HR-negative Breast Cancer Research Articles

Divergent breast cancer incidence trends by hormone receptor status in the state of Sarawak, Malaysia.

Recent studies from high-risk countries such as the US, Denmark and Ireland have shown rising incidence rates of hormone receptor (HR)-positive and falling rates of HR-negative breast cancers (BC). However, it remains unclear whether a similar pattern occurs in low-risk countries. Detailed clinical and risk factor data were collected from 2,977 female invasive BC patients (≥20 years) in Sarawak General Hospital, Malaysia, representing 93% of the population. The population-at-risk was obtained from the Department of Statistics Malaysia. Secular trends in age-standardized incidence rates were assessed using estimated average annual percent changes. Associations between established BC risk factors and tumor subtypes defined by HR or joint human epidermal growth factor receptor 2 (HR/HER2) status were examined by case-case comparisons using logistic regression. From 2006 to 2015, incidence rates increased for HR-positive cancers by 4.46%/year (95% CI = 2.19-6.78) and decreased for HR-negative cancers by 2.29%/year (95% CI = -4.31 to -0.24). When further stratified by HER2, the most contrasting difference in linear trends was observed between HR+/HER2- and HR-/HER2- subtypes. After controlling for potential confounders, cases with excess body weight (ORoverweight vs. normal = 0.82; 95% CI = 0.69-0.98; ORobese vs. normal = 0.62; 95% CI = 0.48-0.80), later age at first birth (OR≥26 years vs. <23 years = 0.82; 95% CI = 0.66-1.02), nulliparity (ORnulliparous vs. <23 years = 0.74; 95% CI = 0.59-0.94) and never-breastfeeding (ORnever vs. ever = 0.73; 95% CI = 0.55-0.97) were less frequent among HR-negative cases than among HR-positive cases. Diverging incidence trends by HR expression were similar in Sarawak and Western countries, possibly reflecting changes in the prevalence of risk factors with opposing effects by tumor subtypes in low- and high-risk populations.

Low Positivity for Hormone Receptors in Early Breast Cancer: Therapy-Response and Prognosis -A Systematic Analysis of a Total of 9027 Patients

Low Positivity for Hormone Receptors in Early Breast Cancer: Therapy-Response and Prognosis -A Systematic Analysis of a Total of 9027 Patients

Anthracycline could be essential for triple-negative breast cancer: A randomised phase II study by the Kanagawa Breast Oncology Group (KBOG) 1101

BackgroundIt is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment. MethodsThe study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated. ResultsOf the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively). ConclusionTC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC.

Role of Renin-Angiotensin-System in Human Breast Cancer Cells: Is There a Difference in Regulation of Angiogenesis between Hormone-Receptor Positive and Negative Breast Cancer Cells?

Objective This study examined the role of the RAS in human breast cancer cells to question if there are differences between HR-positive and HR-negative cells with regard to regulation of VEGF. Methods Expression of different RAS components in hormone receptor (HR)-positive and HR-negative breast cancer cells was investigated using RT-PCR. Different stimulation protocols with different RAS inhibitors were used to investigate the effect on VEGF expression. Angiotensin II-dependent expression of VEGF was quantified by real time PCR. In addition, the effect of intrinsic RAS was studied performing siRNA knockdown of angiotensinogen (AGT). Statistical analysis were calculated using IBM SPSS Statistics Version 21. Results Expression of AT 1 R, AT 2 R, AGT and ACE was shown in HR-positive and HR-negative breast cancer cell lines. Extrinsic stimulation with angiotensin II increased VEGF significantly. After treatment with captopril or AT 1 R-inhibitor candesartan, VEGF-expression decreased significantly in HR-positive and HR-negative cell lines. However, inhibition of AT 2 R using PD 123,319 did not show any significant changes of VEGF. After prevention of intrinsic angiotensin II, extrinsic angiotensin II as well as the combination with inhibitors of the receptors caused a significant reduction of VEGF. Surprisingly, the overall effect of the RAS after knockdown of AGT revealed a significant increase of VEGF in HR-positive cells at any time while a significant decrease was observed in HR-negative cells after 144 hours incubation. Conclusion The RAS-dependent regulation of VEGF between HR-positive and HR-negative breast cancer cells seems do be different. These findings provide evidence for a possible future therapeutic strategy.

