier P. , Camatte S. , Lhomme C. , Haie-Meder C. , Duvillard P.
Published: August 2020

5573

Background: The aim of this study was to determine prognostic factors in a large series of patients with stage II or III serous low malignant potential ovarian tumor (LMPOT) and peritoneal implants. Methods: A retrospective review of patients with a serous LMPOT and peritoneal implants treated or referred in our institution. The slides of ovarian tumors and peritoneal implants were reviewed by the same pathologist. Prognostic factors were studied. Results: From 1969 to 2006, 168 patients were reviewed, 21 of whom had invasive implants. Tumors exhibited a micropapillary pattern in 56 patients. Adjuvant treatment had been administered to 61 patients. The median duration of follow-up was 57 (range, 1–437) months. Forty-four patients had relapsed and 10 patients had died. 5-year overall survival of patients was 98%. Among patients with noninvasive and invasive implants, 8% and 10%, respectively, relapsed at 5 years in the form of invasive disease (p = 0.08). Prognostic factors for recurrence in the univariate analysis were: a laparoscopic approach, conservative treatment and positive second-look surgery. In the multivariate analysis the use of conservative treatment was the only prognostic factors for recurrence. Conclusions: The prognosis of serous LMPOT with peritoneal implants remains good. The strongest prognostic factor in patients with an advanced-stage borderline tumor is the use of conservative surgery. In this series, a micropapillary pattern and implant subtypes (invasive vs. noninvasive) were not prognostic factors.

No significant financial relationships to disclose.
Clinical relevance of angiogenesis and lymphangiogenesis in patients with sex cord-stromal ovarian tumors
Authors: Brown J. , Deavers M. T. , Nick A. M. , Milojevic L. , Gershenson D. M. , Sood A. K.
Published: August 2020

5575

Background: Distant metastasis is common in patients with sex cord-stromal ovarian tumors (SCSTs), but lymph node involvement is extremely rare. Given the lack of lymphatics in the normal granulosa layer, we examined the clinical relevance of angiogenesis and lymphangiogenesis in patients with SCSTs. Methods: After Institutional Review Board approval, 80 tumor samples (46 primary, 34 recurrent) were obtained from 65 patients and stained for CD31 (microvessel density; MVD), D2–40 (lymphvascular density; LVD), and VEGF. Clinical data were extracted by chart review and correlated with the angiogenesis and lymphatic markers. Results: The median age of the patients was 42.1 years (range, 8.6–78.6 years). At presentation, 53% of patients had stage I disease, 8% had stage II, 16% had stage III, and 23% were unstaged. Although VEGF expression was noted at some level in 99% of samples, VEGF overexpression (upper tertile of overall score) was noted in 35% of samples. On the basis of ROC analysis, vessel density was stratified into high versus low at a mean MVD cutoff of 12.3. High MVD was present in 41% of all tumors. High MVD was significantly associated with shorter disease-specific survival (mean 16.7 versus 32.3 months; p = 0.024), increased risk of recurrence (p < 0.04), and shorter overall survival (median 108.6 versus 388.5 months; p < 0.001). High MVD was strongly related to VEGF overexpression (p = 0.009). While VEGF expression was not related to the pattern of recurrence, high MVD was strongly associated with distant metastasis (abdomen, liver, lung, bone) compared with local recurrence (p < 0.001). Lymph node metastasis was clinically evident in only 3 of the 65 patients. Most tumors had either absent or low LVD. Interestingly, all 3 tumors with nodal metastasis had significantly greater LVD (LVD = 35.8 vessels/hpf) compared to those without nodal metastasis (LVD = 2.7 vessels/hpf; p < 0.001). Conclusions: Increased angiogenesis is a significant predictor of poor clinical outcome in patients with sex-cord stromal tumors. Most of these tumors have poor lymphatic development that might explain the low likelihood of nodal metastasis. These data provide support for further investigation of antiangiogenic biological agents in these patients.

No significant financial relationships to disclose.
Predictive value of gain of 3q for cervical dysplasia and potential utility in the clinical management of LSIL
Authors: Kilpatrick M. W. , Jalali G. R. , Scamporino J. , Menzin A. , Tafas T. , Walat R. , Tsipouras P.
Published: August 2020

5583

Background: Physicians need better tools for determining whether an LSIL will progress to HSIL or regress. Research demonstrates that the chromosome 3q26 region is found to be amplified in patients with cervical cancer and that the frequency of this 3q gain increases with dysplasia severity. The objective of this study was to demonstrate that 3q can be used as a risk stratification tool to identify patients likely to regress/progress. Methods: Slide-based, archival thin-layer specimens and longitudinal follow-up data for 52 patients (47 usable cases) originally diagnosed as LSIL were obtained from independent cytopathology laboratories. Slides were destained, then hybridized with a single-copy probe for the chromosome 3q26 region and a probe for the centromeric alpha-repeat sequence of chromosome 7, using standard FISH methods. Results: Of the 47 cases analyzed, 30 showed a negative FISH test result for a sensitivity of 92% (95% CI of 64, 100), specificity of 85% (95% CI of 69, 95) and a negative predictive value of 97% (95% CI of 83, 100). In a subset of cases a biopsy was obtained. Of the 32 cases with tissue diagnosis, 11 women had progressed to CIN2+, of which 10 were FISH positive; and 18 of 21 women with tissue diagnosis of ≤CIN1 were FISH negative, for a sensitivity of 91% (95% CI of 59, 100), specificity of 86% (95% CI of 64, 97) and a negative predictive value of 95% (95% CI of 74, 100). If the analysis is confined to the 36 cases for which follow-up of at least 12 months after the index LSIL was available, 26 showed a negative FISH test result for a sensitivity of 100% (95% CI of 48, 100), specificity of 84% (95% CI of 66, 95) and a negative predictive value of 100% (95% CI of 87, 100). Of the 22 cases with tissue diagnosis, 4 women had progressed to CIN2+, all FISH positive; and 16 of 18 women with ≤CIN1 were FISH negative, for a sensitivity of 100% (95% CI of 40, 100), specificity of 89% (95% CI of 65, 99) and a negative predictive value of 100% (95% CI of 79, 100). Conclusions: Analysis of 47 specimens demonstrated the ability of 3q gain to predict disease progression/regression in cytology samples. 3q gain can serve as a risk stratification tool for LSIL cases.