Phase II study of preoperative chemotherapy versus standard postoperative chemotherapy in HR-negative HER2-positive breast cancer patients.

e12118 Background: HR-/HER2+ breast cancer is a subtype with aggressive characteristic and poor survival. More clinical evidence are needed for choice of therapeutic strategies. Methods: Patients with T1-3N0-3M0 received preoperative chemotherapy (PTX 175 mg/m2, CBP AUC 4, q2w*6) combined with trastuzumab (2mg/kg qw) or standard postoperative chemotherapy such as ddAC-PH, AC-PH, TCH. The primary endpoint was RFS. Results: 86 patients were enrolled, 43 received preoperative chemotherapy (pre arm) and the other 43 received postoperative chemotherapy (post arm). There was no significant difference in baseline between the two arms. 22.1% of patients were stage IIA, 25.6% IIB, 34.9% IIIA, and 18.6% IIIC. At a median follow-up of 33.4 months, 16 patients had relapsed (pre arm 8, post arm 8). The median time from diagnosis to relapse was 22.8 months (7.1-49.2) and 23.8 months (11.4-37.4) in pre and post arm. Kaplan-Meier survival analysis estimated that the 3-year RFS were similar (pre vs post: 73.4% vs 75.4%, p= 0.631). Only 1 death occurred in post arm. Table showed that in subgroups, there was no statistical difference in risk of recurrence between pre and post arms. In pre arm, ORR was 97.7% clinically, and pCR (ypT0/TisN0) was 39.0%. No patients achieved pCR relapsed, and the residual invasive lesions indicated poor prognosis. Table showed that Neo-Bioscore 4-5 was related to recurrence event significantly ( p= 0.021). The rate of breast-conserving in pre arm was higher (19.5% vs 9.3%), and PCb regiments every 2 weeks had similar adverse effects with standard chemotherapy, and less patients had dose reductions (18.6% vs 25.6%). Conclusions: Preoperative chemotherapy versus standard postoperative chemotherapy results in similar RFS among HR-/HER2+ patients. Preoperative chemotherapy can identify prognosis of patients early by Neo-Bioscore and adjuvant therapy should be strengthened for high-risk patients. PCb every 2 weeks combined with trastuzumab can be an option of preoperative therapy for HER2+ breast cancer. Clinical trial information: NCT02934828. [Table: see text]

Elevated tumor mutation burden and immunogenic activity in patients with hormone receptor-negative or human epidermal growth factor receptor 2-positive breast cancer.

Immunotherapy has been found to be efficient in a variety of cancers and, therefore, may be a promising strategy for breast cancer (BC), particularly due to the limited therapeutic options currently available for triple-negative BC (TNBC). However, heterogeneity of tumor mutation burden (TMB), immune gene expression and mismatch repair (MMR) gene activity across BC subtypes has not been well characterized. In the present study, a comprehensive analysis of TMB, expression levels of immune cell type marker genes, and expression levels of MMR-associated genes was performed. A total of 5 MMR-associated genes, including MLH1, MLH3, MSH2, MSH6 and PMS2, were analyzed. Patients that harbored at least two MMR genes with expression levels in the lower 10% percentile across the cohort were considered as potentially aberrant (lost expression). Hormone receptor (HR)-negative BC is associated with a higher TMB and immune gene expression compared with HR-positive BC [TMB, estrogen receptor (ER)-negative vs. ER-negative, 55 vs. 32, respectively; P=4.1×10−13; progesterone receptor (PR)-negative vs. PR-positive, 53 vs. 31, respectively; P<2.2×10−16]. By contrast, human epidermal growth factor receptor 2 (HER2)-negative BC tended to have a lower TMB and decreased immune gene expression compared with HER2-positive BC (TMB, HER2-negative vs. HER2-positive, 36 vs. 48, respectively; P=0.02). Furthermore, aberrant expression of MMR genes was found to be more common in HR-negative compared with HR-positive BC (P<0.001). Significantly higher expression levels of each immune marker gene of four major immune cell types were found in patients who were HR-negative compared with patients who were HR-positive (P<0.001). The findings of the present study suggest that HR-negative or HER2-positive BC exhibits elevated TMB and immunogenic activity, and immunotherapeutic options are recommended.

Abstract P1-02-04: Is asymptomatic surveillance after standard treatment beneficial? : A 10yr-survival analysis of recurrent breast cancer patients by detection method of recurrence

Abstract Surveillance of recurrence after standard treatment of breast cancer (BC) for early detection and it's impact on overall survival are known to differ depending on recurrent site. Current guideline recommends asymptomatic surveillance to only detect loco-regional recurrences. As the evidences depend on historical randomized clinical trials we aimed to address questions whether earlier detection might have impact on survival now that plenty of new treatment strategies can be offered. Also to give answers to heterogeneous surveillance strategy in real-world practice we performed a retrospective 10yr-survival analysis of a large cohort of recurrent BC patients according to their detection method. From 4188 operable breast cancer patients who completed standard treatment Asan Medical Center from 2006 to 2008 469 patients with recurrent BC were analyzed. Median disease free interval was 35.3 months (range 2.8-97.6) and overall survival (OS) was analyzed as time from initial diagnosis/surgery to death. Among 469 patients who developed recurrence 23.7% were local (ipsilateral breast skin chest wall) 22.6% were regional (ipsilateral axillary internal mammary lymph nodes) and 53.7% developed distant metastasis. 10yr-overall survival was analyzed according to recurrent site and it's detection method. Detection of recurrence were categorized as 'asymptomatic surveillance (N=162, 34.5%)' and 'symptom-guided (N=307, 65.5%)'. Asymptomatic screening method included mammography breast-ultrasound serum tumor marker (CA15-3) and systemic images (eg. chest X-ray bone scan PET scans). Symptom-guided detection rate for local regional and distant metastasis was 14.9%, 5.5% and 15.1% respectively. Overall asymptomatic vs symptomatic 10yr-OS did not differ (81.3 vs 78.8 months, p=0.778). Among patients with distant metastasis 10ys-OS was not significantly different (70.3 vs 66.7 months p=0.846) and was similar according to stage/subtype. Among patients with local recurrence only 10yr-OS was 95.1 months ('symptomatic' vs 'aymptomatic 94.4 vs 94.5, p=0.809) which may be insufficient number of events to show significant difference. Among regional recurrent BCs, longer OS was observed in asymptomatically detected patients than symptom-guided group (86.1 vs 63.4, p=0.004). In Cox regression analyses asymptomatic detection showed significant better survival (HR=3.9, 95%CI:1.6-9.5) and this observation was more evident in patients with hormone receptor(HR) negative primary BCs (69.9 vs 47.9, p=0.029). Intriguingly, only 8.6% (7/80) of regional recurrence were diagnosed by mammography. We observed survival benefit with asymptomatic screening in detecting regional recurrence especially in HR-negative primary BC patients. And role of systemic radiology even in advanced high risk breast cancer patients were limited. Although with limitation that surveillance method varied widely we emphasize the role of aymptomatic surveillance of regional nodal evaluation including breast-ultrasound. These findings are to be validated from a prospective clinical study along with using cutting edge modalities other than radiology which enable detection of micro-metastasis. Citation Format: Lee Y, Lee HS, Ahn SH, Son BH, Kim J, Lee SB. Is asymptomatic surveillance after standard treatment beneficial? : A 10yr-survival analysis of recurrent breast cancer patients by detection method of recurrence [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-02-04.

Early and late outcomes of bevacizumab plus chemotherapy versus chemotherapy alone as a neoadjuvant treatment in HER2-negative nonmetastatic breast cancer: a meta-analysis of randomized controlled trials.

PurposeTo better clarify the efficacy of neoadjuvant bevacizumab plus chemotherapy (BEV + CT) vs chemotherapy (CT) alone in the treatment of HER2-negative nonmetastatic breast cancer.MethodsPubMed, Embase, Web of Science, and Cochrane Library databases were searched for relevant articles published from January 1, 2000 to July 31, 2018. Review Manager software version 5.3 was used to perform this meta-analysis.ResultsSix randomized controlled trials matched the selection criteria, yielding a total of 4,354 patients with early outcomes and 3,777 patients with late outcomes. Pooled pathological complete response (pCR) and 5-year disease-free survival (DFS) rates were higher for the neoadjuvant BEV + CT group (OR =1.37 [1.19, 1.58]; P<0.001 and HR =0.84 [0.72, 0.98]; P=0.020, respectively), but 5-year overall survival (OS) rate showed no significant difference (HR =0.79 [0.55, 1.11]; P=0.180). Subgroup analysis showed that the pCR rate was significantly higher in both patients with hormone receptor (HR)-positive breast cancer (OR =1.30 [1.01, 1.66]; P=0.040) and those with HR-negative breast cancer (OR =1.52 [1.25, 1.83]; P<0.001) in BEV + CT group.ConclusionCompared with CT alone, neoadjuvant BEV + CT significantly improved the 5-year DFS rate of HER2-negative breast cancer patients, but showed no benefit in terms of 5-year OS rate.

Predictive value of genetic analysis for pathological complete response to preoperative treatment in HER2 positive, HR negative early breast cancer (PASSION trial)

We previously reported a potential predictive value of HSD17B4 hypermethylation for pathological complete response after preoperative trastuzumab plus chemotherapy in HER2-positive breast cancer. We will prospectively evaluate the predictive performance of HSD17B4 hypermethylation in patients with HER2-positive/HR-negative breast cancer treated with sequential chemo-radiotherapy. The primary endpoint is the rate of pathological complete response, defined as the absence of invasive and intraductal tumor cells in the breast at surgery, in breast cancer with HSD17B4 hypermethylation. If the pCR rates are extremely high, the ultimate breast-conserving treatment excluding the need for surgery could be a future treatment option. A total of 200 patients will be enrolled. This trial is registered at the UMIN Clinical Trials Registry as UMIN000028065 and is financially supported by the Japan Agency for Medical Research and Development, AMED.