[Table: see text]
High interstitial fluid pressure (IFP) and hypoxia as biomarkers of cisplatin chemoradiation response in advanced cervix cancer
Authors: Fyles A. , Pintilie M. , Hedley D. , Bristow R. , Wouters B. , Hill R. , Milosevic M.
Published: August 2020

5584

Background: Chemoradiotherapy (CRT) has been shown to improve survival compared to RT alone for locally advanced cervix cancer. The tumour microenvironment in cervix cancer is also known to influence disease progression and response to treatment. In this prospective study, pre-treatment tumour hypoxia and interstitial fluid pressure (IFP) were examined as potential biomarkers of improved treatment effectiveness in a cohort of patients treated with definitive radiation alone, or with the addition of concurrent cisplatin CRT. Methods: Between April 1994 and January 2006, 309 eligible patients with cervix cancer were entered into a prospective study of hypoxia and IFP prior to definitive treatment. Patients accrued between 1994 and 1999 (n = 115) were treated with RT alone, and those accrued between 2000 and 2006 (n = 194) received RT and concurrent weekly cisplatin CRT. Clinical characteristics were similar between the two cohorts except pelvic lymph node metastases were more frequent in the CRT cohort (42% vs. 19%, p = 0.0005), likely due to changes in definition of positive nodes on CT or MR imaging. The median follow-up was 3.6 years (2.9 years for CRT and 7.8 years for RT). Results: The use of CRT improved outcome in hypoxic tumors compared to RT (57% 3-yr DFS vs. 42%, p = 0.045) with a trend to improved DFS in patients with high IFP tumors (57% 3-yr DFS vs. 44% for RT alone, p = 0.056). A strong interaction was identified between IFP and treatment (CRT vs. RT, p = 0.007). After correcting for the effects of clinical prognostic factors, cisplatin significantly improved DFS in the high IFP group (p = 0.02), and showed a trend towards improved DFS in those with hypoxia (p = 0.1). In patients with both high IFP and hypoxia a similar benefit of cisplatin was seen. Conclusions: Patients with high IFP and hypoxic tumours may selectively benefit from the addition of concurrent cisplatin CRT to their treatment regimen. This observation is contrary to an effect of high IFP on impaired drug delivery, but may reflect reduced DNA repair under hypoxic conditions, which could facilitate cell killing with both radiation and cisplatin chemotherapy.

No significant financial relationships to disclose.
Secondary platinum therapy in patients with uterine cervical cancer previously treated with platinum chemotherapy
Authors: Tanioka M. , Katsumata N. , Hirata T. , Yunokawa M. , Yonemori K. , Kouno T. , Shimizu C. , Tamura K. , Andoh M. , Fujiwara Y.
Published: August 2020

5588

Background: Second-line chemotherapy after the front-line platinum based regimens including concurrent chemoradiation (CCRT) has not been established for patients with advanced or recurrent cervical cancer. Platinum based regimens are often selected, but the predictive and prognostic factors of secondary platinum therapy are unclear. We therefore evaluated the relative influence of platinum free interval ( PFI ) between the completion of front-line regimen and the institution of second-line regimen. Methods: This retrospective review was undertaken of 65 patients who received ≥ 2 platinum-based regimens and were assessable for secondary response in National Cancer Center Hospital between 1996 and 2008. We analyzed independent predictive factors associated with secondary response by logistic regression model and prognostic factors associated with subsequent survival by Cox regression model. Results: The median age was 54 years old (range, 28 to 73). The median follow-up of subsequent survival was 11.0 months (1.1 to 66.6). The median PFI was 11.1 months (0.7 to 77.6). Overall secondary response rate was 40%, while response rate for 36 patients after CCRT was 36%. The response increases in frequency with longer PFI ( Table ). Univariate and multivariate analyses using logistic regression model showed PFI for ≥ 9 months (odds ratio [OR] = 0.28; P =.04), PS 0 (OR = 0.19; P =.006) and maximum tumor diameter ≥ 30 mm (OR = 0.23; P =.02) were independent predictive factors of secondary response. Univariate and multivariate analyses using Cox regression model revealed PFI for ≥ 9 months (hazard ratio [HR] = 0.44; P =.005), PS 0 (HR = 0.30; P =.000) and histology of squamous cell carcinoma (HR = 2.20; P =.02) were independent prognostic factors of subsequent survival. Conclusions: Our exploratory study demonstrates that platinum free interval has both predictive and prognostic value for secondary platinum-based treatment for patients with advanced or recurrent cervical cancer.