Abstract P2-07-01: Integrative analyses of immunophenotypes and multi-omics profiles in breast cancers

Abstract The advent of immuno-oncology (IO) therapies has made it an imperative to characterize intratumoral immune microenvironment in addition to oncogenic alterations through molecular profiling of the tumor. To elucidate the baseline profiles of tumor infiltrating leukocytes (TILs) in breast cancer (BC) in the context of molecular subtypes and oncogenic alterations, we performed whole-exome sequencing (WES) and RNA-Seq of an Asian BC cohort (SMC) consisting of 178 treatment naïve primary tumors. A subset of 120 tumors was further analyzed by H&amp;E and IHC using a panel of 8 TIL markers (CD45, CD4, CD8, CD163, PD1, PD-L1, IDO1 and FOXP3). Using expression signatures representing distinct immune cell types, we classified an expression compendium of 2,781 tumor samples, including SMC and multiple cancers from TCGA, into three immune subtypes with high, medium and low levels of TILs. Basal and HER2 subtypes show higher levels of TILs than Luminal subtypes, consistent with observed clinical responses to checkpoint blockade in clinical trials. Moreover, Asian BCs were significantly enriched in TIL-high subtype (35.3%) compared to the primarily Caucasian TCGA BC cohort (20.2%) while 50.6% of the highly immunogenic Lung adenocarcinoma was TIL-high. We then applied machine learning methods to detect and quantify TILs from H&amp;E images of 120 SMC and 349 TCGA BC tumors. The expression signature analysis results were concordant with independently derived histology based TIL data. Taken together, our findings suggest that IO therapies may be more effective in HR negative BC subtypes and Asian BCs. Leukocyte exclusion (LE), an immunophenotype where TILs concentrate at the tumor periphery, has been linked to worse prognosis and resistance to IO therapies. Visual assessment of whole tumor IHC images identified LE patterns in 25% of SMC cases. We observed differential distribution of LE by molecular subtype and evidence for selective exclusion of immune cell subsets. Covariate analyses with clinical and molecular data while controlling for subtype as a confounder identified significant associations with tumor proliferation index, percent tumor purity and TP53 mutations. LE is also significantly associated with expression signatures of chemokine signaling, macrophages, angiogenesis and hypoxia, indicating that marked distinctions exist in both tumor intrinsic and microenvironment characteristics between TIL excluded and TIL infiltrated tumors. To validate these findings, we independently identified LE for 200 cases of TCGA BCs based on patterns of TILs extracted from H&amp;E images and saw significant concordance of covariate relationships identified between TCGA and SMC. Our study provided a rare comprehensive resource for studying tumor associated immunity in breast cancers by generating the integrated multi-omics and IO profiles for a large cohort of primary tumors. Comparative analyses revealed that TIL activities are highly variable across different intrinsic subtypes and geographic origins of BC, with potential implications for IO therapeutic application. Correlative analyses of immunophenotypes with molecular data further yielded insights into LE's role in immune escape and identified hallmark signatures for LE indicative of causal molecular mechanisms. Citation Format: Kan Z, Powell E, Ram S, Ching K, Ding Y, Vizcarra P, Nichols T, Hardwick J, Lee S-H, Cho SY, Choi Y-L, Yu J-H, Park YH. Integrative analyses of immunophenotypes and multi-omics profiles in breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-07-01.

Abstract 1767: Analysis of biomarkers and anthracycline benefit for hormone receptor-negative breast cancer: results from a randomized phase 2 neoadjuvant study (KBOG 1101 Study)

Abstract AIM: We compared 6 cycles of docetaxel and cyclophosphamide (TC6) with 3 cycles of 5-fluorouracil and epirubicin and cyclophosphamide followed by 3 cycles of docetaxel (FEC-D) as neoadjuvant chemotherapy for patients with hormone receptor (HR)-negative breast cancer (BC) to identify biomarkers requiring anthracycline treatment. Methods: In total, 103 patients with operable HR-negative BC were administered TC6 or FEC-D. Triple-negative BC was subdivided by CK5/6 and EGFR into basal- and non-basal BCs. The primary endpoint was pathological complete response (pCR). Secondary endpoints were safety, breast-conserving surgery ratio, disease-free survival, overall survival, and predictive factors (Ki-67, P-53, ALDH1 and TOP2A by IHC and TOP2A by FISH) for each regimen. Results: Of the 103 patients, 97 completed the study. Overall pCR was higher for patients treated with FEC-D (36%) than for those treated with TC6 (25.5%) (P=0.265). FEC-D was significantly superior to TC6 in basal BC (42.9% vs 13.6%; P=0.033), while no differences in HER2 and non-basal BCs. Aldehyde dehydrogenase 1 (ALDH1) positivity was inversely associated with pCR for both regimens, significantly for FEC-D (FEC-D: p=0.047, TC6: p=0.085). Patients who achieved pCR tended to have longer DFS (P = 0.287) and OS (P = 0.069). Patients with basal and non-basal BC treated with FEC-D had significantly better DFS (P = 0.016) and OS (P = 0.034) than those with TC6. Conclusion: We found TC6 was less effective than FEC-D for HR-negative BC because it was not sufficient to treat basal-BC. This suggests that DNA damaging agents like anthracyclines are required for treating basal-BC. Additionally, ALDH1 could be a marker for resistance to conventional chemotherapy. Citation Format: Takashi Ishikawa, Kazutaka Narui, Mari S. Oba, Akimitsu Yamada, Kumiko Kida, Mikiko Tanabe, Yasushi Ichikawa. Analysis of biomarkers and anthracycline benefit for hormone receptor-negative breast cancer: results from a randomized phase 2 neoadjuvant study (KBOG 1101 Study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1767. doi:10.1158/1538-7445.AM2017-1767

Abstract P5-16-04: A randomized phase II neoadjuvant study comparing docetaxel and cyclophosphamide (TC) with 5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel (FEC-D) for hormone receptor-negative breast cancer: The Kanagawa breast oncology group (KBOG) 1101 study

Abstract Purpose: This study aimed to evaluate response to neoadjuvant chemotherapy (NAC) for patients with hormone receptor-negative (HR-negative) breast cancer (BC) to identify subtypes that require anthracycline treatment. Methods: In total, 103 patients with operable HR-negative BC were registered. They were randomely assigned to administration of 6 cycles of docetaxel (75mg/m2) and cyclophosphamide (600 mg/m2) (TC6) or 3 cycles of 5-fluorouracil (500 mg/m2), epirubicin (100mg/m2), and cyclophosphamide (500mg/m2) followed by 3 cycles of docetaxel (100mg/m2) (FEC-D). Cytokeratin (CK) 5/6 and EGFR expression were used to identify basal and non-basal triple-negative (TN) BC. The primary endpoint was pathological complete response (pCR); secondary endpoints were safety, breast-conserving surgery, disease-free survival, and overall survival. Predictive factors of pCR for each regimen were also evaluated. Results: The pCR rate was 36% for FEC-D and 25.5% for TC6, which did not differ significantly (P=0.265). When TN BC was subdivided into basal and non-basal subtypes, the pCR rate in the basal subtype was significantly lower for TC6 (13.6%) than for FEC-D (42.9%) (P=0.033), but did not significantly differ in the non-basal (TC6, 36.4%; FEC-D, 25.0%) and HER2-positive (TC6, 41.7%; FEC-D, 35.7%) cases. The relative dose intensities of epirubicin and docetaxel in FEC-D and docetaxel in TC6 were 96.3±13.0%, 93.5±14.6%, and 93.9±16.3% (mean±SD), respectively. Occurrence of grade ≥2 adverse events was significant in FEC-D-treated patients. Poor appetite (P&amp;lt;0.001), nausea (P&amp;lt;0.001), vomiting (P&amp;lt;0.001), dysgeusia (P=0.03), and fatigue (P=0.05) were significantly more common for FEC-D than TC6. Patients treated with FEC-D experienced significantly more febrile neutropenia and anemia (P=0.016 and 0.017, respectively). The rates of breast-conserving surgery were 68.0 and 72.3% for FEC-D and TC6, respectively (P=0.641). Patients achieved pCR had better DFS (log rank test, P = 0.287) and OS (log rank test, P = 0.069), though not significant. Patients treated with FEC-D had better DFS (log rank test, P = 0.107) and OS (log rank test, P = 0.159), though not significant. Among patients with TN BC, those treated with FEC-D had significantly better DFS (log rank test, P = 0.016) and OS (log rank test, P = 0.034) than treated with TC6. Low ALDH1 expression and high topo IIα protein expression were strongly correlated with pCR in FEC-D, with odds ratios (ORs) of 4.33 [95% CI, 1.02–18.38] and 4.08 [0.97–17.2], respectively. ALDH1 was also associated with pCR in TC, OR=3.50 [0.84–14.6]. Other factors, including age, tumor size, nodal status, tumor grade, Ki67, p53, and TOP 2A status were not associated with pCR in either regimen. Conclusions:We found that TC6 was less effective than FEC-D for treating HR-negative BC because it was insufficient for TNBC, particularly for basal BC. This suggests that anthracycline is more important than taxane for basal BC. Additionally, ALDH1 could be a marker for resistance to conventional chemotherapy. Citation Format: Narui K, Ishikawa T, Shimizu D, Tanabe M, Sasaki T, Oba MS, Morita S, Nawata S, Kida K, Mogaki M, Doi T, Tsugawa K, Ogata H, Ota T, Kosaka Y, Sengoku N, Kuranami M, Saito Y, Suzuki Y, Suto A, Arioka H, Chishima T, Ichikawa Y, Endo I, Tokuda Y. A randomized phase II neoadjuvant study comparing docetaxel and cyclophosphamide (TC) with 5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel (FEC-D) for hormone receptor-negative breast cancer: The Kanagawa breast oncology group (KBOG) 1101 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-04.