[Table: see text]

[Table: see text]
Incidence of adnexal and lymph node metastases in endometrial stromal sarcoma
Authors: dos Santos L. , Garg K. , Diaz J. P. , Soslow R. A. , Hensley M. L. , Alektiar K. M. , Barakat R. R. , Leitao M. M.
Published: August 2020

5589

Background: To determine the incidence of adnexal and lymph node (LN) metastases in endometrial stromal sarcoma (ESS). Methods: We identified all cases evaluated at our institution with a diagnosis of ESS from January 1, 1980 to December 31, 2007. All uterine pathology was reviewed at our center. High-grade or undifferentiated tumors and ESS arising in extrauterine sites were excluded. Pertinent clinical data were abstracted from electronic medical records. Appropriate statistical tests were performed using SPSS 15.0. Results: We identified 91 cases with ESS. All except two underwent hysterectomy. Eighty-four cases (92%) underwent salpingo-oophorectomy (bilateral in 81 [96%]). Adnexal metastases were identified in 8 (9.5%) of 84 cases. All adnexal metastases were manifested by gross adnexal tumor and occurred in patients with other gross pelvic extrauterine disease. Seven of these 8 patients also had lymph-vascular space invasion (LVSI). LVSI status was not reported in the other patient. In patients with gross pelvic extrauterine disease, adnexal metastasis did not affect survival. LN metastases were identified in 8 (24%) of the 34 patients who underwent LN evaluation. Thirty-three evaluations were performed intraoperatively and one was via postoperative CT-guided biopsy of an enlarged LN. Five of the 8 cases with LN metastases had LVSI. LVSI status was not reported in the other 3 cases. Of 20 patients with disease grossly limited to the uterus and grossly normal LN, 2 (10%) had LN metastases. Both of these cases had LVSI and extensive myoinvasion approaching the serosa. Four of the remaining 6 patients with LN metastases had grossly positive LN and other gross extrauterine disease. The final 2 patients had grossly positive LN without other extrauterine disease. Conclusions: The incidence of LN metastases in ESS is most commonly associated with gross extrauterine disease, extensive myoinvasion and LVSI. However, since myoinvasion and LVSI status often are not assessable at the time of initial hysterectomy, LN dissection remains a reasonable option at primary surgery. The rate of adnexal metastasis appears to be negligible in the absence of gross adnexal and extrauterine tumor, but there may be a role for oophorectomy in the hormonal management of ESS.

No significant financial relationships to disclose.
Evaluation of the role of aromatase inhibitors (AIs) in the treatment of uterine leiomyosarcoma (uLMS)
Authors: O'Cearbhaill R. , Zhou Q. , Iasonos A. , Soslow R. A. , Leitao M. M. , Aghajanian C. A. , Hensley M. L.
Published: August 2020

5590

Background: Although AIs are sometimes used in selected patients with uLMS, there are few data assessing the efficacy of AIs in this setting. Methods: A retrospective electronic medical record review of patients (pts) with uLMS treated with an AI at Memorial Sloan-Kettering Cancer Center between 1998–2008 was performed. The primary endpoint was progression free survival (PFS), defined as time from the start of AI until death, progression or last follow-up. PFS was estimated by Kaplan-Meier method. Best response using RECIST was also assessed. Results: 34 pts with advanced, measurable uLMS were treated with AIs. Median age was 53 yrs (range 35–74); median body mass index 28.1 kg/m2 (range 16.1–52.1); LMS grade low: 5, high: 29; hormone receptor status: 19 ER+, 9 ER-, 6 ER unknown, 9 PR+, 9 PR-, 16 PR unknown; low volume of disease (no lesion >2 cm): 19 pts(56%), high volume: 15 pts (44%). 23 pts (68%) had had prior chemotherapy (1 regimen: 29%, 2 regimens: 18%, 3 regimens: 15%, >4 regimens: 6%); 12 pts (35%) had had prior pelvic radiotherapy. AIs used were: letrozole 74% (9% with leuprolide if premenopausal), anastrozole 21%, exemestane 6%. Median PFS was 2.9 months (95% CI: 1.8–5.1). 8 pts (23.5%) had a PFS >6months. Among pts with ER or PR + uLMS, median PFS was 5months (95% CI: 1.8–9.4) versus 1.9months (95% CI: 0.9–3.2) with ER and PR negative uLMS. Best response was partial response in 3 pts (8.8%) (all of whom were ER+), stable disease in 12 (35%), and progressive disease in 19 (56%). Common toxicities were grade 1–2 asthenia (30%), hot flashes (30%), and arthralgias (27%). Conclusions: In this highly selected population of pts with uLMS AIs fail to achieve objective response. While relatively prolonged PFS was observed among ER and/or PR+ uLMS pts, in the absence of a no-treatment control group this outcome cannot be attributed solely to the activity of the AI treatment.