Retrospective study of the efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab/pertuzumab (TCH-P) in nonmetastatic HER2-positive breast cancer.

Pertuzumab is FDA approved in the preoperative setting in combination with trastuzumab and chemotherapy, in women with nonmetastatic HER2+breast cancer. The TRYPHAENA trial (n=77) reported a pathologic complete response rate (pCR), i.e., ypT0ypN0, of 52% in patients treated with neoadjuvant (docetaxel, carboplatin, trastuzumab, & pertuzumab) TCH-P. Aside from this study, there is limited information regarding the safety and efficacy of TCH-P in the neoadjuvant setting. Our goal was to evaluate the safety and efficacy of neoadjuvant TCH-P in a non-clinical trial setting. Cancer data registry was utilized to identify patients with HER2+nonmetastatic breast cancer that received neoadjuvant TCH-P. pCR was defined as the absence of invasive or noninvasive cancer in breast and lymph nodes, i.e., ypT0ypN0. 70 patients with a median age of 52years met our inclusion criteria. Clinical staging was I-8.5%; II-68.5%; and III-22.8%. 60% of patients had hormone receptor (HR)-positive tumors. 23% (16/71) of patients required dose reduction for rash, diarrhea, neuropathy, or thrombocytopenia. Overall, no patients developed grade 3-4 left ventricular systolic dysfunction(LVSD); an asymptomatic reduction in LVEF of>10% was observed in three patients. The overall observed pCR rate was 53%. As expected, the pCR rate was higher in patients with HR-negative breast cancer than for patients with HR+ disease: 69% (20/29) vs. 42% (17/41), respectively. The axillary downstaging rate was approximately 53% (19/36). Neoadjuvant TCH-P, in a nonclinical trial setting, was associated with a pCR rate of 53% similar the reported rate in TRYPHAENA. Toxicity was manageable, with no patients experiencing symptomatic heart failure.

Impact of race and tumor subtype on second malignancy risk in women with breast cancer

PurposeWomen with breast cancer are at increased risk of second malignancy (SM). However, the impact of race and the hormone receptor (HR) status of the primary breast tumor on risk of SM are not known. The purpose of this study is to analyze the incidence of SM in women with a history of breast cancer according to race and HR status.MethodsIn the surveillance, epidemiology, and end results database, multiple primary standardized incidence ratio sessions were used to compare the incidence of SM in women with a history breast cancer to the cancer incidence in the general population. Analyses of SM by age, race, and hormone-receptor status were performed using the absolute excess risk (AER) and observed/expected (O/E) ratio.ResultsYounger black women (under the age of 50) were at greater risk of SM with an AER = 76.03 (O/E = 2.3, 95 % CI = 12.19–2.4) compared to younger white women who had an AER = 38.59 (O/E = 1.55, 95 % CI = 1.53–1.58). Older black women (50 years and older) had at an increased risk of SM with an AER = 42.26 (O/E = 1.3, 95 % CI = 1.26–1.34) compared to older white women who had an AER = 11.56 (O/E = 1.07, 95 % CI = 1.06–1.08). Second breast malignancy is the predominant SM in both black and white women. Women with hormone-receptor (HR)-negative breast cancer had higher risk of SMs with an AER = 43.53 (O/E = 1.41, 95 % CI = 1.38– 0.145–3.31) compared to women with HR-positive disease with an AER = 21.43 (O/E = 1.17, 95 % CI = 1.16–0.1.18). In HR-negative women, younger black women had an AER = 96.46 (O/E = 2.99, 95 % CI = 2.70–3.31), younger white women had an AER = 66 (O/E = 2.25, 95 % CI = 2.13–2.36), older black women had an AER = 58.58 (O/E = 1.45, 95 % CI = 1.34–1.57), and older white women had an AER = 20.88 (O/E = 1.14, 95 % CI = 1.11–1.18).ConclusionsBlack breast cancer survivors and women with HR-negative breast cancer are at increased risk of SM, which deserves further evaluation to understand the biological and clinical basis for this increased risk.

Neoadjuvant Bevacizumab plus Chemotherapy versus Chemotherapy Alone to Treat Non-Metastatic Breast Cancer: A Meta-Analysis of Randomised Controlled Trials.

PurposeResults from previous randomised controlled trials (RCTs) investigating whether the addition of bevacizumab to neoadjuvant chemotherapy (NAC) could statistically significantly increase the pathological complete response (pCR) and to identify which subgroup would benefit most from such regimens have produced conflicting results. This meta-analysis was designed to assess the efficacy and safety of bevacizumab plus chemotherapy compared with chemotherapy alone in the neoadjuvant setting.MethodsA literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane library was performed to identify eligible studies. The primary endpoint of interest was pCR. The secondary endpoints were clinical complete rate (cCR), surgery rate, breast-conserving surgery (BCS) rate, and toxicity. The meta-analysis was performed using Review Manager software version 5.3.ResultsNine RCTs matched the selection criteria, yielding a total of 4967 patients (bevacizumab plus chemotherapy: 50.1%, chemotherapy alone: 49.9%). The results of this meta-analysis demonstrated that the addition of bevacizumab to NAC significantly increased the pCR rate (odds ratio [OR] = 1.34 [1.18–1.54]; P < 0.0001) compared with chemotherapy alone. Subgroup analysis showed that the effect of bevacizumab was more pronounced in patients with HER2-negative cancer (OR = 1.34 [1.17–1.54]; P < 0.0001) compared with HER2-positive cancer (OR = 1.69 [0.90–3.20]; P = 0.11). Similarly, in patients with HER2-negative cancer, the effect of bevacizumab was also more pronounced in patients with HR-negative cancer (OR = 1.38 [1.09–1.74]; P = 0.007) compared with HR-positive cancer (OR = 1.36 [0.78–2.35]; P = 0.27). No significant differences were observed between the groups with respect to cCR, surgery rate, or BCS rate. Additionally bevacizumab was associated with a higher incidence of neutropenia, febrile neutropenia, and hand–foot syndrome.ConclusionsHigher proportions of patients achieved pCR when bevacizumab was added to NAC compared with when they received chemotherapy alone; acceptable toxicities were also found. Subgroup analysis demonstrated that patients with histologically confirmed HER2-negative and HR-negative breast cancer benefited the most.

High incidence of germline BRCA mutation in patients with ER low-positive/PR low-positive/HER-2 neu negative tumors.

The 2015 National Comprehensive Cancer Network guidelines recommend that genetic counseling and germline BRCA mutation testing be offered to women under age 60 with triple-negative breast cancer (TNBC). As a result of the 2010 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for breast cancer, patients with breast cancers that are estrogen receptor (ER) or progesterone receptor (PR) low-positive (1%-9% on immunohistochemistry) are no longer strictly considered to have TNBC and may not be referred for genetic counseling. However, the incidence of BRCA mutation in patients with hormone receptor (HR) low-positive breast cancers remains unknown, and current ASCO/CAP guidelines may result in undertesting for BRCA mutations. A prospectively maintained research database of breast cancer patients evaluated at The University of Texas MD Anderson Cancer Center between 2004 and 2014 was reviewed; 314 patients were identified with HER2/neu-negative breast cancers expressing ER and PR <10% with known BRCA mutation status. Three hundred fourteen patients had breast cancers expressing ER and PR <10%; 238 (75.8%) had HR-negative cancers (<1% ER and PR), and 76 (24.2%) had HR-low-positive cancers (1%-9% ER and/or PR). Among patients with HR-negative tumors, 86 of 238 (36.1%) had a BRCA1/2 mutation, whereas in the HR-low-positive group, 30 of 76 (39.5%) had a BRCA1/2 mutation. In multivariate analysis, HR status (<1% vs 1%-9%) was not significantly associated with BRCA1/2 mutations. The incidence of BRCA1/2 mutations is similar in patients with HR-low-positive breast cancer and patients with HR-negative breast cancer. Genetic counseling and BRCA testing should be offered to patients under age 60 who have HR-low-positive breast cancers. Cancer 2015;121:3435-43. © 2015 American Cancer Society.

Prognostic Implications of Tumor-Infiltrating Lymphocytes in Association With Programmed Death Ligand 1 Expression in Early-Stage Breast Cancer

BackgroundThe immune system might influence breast cancer (BC) prognosis. However, the relationship between programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocyte (TIL) profiles remains unclear with respect to BC subtypes. Patients and MethodsWe investigated the relationship between TIL profiles for CD8+ and forkhead box P3-positive (FOXP3+) and PD-L1 expression in primary tumor tissue using immunohistochemistry and the clinical outcomes in 2 patient cohorts at the National Cancer Center: 256 patients diagnosed with early-stage BC from January 2001 to December 2005 and 77 hormone receptor (HR)-negative BC patients diagnosed from January 2006 to December 2008. Clinical data were collected, including HR status, human epidermal growth factor receptor 2 expression, disease-free survival, and overall survival (OS). ResultsThe median patient age was 47 years (range, 28-78), and the median follow-up period was 9.8 years. Of the 333 patients, 186 (55.9%) had HR-positive and 125 (37.5%) had node-positive BC. We found a strong positive correlation between CD8+ TILs and FOXP3+ TILs (P < .001). CD8+ TILs were more abundant in tumors with low PD-L1 expression (P < .001), although no association was found between FOXP3+ TILs and PD-L1 expression. More CD8+ TILs were present in HR-negative than in HR-positive BC (P < .001), and PD-L1 expression was more frequent in HR-positive BC (P < .001). A greater number of CD8+ TILs (increase in quartile) was strongly associated with OS (hazard ratio, 0.61; 95% confidence interval, 0.39-0.95; P = .03) only in HR-negative BC when adjusted for various clinical factors. PD-L1 expression and FOXP3+ TILs did not exhibit such associations. ConclusionHigher CD8+ lymphocyte infiltration was related to lower PD-L1 expression and higher FOXP3+ TIL infiltration in BC. Higher CD8+ TIL expression was associated with prolonged survival only in those with HR-negative BC.