No significant financial relationships to disclose.
Cardiotoxicity risks of adjuvant trastuzumab in Asian breast cancer patients
Authors: Shih V. , Chan A. , Chiang J. , Teo C. , Chen J. , Wong Z.
Published: August 2020

561

Background: Adjuvant trastuzumab (T)-based chemotherapy has been shown to reduce relapse and improve survival in breast cancer patients but has been associated with increased risks of cardiotoxicity. Our study aims to define the incidence and severity of cardiotoxicity amongst Asian breast cancer patients. Methods: This is a retrospective review of patients who have received adjuvant T from June 2005 to 2007. Cardiotoxicity was defined as a drop in left ventricular ejection fraction (LVEF) to less than 50% and/or reduction of > 10% of baseline. Cardiovascular (CVS) risk factors were defined as having a family history or presence of CAD, hypertension, diabetes mellitus, hyperlipidemia and smoking. We used pair sampled t-test to evaluate the mean LVEF change and Chi-square test to evaluate the association of cardiotoxicity and demographics. Results: There were 179 female patients. Cardiotoxicity was reported in 70 (39.1%), of whom 59 had asymptomatic decline in LVEF and 11 experienced CHF. Mean LVEF, comparing various time points (3, 6, 9 and 12 months) against baseline showed statistically significant decline (p<0.05). T was withheld (n=33) due to asymptomatic decline in LVEF (n=24), symptomatic heart failure (n=4) and both (n=5). Twenty-one with resolution of CHF (n=7) or LVEF recovery (n=14) were rechallenged. Cardiotoxicity recurred in 9 - asymptomatic decline in LVEF (n=8) and recurrent CHF (n=1). There were no cardiac-related deaths. Neither patient demographics nor CVS risk factors predicted for cardiotoxicity. Conclusions: This is one of the largest series reported in Asians receiving T. As previously reported, T-induced cardiotoxicity resulted in mostly asymptomatic reversible decline in LVEF. Our incidence of cardiotoxicity appeared higher (39.1%) in Asians and more importantly, almost half of the patients experienced cardiotoxicity upon rechallenge. It would be prudent to explore whether there is any difference in susceptibility to T-induced cardiotoxicity between the different races.

[Table: see text]

No significant financial relationships to disclose.
Long-term survival benefits of docetaxel plus cyclophosphamide compared to doxorubicin plus cyclophosphamide in the adjuvant treatment of operable breast cancer
Authors: Thompson M. , Seal B. , Tangirala M. , Asmar L. , Jones S.
Published: August 2020

563

Background: The U.S. Oncology Adjuvant Trial 9735 recently demonstrated disease-free survival and overall survival (OS) benefits over 7 years for docetaxel plus cyclophosphamide (TC) compared with doxorubicin plus cyclophosphamide (AC) as adjuvant treatment for women with operable stage I-III invasive breast cancer (BC). The life-time benefits of TC vs. AC, however, are unknown. This analysis aimed to project potential life-time survival benefits of TC vs. AC as adjuvant therapy for operable BC. Methods: The 7-year follow-up results of the 9735 study combined with US average life expectancy were used to project the life-time survival benefits of TC vs. AC. In the base case (scenario 1), it was assumed the survival advantage of TC did not persist beyond the 7-year clinical trial period. Rather, all patients alive and disease-free at 7 years (from the starting age of 51 to the age of 58), regardless of treatment, were assumed to be cured and received the average remaining life expectancy of a 58-year old woman in the US general population. As survival benefits from chemotherapy may persist beyond the clinical trial period, two sensitivity analyses were conducted: 1) greater life expectancy in the TC arm of 1.8 months equivalent to the mean difference in OS between TC and AC within the clinical trial period (scenario 2) and 2) greater life expectancy in the TC arm of 22 months equivalent to the difference in survival at the end of 7 years (scenario 3). The total life years gained (LYs) and quality-adjusted life years gained (QALYs) were then calculated. Results: Per patient LYs gained in scenarios 1, 2, and 3 were 0.850, 0.930, and 1.755, respectively; while QALYs gained were slightly lower at 0.674, 0.736 and 1.383, respectively. Applying this benefit to a cohort of 167,133 women in the US with newly diagnosed stage I-III invasive BC in 2008, the gains were 142,063 LYs and 112,648 QALYS in scenario 1. Conclusions: In addition to survival benefit observed within the clinical trial period, the use of TC is associated with long-term survival benefits compared to AC in patients with stage I-III invasive BC. The results provide additional support of the value of TC in the management of early stage BC.

[Table: see text]
Risk stratification by hormonal receptor (ER, PgR) and HER2 status in small (≤1cm) invasive breast cancer: Who might be a possible candidate for adjuvant treatment?
Authors: Park Y. , Kim S. , Ok O. , Baek H. , Lee J. , Nam S. , Yang J. , Cho E. , Ahn J. , Im Y.
Published: August 2020

564

Background: With the increasing use of screening mammography, the proportion of ≤ 1 cm invasive breast cancer is increasing. Identification of breast cancer molecular subtypes has resulted in a better appreciation of the biologic heterogeneity, which is not fully explained by clinicopathologic features including staging system. The aims of this study were: 1) to identify the risk factors of systemic metastases in patients with ≤ 1 cm invasive breast cancer and 2) to investigate the patients group at greatest risk of such failure even in these small tumors. Method: Data were collected retrospectively in the breast cancer registry of our institution for patients with invasive breast cancer from October 1994 to December 2004. Results: Of 4,036 patients who received curative breast cancer surgery, 466 patients who had T1a or T1b breast cancer were identified. 39 patients who received neoadjuvant chemotherapy were excluded in this study. Ipsilateral axillary lymph node involvement was found in 13% (57/427) at the time of surgery. Axillary lymph node involvement was much more common in HER-2 positive group (33% vs 11%, p < 0.0001) and triple negative (TN) group (24% vs 11%, p = 0.002) than in hormone receptor positive group. During median 61 months of follow-up, overall 10 year estimated distant relapse-free survival (DRFS) and overall survival (OS) were 95% and 92%, respectively. Multivariate analysis was conducted in 370 (T1aN0, T1bN0) patients, who had no lymph node involvement. In Cox-regression model, HER-2 positivity and triple negativity were identified as independent prognostic factors to predict DRFS [Hazard ratio (HR) 8.8, p = 0.003 for HER-2 positive group; HR 5.1, p = 0.026 for TN group] and OS (HR 5.0, p = 0.067 for HER-2 positive group; HR 11.1, p = 0.017 for TN group) in T1bN0 tumors. Limiting to T1aN0 tumors, statistical significance was not maintained. Conclusions: Even though T1aN0 and T1bN0 tumors have been known to have a relative low risk of systemic failure, anti-HER-2 directed therapy for HER-2 positive group and new innovative adjuvant systemic treatment for TN group in patients with T1bN0 tumor should be considered. Prospective adjuvant trials should be warranted in these subgroups of patients.

No significant financial relationships to disclose.
Preplanned first-step analysis of LET-LOB neoadjuvant study: A double-blind randomized phase IIb trial of letrozole (L) plus lapatinib (Lp) or placebo (P) in postmenopausal HER2-ve, HR+ve operable breast cancer
Authors: Frassoldati A. , Guarneri V. , Bottini A. , Cagossi K. , Cavanna L. , Bisagni G. , D'Amico R. , Piacentini F. , Oliva C. , Conte P.
Published: August 2020

570

Background: In HR+ve BC, the simultaneous blockade of ER and HER-related pathways could prevent the hormone-resistance due to activation of EGFR-family signalling, as shows the high activity of the combination of letrozole and lapatinib in HR+ve/HER2+ve advanced BC. The LET-LOB trial evaluates the clinical and biological effects of the combined inhibitory strategy with letrozole + lapatinib in untreated ER+ve/HER2-ve BC patients suitable for hormonal neoadjuvant therapy. Methods: Postmenopausal women with stage II-IIIa, HR+ve/HER2-ve BC are randomized to L (2.5 mg/d) + Lp (1500 mg/d) or L + P, given continuously for 24 weeks before surgery. Primary end point is the clinical RR (with ultrasonography, US); secondary endpoints are the pathological RR, the safety, and HR/EGFR-related biomarker evaluation. According to the “two step Simon's design” of the study, at least 20 cORs (8 in L+P and 12 in L+Lp) must be observed in the first 43 patients; then, additional 48 patients will be recruited to demonstrate a 40% increase in cOR with L+Lp, assuming a cOR of 50% with L+P. Results: Since April 2007, 39/55 randomized patients completed the preoperative treatment. Median age was 68 yrs. At diagnosis, mean US tumor size was 3 cm. All patients were HER2-ve, and either ER+ve or PR+ve (both +ve: 76%). After 3 and 6 months of therapy, a 29% and 41% reduction from baseline mean US longest tumor diameter was observed. No change in mean LVEF has been reported at the 3- and 6-month evaluations. 5 episodes of G3 toxicity have occured (skin rash, 1; liver function parameters, 4). So far 31 women underwent surgery (conservative in 65 %). The efficacy results according to the first step Simon's analysis will be performed by the IDMC on march 2009, and will be presented at the meeting along with updated clinical and safety data. Conclusions: Preliminary blinded results suggest that the combination of L+Lp in ER+ve/HER2-ve operable BC is feasible, without early cardiac events or other severe toxicities, and associated with clear tumor downstaging. Biological correlative studies will clarify the relationship between the double inhibition strategy and the clinical response. Supported by GlaxoSmithKline.

[Table: see text]
Anthracycline-based preoperative chemotherapy plus lapatinib and trastuzumab or both in HER2-positive breast cancer: Preliminary cardiac safety report of the CHER LOB trial
Authors: Guarneri V. , Frassoldati A. , Bottini A. , Cagossi K. , Cavanna L. , Ravaioli A. , Amadori D. , Giardina G. , Oliva C. , Conte P.
Published: August 2020

573

Background: The combination of anthracyclines and anti-HER-2 agents is highly active in HER-2 positive breast cancer, but its use is limited by an enhanced risk of cardiac toxicity. We are running a randomized phase II trial of combined preoperative chemotherapy (CT) with anthracycline plus trastuzumab, lapatinib, or both in HER-2 positive stage II-IIIA breast cancer patients. Aims of the study are the percentage of pathological complete response (pCR = breast + axillary nodes) and cardiac safety. We report the updated cardiac safety and activity data following the IDMC recommendation to continue study accrual. Methods: CT consists of sequential paclitaxel (P) 80 mg/m2 weekly for 12 weeks followed by 4 courses of FE75C administered every 3 weeks. Arm A is CT + trastuzumab 2 mg/kg weekly; arm B is CT + lapatinib 1500 mg po daily; arm C is CT + trastuzumab 2 mg/kg weekly + lapatinib 1,000 mg po daily. Both trastuzumab and lapatinib are started concomitantly with the first P administration, and are administered throughout the duration of CT. Left ventricular ejection fraction (LVEF) is evaluated at baseline, before the start of FE75C, and at the completion of treatment. The planned sample size is 120 patients, and has been calculated according to the two steps Simon's design. Results: 53 out of the 120 planned patients have been randomized: 16 in arm A, 17 in arm B, and 20 in arm C. Median age is 48 years (range 27–66). The mean LVEF was 63% (range 54–77%) at baseline, 61% (50–78%) at the completion of weekly P + trastuzumab, lapatinib, or trastuzumab + lapatinib, and 60.3% (54–74%) at the completion of the whole treatment plan. Thirty patients underwent surgery: 19 patients (63%) received breast conserving surgery; 13 patients (43%) achieved a pCR. Conclusions Following the updated interim analysis, the combination of T, L or both with an anthracycline-containing regimen is feasible, with very interesting level of activity. The next planned analysis will be performed when 60 patients will be evaluable and will be presented at the Meeting.

[Table: see text]
Improved clinical response from neoadjuvant taxane chemotherapy across breast cancer subtypes
Authors: Jenkins E. O. , Deal A. M. , Burrows E. , Drobish A. , Carey L. A.
Published: August 2020

576

Background: Adjuvant trials suggest that taxane (T) after doxorubicin and cyclophosphamide (AC) has little benefit in hormone receptor positive (HR+) patients compared to hormone receptor negative (HR-) patients, particularly if HER2 negative. Primary chemotherapy sensitivity is best determined from the neoadjuvant setting, therefore we sought to determine if HR+ primary tumors are less sensitive to taxane chemotherapy than HR- tumors. Methods: Clinical stage II-III breast cancer patients from the UNC Neoadjuvant Database who received sequential AC and T chemotherapy were evaluated. Clinical and radiographic responses were determined after AC and again after T allowing intrapatient sensitivity comparison, and included RECIST-defined complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Hormone receptor status was determined at diagnosis, and subtypes included ER or PR positive, HER2 negative (HR+), ER and PR negative, HER2 positive (HER2+/ER-), and ER, PR and HER2 negative (TN). The ER or PR+, HER2+ group was too small for analysis. Patients who received neoadjuvant trastuzumab were excluded. Relationships of subtype and clinical response to AC and to T were assessed using Fisher's exact test. Results: 157 patients received neoadjuvant AC sequentially followed by T and were eligible for analysis. The majority of TN patients had PR to AC (56%), while the majority of HR+ patients had SD (54%). Of those with measurable disease after AC (n=127), a higher proportion of TN and HER2+/ER- patients had CR to T (43% and 45%, respectively) than HR+ patients (13%, p = 0.008 and p = 0.0393, respectively). While the majority of HR+ patients again had SD (52%), 42% responded to T. Conclusions: Our data suggests that TN and HER2+/ER- patients benefit more from neoadjuvant taxane chemotherapy than HR+ patients, however HR+ patients clearly derived benefit from T administered after AC.

[Table: see text]

No significant financial relationships to disclose.
Prognostic significance of PI3K mRNA expression in patients with operable high-risk breast cancer
Authors: Papaxoinis G. , Pectasides D. , Wirtz R. M. , Kotoula V. , Papadimitriou C. , Gogas H. , Aravantinos G. , Skarlos D. , Kalogeras K. T. , Fountzilas G.
Published: August 2020

577

Background: The aim of the study was to examine the prognostic and predictive significance of PI3K, AKT-1, mTOR, and PTEN mRNA expression and PIK3CA mutations in patients with operable high-risk breast cancer. Methods: Formalin-fixed paraffin-embedded tumor tissue blocks were available from 279 out of 595 operable high-risk breast cancer patients enrolled in a phase III clinical trial of E-T-CMF vs E-CMF. Updated clinical data were retrospectively used in the present translational research study. RNA was isolated followed by kinetic one-step quantitative RT-PCR for assessment of the expression of PI3K, AKT-1, mTOR, and PTEN. Mutations (E542K, E545K and H1047R) in the helical (exon 9) and the kinase (exon 20) domains of the PIK3CA gene encoding the catalytic p110 subunit of PI3K were investigated with custom Taqman SNP genotyping assays in 223 tumor DNA samples from the patient population enrolled in this study. Results: The two groups were well balanced concerning their basic characteristics except for grade (p = 0.015). The vast majority of hormone receptor positive patients (92%) received tamoxifen for 5 years, with LHRH analogs for premenopausal patients. The distribution of AKT-1 values was bimodal and therefore the 25th percentile was a natural cut-off. The median was used as a cut-off for all other genes. Mutations of the PIK3CA gene were detected in 51 patients (23%) (E542K in 8, E545K in 17 and H1047R in 26 patients). After a median follow-up time of 97 months, 93 patients (33%) had relapsed and 65 (23%) had died. High PI3K mRNA expression was associated with significantly shorter DFS (p = 0.044), irrespectively of the treatment arm. Multivariate analysis showed that high PI3K mRNA expression was an adverse prognostic factor for OS (HR = 2.14, 95% CI = 1.16–3.94, p = 0.015) and DFS (HR = 1.71, 95% CI = 1.09–2.68, p = 0.02), while PIK3CA mutations negatively affected OS (HR = 2.05, 95% CI = 1.07–3.95, p = 0.031). None of the other genes assessed was found to be of prognostic significance. Conclusions: High PI3K mRNA expression and PIK3CA mutations appear to be of adverse prognostic significance in patients with high-risk operable breast cancer.

No significant financial relationships to disclose.
Association between HER2/neu overexpression and calcifications in breast cancer
Authors: Christy C. J. , Rishi M. , Schwartz J. , Grube B. J. , Bossuyt V. , Philpotts L. , DiGiovanna M. P. , Tavassoli F. , Lannin D. R.
Published: August 2020

579

Background: HER-2/neu overexpression is an important parameter that influences prognosis and treatment for breast cancer. The purpose of this study is to explore the relationship between HER-2/neu overexpression and calcifications identified by either mammographic imaging or histologic examination. Methods: A retrospective review of the prospectively collected database was performed to evaluate the mammographic and histologic characteristics of all cases of invasive breast cancers diagnosed between 2003 and 2008. HER-2/neu positivity was defined as either overexpression by FISH analysis or 3+ staining on immunohistochemistry. Results: Of 502 invasive cancers, 165 (33%) had calcifications on mammography and 337 (67%) did not. HER-2/neu positivity was found in 63 (38%) of the calcification cases and 40 (12%) of the non-calcified cases (p < 0.001). This association persisted across all age groups and races and was independent of tumor size, nodal status, or hormone receptor status. Calcifications seen histologically also correlated with HER-2/neu overexpression, but the relationship was more complex. Among 155 cases with histologic calcifications seen within a ductal intraepithelial neoplasia (DIN) component, there were 45 (29%) that were HER-2/neu positive, compared with 67/414 (16%) that did not have calcifications within DIN (p < 0.001). If the calcifications were only within invasive tumor, the rate of HER-2/neu overexpression was less, 9/63 (14%). Univariate analysis demonstrated that tumor grade, necrosis, lymphovascular invasion and hormone receptor negativity were significantly associated with HER-2/neu overexpression (all p < 0.01). Multivariate logistic regression showed only the following factors to be significantly associated with HER-2/neu overexpression: grade of invasive tumor, presence of necrosis, progesterone receptor negativity in either the invasive or the in situ component, and mammographic calcifications. Conclusions: Recognition of the strong association between HER-2/neu overexpression and mammographic calcifications may have clinical usefulness and could lead to a better understanding of the underlying tumor biology of this important tumor marker.

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Cardiac effects when using trial-derived monitoring protocols for adjuvant trastuzumab: Results from a retrospective multicenter UK audit
Authors: Canney P. , Linsday C. , Wardley A. , Jones A. , Verril M. , Todd R. , Barrett-Lee P. , Keni M. , Robb S. , Plummer C.
Published: August 2020

582

Background: Guidelines for cardiac scanning in adjuvant Trastuzumab (T) trials were developed due to clinical concerns regarding cardiotoxicity, and these same guidelines are now used in clinical practice. This was a retrospective audit to assess adherence to these guidelines and characterise the nature and timescale of problems experienced with adjuvant T in clinical practice. Methods: A retrospective review of MUGA/ECHO results was conducted in patients who received adjuvant T for breast cancer. Data was compiled from five UK cancer centres: Glasgow, Manchester, Cardiff, The Royal Free hospital and Newcastle. Results: A total of 424 patients received at least one dose of adjuvant T between September 2005 and January 2008, using a HERA trial schedule. There were 262 with detailed information regarding treatment delays/withdrawals for cardiac reasons. 12% (32/262 pts) were withdrawn from adjuvant trastuzumab treatment for cardiac reasons, with another 11% (29/262 pts) experiencing at least 1 delay in treatment. Analysis of cardiac scan results for the remaining 162 pts suggested a total cardiac delay/withdrawal percentage of 14.4% (61/424 pts). There was no age effect with 15% (50/338) of <65 year olds experiencing cardiac delays/withdrawals compared to 18% (9/50) of ≥65 year olds. Preherceptin cardiac scan results did appear to be predictive of subsequent problems, with 29% (38/132 pts) who had an ejection fraction (EF) of 40–59% experiencing cardiac delays/withdrawals compared to 10% (19/183 pts) with an EF of 60–69% and 4% (4/98 pts) with an EF ≥ 70%. Pretreatment with Doxorubicin was associated with an approximate doubling of cardiac problems (6/20 pts; 30%) compared to pretreatment with Epirubicin containing chemotherapy regimens. No temporal relationship existed between timing of cardiac delays/withdrawals and stage of T treatment. Conclusions: Significant numbers of patients are experiencing delays/withdrawals during adjuvant T treatment. In routine practice the withdrawal rates are more than twice those reported in the HERA trial population. There is a clear role for a re-assessment of the trial-derived cardiac management guidelines, which should be prospectively audited.

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Adding cisplatin to an anthracycline-based primary chemotherapy in triple-negative (TN) and non-triple negative (non-TN) T4 breast cancer patients (pts): Long-term outcomes
Authors: Ionta M. , Atzori F. , Murgia M. , Frau B. , Barca M. , Coinu A. , Trogu A. , Eltrudis F. , Minerba L. , Massidda B.
Published: August 2020

583

Background: Clinical data demonstrated that standard anthracycline-based chemotherapy may be less beneficial in TN. Conversely, there is extensive preclinical work showing that TN tumors are highly sensitive to platinum agents. Only a few studies compared cisplatin vs non-cisplatin containing regimens among TN or non-TN homogeneous populations. The aim of this study was to evaluate the efficacy in terms of long-term outcomes of adding cisplatin to an anthracycline-based neoadjuvant regimen (cisplatin, C) compared with a standard anthracycline-based (Non-C) regimen in T4 breast cancer according to TN or non-TN status. Methods: We retrospectively analyzed 125 consecutive T4 breast cancer pts available for ER/PR and HER2 status; 98 pts (80%) were non-TN, of whom 63 treated with Non-C and 35 treated with C regimen; 27 pts (20%) were TN, of whom 10 treated with Non-C and 17 treated with C regimen. All pts received CMF, RT and hormone-therapy if indicated as adjuvant setting. None of the HER2 positive pts received peri-operative trastuzumab. Results: At a median follow-up of 101 months (8–217), estimated 10-year DFS and OS in TN pts treated with C were 47% and 59% versus 10% and 30% in pts treated with Non-C. In non-TN pts DFS and OS were 57% and 70% in pts treated with C versus 37% and 49% in pts treated with Non-C. Conclusions: Our data suggest that both TN and non-TN pts derive a better outcomes from the add of cisplatin over a standard anthracycline-based regimen. Of note, the magnitude of the benefit of cisplatin appears greater in the TN group. In order to validate these findings large prospective randomized trials are warranted.

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No significant financial relationships to disclose.
Evaluation of Adjuvant! Online to predict the effect of optimal endocrine therapy (ovarian function suppression plus tamoxifen) for premenopausal breast cancer patients with estrogen-receptor-positive breast cancer
Authors: Paridaens R. J. , Gelber S. , Cole B. F. , Gelber R. D. , Thürlimann B. , Price K. , Holmberg S. , Crivellari D. , Coates A. S. , Goldhirsch A.
Published: August 2020

585

Background: Adjuvant! Online (AOL) is a user-friendly, web-based tool that provides estimates of adjuvant therapy outcomes for individual patients. While reliable evidence underpins estimates for most patient cohorts, there is a paucity of data on the effect of adding chemotherapy to complete estrogen blockade for premenopausal women with estrogen-receptor positive breast cancer. Methods: International Breast Cancer Study Group (IBCSG) Trial 11–93 enrolled 174 premenopausal women with estrogen-receptor positive, node-positive breast cancer from 1993 to 1998. Fifty percent of patients had 1 positive axillary lymph node and 97% had between 1 and 3 positive nodes. Patients were randomized to receive ovarian function suppression plus five years of tamoxifen with or without chemotherapy. The estimated hazard rates and corresponding 10-year relapse-free survival percents obtained from Trial 11–93 data (Breast Cancer Res Treat. 2009;113:137–144) were compared with those predicted using AOL. Results: The 10-year relapse-free survival percents predicted from AOL were 64.4% (95% CI, 61.9% to 67.2%) for endocrine therapy alone and 74.9% (95% CI, 73.1% to 76.8%) for chemoendocrine therapy. By contrast, these estimates in Trial 11–93 were 76.4% (95% CI, 65.8% to 84.0%) for endocrine therapy alone and 74.9% (95% CI, 64.5% to 82.7%) for chemoendocrine therapy. The AOL estimate for the endocrine alone control group is lower than that observed in Trial 11–93 (p = 0.03), while the estimates for the two chemoendocrine therapy groups are similar. Conclusions: AOL appears to underestimate the effectiveness of adjuvant endocrine therapy alone for premenopausal women with endocrine responsive breast cancer, thus overestimating the added benefit - if any - from chemotherapy for this patient population. Prospective clinical trials addressing the question are warranted.

No significant financial relationships to disclose.
Neoadjuvant exemestane for 24 weeks in postmenopausal women with hormone receptor positive stage II or IIIA breast cancer (JFMC34–0601)
Authors: Sato N. , Masuda N. , Saji S. , Takei H. , Yamamoto Y. , Sasano H. , Toi M.
Published: August 2020

591

Background: Exemestane (EXE) is a steroidal aromatase inhibitor and has shown efficacy for not only metastatic breast cancer but also for primary breast cancer situation. Recently it is reported that preoperative treatment with EXE for 24weeks (wks) is more effective than 8 or 16wks. This study aimed to evaluate 24wks treatment of EXE in the neoadjuvant setting for hormone receptor positive, stage II/IIIA, postmenopausal breast cancer. Methods: Stage II/IIIA pts were eligible with confirmed invasive breast cancer and ER/PgR status using needle biopsy. Primary endpoints were ORR and Safety. EXE 25mg/day was administered, and if pts were evaluated CR, PR, SD at 16wks, 8wks treatment was added. Additionally rates of breast conserving surgery (BCS), nodal status, biomarker changes and the relationship between response and survival are being investigated. Results: Between March 2006 and January 2008, 116 pts were enrolled (stage IIA:77%, IIB:20%, III:3%). All pts were ER +, and 80 (69%) were PgR+, and 29 (27.1%) were HER-2+, respectively. At 24 wks, 109pts were evaluable. OR rate was 53% (58/109) and SD rate was 39% (43/109) by investigator's evaluation. Two pts withdrew due to the adverse events. At diagnosis 14 pts would have required mastectomy and after treatment only 5 pts underwent mastectomy. Central pathological review exhibited that biomarker changes during the treatment correlated with tumor response. Conclusions: EXE has shown attractive response for hormone receptor positive breast cancer in neoadjuvant setting. Especially 24wks treatment seems effective with sufficient safety and tolerability. Additional investigations are conducted to explore predictive biomarkers for response and survival.

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