Serum 25-hydroxyvitamin D deficiency and increased risk of breast cancer among Korean women: a case-control study.

Despite the emerging literature supporting the beneficial role of vitamin D on various health outcomes including carcinogenesis, current evidence on the association between vitamin D and breast cancer is still largely inconsistent. Furthermore, this relationship is particularly under explored among Asian population. We conducted a large case-control study with Korean women. We obtained and compared serum 25-hydroxyvitamin D (25(OH)D) between breast cancer patients (N = 3634) and general population (N = 17,133). Moreover, we further examined the association between serum 25(OH)D and breast cancer risk stratified by menopausal status and hormone receptor (HR) status of the tumor. Adjusted odds ratio (OR) for breast cancer comparing women with deficient level of serum 25(OH)D to women with sufficient level of serum 25(OH)D was 1.27 [95 % confidence interval (CI) 1.15-1.39]. This association did not significantly vary by menopausal status [pre-menopause: 1.26 (95 % CI 1.09-1.45) vs. post-menopause: 1.25 (95 % CI 1.10-1.41)]. When stratified by HR status, the inverse association remained significant in both positive and negative statuses. However, this association was more pronounced in HR-negative breast cancer, particularly with triple-negative breast cancer patients (1.45, 95 % CI 1.15-1.82). Given the growing burden of breast cancer in Asia and dearth of studies examining the association between vitamin D and breast cancer risk in Asian women thus far, this study provides a meaningful evidence for potential preventive effect of vitamin D on breast cancer for this particular population.

Abstract 1899: Predictive factors of anthracycline or taxan based chemotherapy: Analysis from a randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy for hormone receptor-negative breast cancer

Abstract Background: Taxane-based regimens have been developed and used widely to treat breast cancer. It has therefore become important to identify subgroups of patients in which anthracyclines are indispensable. Thus, we had conducted a randomized phase II NAC study to compare a taxane with and without an anthracycline in hormone receptor (HR) negative breast-cancer subtypes and examined predictive factors for each regimen. Aim: To examine the predictive factors for six cycles of docetaxel and cyclophosphamide (TC6) compared with 5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel (FEC-D). Methods: Eligibility criteria were operable HR-negative breast cancer, age younger than 75 years and ECOG PS0-1. According to HER2 status, 103 patients were randomly assigned to TC (75/600 mg/m2) every 3 weeks ×6 or FEC (500/100/500 mg/m2) every 3 weeks ×3 followed by D (100 mg/m2) every 3 weeks ×3. Triple-negative (TN) breast cancer was subdivided by cytokeratin 5/6 and epidermal growth factor receptor into basal- and non-basal subtypes. The association of grade 3 pathological complete response (pCR) was examined with Ki-67, p53, aldehyde dehydrogenase (ALDH) 1 and topoisomerase 2A (TOP2A) by immunohistochemistry and TOP2A by fluorescence in situ hybridization) for each regimen. Results: Ninety-seven of 103 patients were analyzed successfully (50 for FEC-D and 47 for TC6). The pCR rate tended to be higher in FEC-D-treated patients compared with TC6-treated patients (pCR: 36.0 vs. 25.5%, n.s.). FEC-D treatment was significantly more effective than TC6 in basal-type (p=0.033) but not in non-basal and HER2 subtypes. ALDH1 was associated with resistance to both regimens (FEC-D: p=0.047, TC6: p=0.085) Conclusions: TC6 was not more effective than FEC-D in HR negative breast cancer. TC6 was significantly less active than FEC-D in basal subtype, and equivalent to FEC-D in HER2 and non-basal subtypes. ALDH1 could provide a marker for novel strategies such as stem cell-based therapies for breast cancer. The association of BRCAness with pCR is being investigated and will be presented at the meeting. Citation Format: Takashi Ishikawa, Kazutaka Narui, Kazuhiro Shimada, Kumiko Kida, Sadatoshi Sugae, Yasushi Ichikawa, Mikiko Tanabe, Itaru Endo, Mari S. Oba. Predictive factors of anthracycline or taxan based chemotherapy: Analysis from a randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy for hormone receptor-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1899. doi:10.1158/1538-7445.AM2014-1899

A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000-1,500mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50mg/day and 2.5mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease>6months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA+ldCM); median age was 55 (35-80); nearly all had visceral involvement. Despite dose escalation in 90% of patients, only 17 (57%) patients ever achieved MPA trough concentrations>50ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7%) had stable disease for>6months. Skin Nm23 expression increased after 4weeks of MPA+ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation.