bluuebunny/crossref_metadata_2025 huggingface dataset:
A study of pre-operative (neoadjuvant) letrozole in combination with bevacizumab in post-menopausal women with newly diagnosed operable breast cancer: A preliminary safety report
Authors: Forero-Torres A. , Percent I. , Galleshaw J. , Nabell L. , Carpenter J. , Falkson C. , Jones C. , Krontriras H. , De Los Santos J. , Saleh M.
Published: March 2020

11020

Background: Our preclinical studies suggest that up-regulation of tumor cell VEGF is a mechanism to subvert estrogen dependence in hormone responsive breast cancer resulting in reduced efficacy or acquired resistance; we hypothesized that the combination of Bevacizumab (an anti-VEGF MoAb) and hormonal therapy would be more effective than hormonal therapy alone for breast cancer. Methods: Post-menopausal patients with ER and/or PR positive and Her-2-neu negative operable (T2–4a-c/N 0–2/M0) breast cancer were enrolled. Patients received letrozole (2.5 mg po daily) and Bevacizumab (15 mg/kg IV q 3 wks). Patients were reevaluated every 6 wks for a total of 24 wks; patients with CR/PR/SD in the first evaluation continued in the trial; after an additional 6 weeks of therapy patients with PD or SD were taken off-study and only patients with PR/CR completed 24 weeks of therapy. Definitive surgery was performed at the discretion of the surgeon no sooner than 4 wks after the last dose of bevacizumab. Patients continued letrozole while waiting for surgery. Up to December 2006, 27 patients have been enrolled with 13 patients too early to evaluate. Results: The 14 patients off-study had a median age of 63 years (range; 56 to 79) and an ECOG score of 0 for all patients. None of the patients received therapy for breast cancer before enrollment in the trial. 11 patients were stage II and 3 patients stage III. No treatment-related severe adverse events were seen. Treatment related toxicities were: grade 3 hypertension (n=1), grade 2 hypertension (n=7), grade 2 fatigue (n=2), grade 2 joint pain (n=3), grade 2 hot flashes (n=2), grade 1 proteinuria (n=1); 2 patients were taken off-study because of uncontrolled hypertension occurring on initial infusion of bevacizumab (not evaluable for efficacy). Of the 12 patients evaluable for response, 2 patients had pCR, 8 PR and 2 PD (at 9 weeks and 16 weeks). There have been no problems with wound healing or bleeding related to surgery or progressive disease while awaiting surgery. Conclusions: Combination letrozole and bevacizumab has substantial clinical efficacy and is well tolerated. The combination therapy will be evaluated in a randomized Breast Cancer Research Consortium Trial.

[Table: see text]
Role of p53 mutations in clinical and pathological responses in an open-label study of capecitabine (C) and docetaxel (D) as neoadjuvant treatment for patients with recently diagnosed HER2-neu negative (HER2-) breast cancer (BC)
Authors: Truong S. , Patten N. , Tripathy D. , Gluck S. , Moisa C. , Wu L.
Published: March 2020

11022

Background: The tumor suppressor gene p53 plays a key role in multiple cellular pathways controlling proliferation, survival, and genomic integrity. Disruption of its function promotes checkpoint defects, genomic instability and inappropriate survival leading to uncontrolled proliferation of damaged cells. The relationship of p53 mutation status to the outcome of patients suggests that p53 mutation status is a potential prognostic and predictive indicator of survival. Immunohistochemical analysis cannot accurately identify p53 mutation status and cannot differentiate between the several functional defects that arise from mutations at specific sites of this multifunctional gene. Methods: The primary objective is to define the rate of pCR in the affected breast after neoadjuvant C+D±T for HER2- or HER2+ BC pts, respectively. Eligibility: infiltrating HER2- or HER2+ stage II/III BC with no evidence of metastases and no prior systemic or local primary treatment. Four 3-week cycles consisted of C 825 mg/m2 bid on days 1–14 and D 75 mg/m2 on day 1. HER2+ pts also received T 4 mg/kg x1 on day -1 followed by 2 mg/kg weekly. Enrollment of 99 HER2- patients is planned. The AmpliChip p53 test (Roche Diagnostics, in development), a DNA microarray-based sequencing method, was used to analyze the p53 mutation status. The AmpliChip p53 test is designed to detect all substitution single base changes and single base deletion in all coding regions of the p53 gene. The genomic DNA was extracted from a biopsy sample from each patient and 50–100 ng genomic DNA was used. Results: A total of 47 p53 mutations were found in 44 of 88 (50%) patients, including 32 missense, 6 frameshift, 8 non-sense, and 1 splice site mutation, and were widely distributed in exon 2, 4, 5, 6, 7, 8, 9 and 10. The p53 mutation status including the type and location will be analyzed in relation to clinical and pathological response. Updated data will be presented. Conclusions: The AmpliChip p53 test is a rapid, accurate, and standardized way to detect p53 mutations. These findings suggest that p53 mutations occur in at least 50% of recently diagnosed BC.

No significant financial relationships to disclose.
Anastrozole compared to tamoxifen as primary endocrine therapy for early operable primary breast cancer in the elderly
Authors: Ying M. , Agrawal A. , Winterbottom L. , Morgan D. A. , Ellis I. O. , Cheung K.
Published: March 2020

11025

Background: The optimal management of operable primary breast cancer in elderly is controversial. A high proportion of elderly patients refuse or are unfit for surgery. However the majority have oestrogen receptor positive (ER+) cancer and respond extremely well to endocrine therapy. The use of tamoxifen as primary therapy is well established but its efficacy has not been compared with the newer aromatase inhibitors in this setting. We present the clinical data of the use of anastrozole when compared with tamoxifen in elderly patients as primary therapy for operable breast cancer. Methods: During a period of 2 years, elderly patients with ER+ operable breast cancer (<5cm), who either refused or were unfit for surgery, were given primary endocrine therapy. Tamoxifen was given by default but anastrozole was used when there were contraindications (eg thromboembolic and gynaecological risks). All had disease assessable to UICC criteria and were followed up in a dedicated clinic. Only patients who had treatment for =6 months (except for those who progressed prior) were included for analysis. Results: A total of 93 patients fulfilled the criteria for analysis thus far and the results are summarised as follows: 58 were given anastrozole and 35 with tamoxifen. At a median follow-up of 14.8 months (6 to 57), 8 patients have progressed. The results are summarised as follows: CR = complete response PR= partial response SD = stable disease Treatment was well tolerated in both groups and no patients withdrew due to side effects. Conclusions: The use of primary endocrine therapy in ER+ operable breast cancer in the elderly is highly effective. In this observational non randomised study there was no difference in efficacy detected between tamoxifen and anastrozole at this time, as seen in adjuvant trials. This may be due to the fact that majority of ER+ cancer in the elderly are highly ER rich as shown by high semi-quantitative scoring of immunhistological assays, making the superiority of the aromatase inhibitors less apparent.

[Table: see text]

No significant financial relationships to disclose.
Gemcitabine and concurrent radiation as a salvage treatment of chest wall recurrence in breast cancer
Authors: Shaharyar A. , Alauddin Z. , Shabbir K. , Hafeez M. , Rehman E. U. , Abbasi I.
Published: March 2020

11027

Background: Chest wall recurrences are seen despite postoperative chemotherapy and radiotherapy. For patients with unresectable lesions who have previously received radiotherapy no standard treatment is available. We devised a protocol of low dose gemcitabine as radiosensitizer concurrent with low dose of radiation and conducted this study with the objectives to document the efficacy and toxicity of this protocol. Methods: From January 2003 to August 2005, 48 patients were included in this study. A histopthological or cytological evidence of chest wall recurrence was required. Females between 18–70 years, with previous modified radical mastectomy, post operative radiation and adjuvant chemotherapy were included. Patients with metastatic disease were excluded. Written informed consent was obtained. A dose of 150 mg / m2 of gemcitabine in 200 ml of normal saline was infused in 2 hour on day 1, 8, 15 and 22 of radiation. Radiation was delivered 2 hours after the completion of infusion. Conventional fractionation was used to deliver a total dose of 36 Gy given in 3.5 weeks. RECIST and RTOG criteria were used. Results: Twenty recurrences were related to the scar, 10 to the involved internal mammary lymph node region invading sternum and ribs and 18 were associated with the soft tissue masses outside the scar area. All patients were evaluable for response and toxicity. Complete response was seen in 6 (12.5 %) patients, (95 % CI, 13.87_37.16), partial response was seen in 30 (62.5 %) (95 % CI, 44.92 -71.40) with an over all response rate of 75 % (95 % CI, 70.57—91.40) Stable disease was seen in 9 (18.8 %) patients and disease progression in 3 (6.3 %) patients. Grade I skin reaction was seen in 15 (31.2 % ) patients grade II in 11 ( 22.9 % ) and grade III in 3 ( 6.3 % ) patients. No systemic toxicity was seen. Conclusions: Low dose gemcitabine and concurrent radiotherapy is a reasonable salvage treatment in chest wall recurrence in breast cancer patients who have previously received adjuvant chemotherapy and full dose of radiotherapy. This approach has acceptable toxicity.

No significant financial relationships to disclose.
A multicenter pilot study of adjuvant docetaxel, epirubicin and cyclophosphamide (TEC) in patients (p) with stage II/III and node-positive breast cancer (BC)
Authors: Mayordomo J. I. , Lorenzo A. , Modolell A. , Alvarez I. , Bayo J. , Machengs-M Centelles-K Villadiego I. , Rubio M. J. , Heras L. , Yubero A. , Gonzálvez M. L. , Valero J.
Published: March 2020

11029

Background: Based on wide experience with docetaxel, adriamicin and cyclophosphamide (TAC regimen) for adjuvant therapy of node-positive BC but taking into account the high incidence of febrile neutropenia and mucositis, we performed the present study with TEC aiming for a better toxicity profile at doses equipotent to TAC. Methods: 300 p with histological diagnosis of stage II-III BC, positive axillary lymph nodes, age 18 year old, ECOG PS 0–2 and adequate bone marrow, renal, hepatic and cardiac function were accrued after surgery. Prior chemotherapy, hormone therapy and radiotherapy for BC were not allowed. Treatment: T 75 mg/m2 iv d1, E 75 mg/m2 iv d1 and C 500 mg/m2 iv d1 every 21 days for 6 cycles. G-CSF 5 mcg/Kg /day s.c. was given on days 5 to 9. Results: Two hundred and one p having completed adjuvant therapy have been evaluated in this interim analysis. Median age: 53 years (range 25–77), ECOG PS 0/1 89%/11%, infiltrating ductal carcinoma 77%. Hormone receptor status was ER+ 79% and PR+ 60%. Surgery was mastectomy in 49% and conservative surgery in 51% of pts. Median number of positive axillary lymph nodes was 3. To date, 1,085 cycles were administered (median 6). Median relative dose intensity was 99% for T and 98% for E and C. There were 11 dose reductions for non- hematological toxicity and 4 for hematological toxicity. Toxicity: grade 3–4 neutropenia occurred in 15 p (7.5%), 8 of them were episodes of febrile neutropenia (4.0%). Other grade 3–4 toxicities per p were: leukopenia (7.0%), thrombocytopenia (0.5%), asthenia (6.5%), vomiting (4.5%), nausea (3.5%) and diarrhoea (3.0%). Four p (2.0%) discontinued therapy due to toxicity: 1 p with toxicodermic reaction, 1 p with hematological toxicity, 1 p with febrile neutropenia and 1 p with an allergic reaction to T. After study treatment, radiotherapy was administered to 63% of p and hormonotherapy to 66% of p. Conclusions: These preliminary results show that adjuvant TEC in p with stage II/III BC and positive axillary lymph nodes is feasible and well tolerated.

No significant financial relationships to disclose.
Increasing tripartite cooperation of ER-alpha, c-Src, and IGF-1R plays an important role in tamoxifen resistance
Authors: Shu Y. , Yin Y. , Guo R. , Gu Y. , Liu L. , Wang R.
Published: March 2020

11037

Background: Acquired resistance to tamoxifen is a serious therapeutic problem that limits its clinical benefit. The precise mechanisms for acquired tamoxifen resistance, however, are still not fully understood. Our prior studies suggest that enhancement interaction between growth factors and ERa was associated with development of tamoxifen resistance. Cross-talk between growth factor receptors and estrogen receptor alpha (ERa) makes this problem more complicated. We hypothesized that some other proteins may be involved in this association between two kinds receptors in the development of TAM resistance. Methods: To test our hypothesis, MCF-7 breast cancer cells were continuously treated with TAM (10–7 M) until the cells resist to tamoxifen treatment, which were named as tamoxifen resistant cells (TAM-R). Results: TAM-R cells were more sensitive to E2 and IGF-1 stimulation to express higher level phospho-MAPK than that of control cells. Inhibitory effect of AG1024 on TAM-R cells was about as 2 folds as many as that of control cells. MAPK inhibitor caused dramatic inhibition of growth of TAM-R cells. It was interestingly found that ERa translocated from nucleus to cytosol and an increased amount of ERa was co-immunoprecipitated with IGF-1R from TAM-R cells even though there was no change in the levels of these receptors compared to the control cells. c-Src was an important adapter protein between these two receptors, which increasingly combined with both IGF-1R and ERa in TAM-R cells. Pure antiestrogen ICI, AG1024/IGF-1R SiRNA, and Src family inhibitor PP2 could inhibit the interaction between IGF-1R and ERa. However, only PP2 could completely inhibit ERa translocate from nucleus to cytosol and cytoplasm membrane. Conclusions: Our results suggested that IGF-1R/MAPK signaling pathway was very important for TAM-R cells to develop resistance. c- Src was an critical elements to form a ternary complex with IGF-1R and ERa. This may be one mechanism responsible for tamoxifen resistance in breast cancer cells.

No significant financial relationships to disclose.
Docetaxel (T) + capecitabine (X) with or without trastuzumab (H) neoadjuvant therapy for locally advanced breast cancer (BC): Phase II study
Authors: Lybaert W. , Wildiers H. , Neven P. , Amant F. , Christiaens M. , Van Limbergen E. , Weltens C. , Drijkoningen R. , Debrock G. , Paridaens R.
Published: March 2020

11042

Background: In MBC, adding X to T improves RR, TTP and OS; adding X to TH improves TTP. XT±H is appealing in early BC because H serum concentrations fall during the peri-operative period, potentially reducing the risk of overlapping cardiac toxicity with adjuvant anthracyclines. Methods: Pts with newly diagnosed invasive stage III inoperable BC (cT4 and/or cN2–3) received six 21d cycles of oral X 900 mg/m2 bid d1–14 + iv T 36 mg/m2 d1&8 (+ H on d1 in pts with HER2+ [IHC 3+/FISH+] tumors: 8 mg/kg cycle 1, 6 mg/kg cycles 2–6). After surgery, pts received 4–6 cycles of FEC100 and radiotherapy (+ hormone therapy and H when indicated). Clinical response was assessed after cycles 3 and 6, safety after each cycle, and pathological complete response (pCR: no residual invasive tumor in breast and axilla) after surgery. Results: 71 of 89 planned pts have completed XT±H (Table); 64 have undergone surgery (53 mastectomies, 9 wide excisions, 2 axillary lymph node dissections only). 51 pts are evaluable for safety. The most common treatment-related adverse events (AEs; G1- 2/G3) were stomatitis (61%/8%), nausea (61%/6%), diarrhea (41%/22%), fatigue (57%/4%), neuropathy (59%/0), lacrimation (57%/0) and hand- foot syndrome (33%/16%). Other G3 AEs were anorexia (14%) and vomiting (10%); neutropenic fever occurred in 4 pts (8%). 24 pts had a dose reduction for G2–3 AEs (X 47%, T 27%). 7 pts stopped therapy prematurely for AEs. No unexpected AEs occurred with anthracycline-based adjuvant therapy. Conclusions: Although all pts experienced at least one AE, toxicity was predictable and manageable with dose reduction. Based on the encouraging efficacy of XT+H in HER2+ pts, we are expanding this arm.

[Table: see text]

No significant financial relationships to disclose.
Treatment of invasive lobular carcinoma with breast conserving therapy
Authors: Tulusan A. H. , Bühner M. , Popovich M.
Published: March 2020

11046

Background: Invasive lobular carcinoma (ILC) is the second most common histological type of breast carcinoma .There is still a persisting concern regarding the use of breast-conserving therapy(BCT) in patients with ILC.Difficulty to identify the exact size , location of ILC and multifocality and/or multicentricity are the reasons to suggest that patients with ILC might be poor candidates for BCT. The aim of our current study was to evaluate the possibilty of risk adapted BCT for patients with ILC with or without breast irradiation. Methods: 277 patients with ILC pure or mixed type between 1994 and 2006 were accrued for pospective risk adapted therapy. Contraindications for BCT are multicentricity , inability to obtain negative margins or poor cosmesis. Palpation, mammograpy,ultrasound were routinely done and preoperative MRI in cases with no sharp tumor image. Breast conserving surgery was standardised by performing a radial segmental resection. Inking margins,histological semiserial step sections and specimen radiography was done. Sharp dileneated ILC with a free margins of >/= 1cm and no lymphvesel invasion(LVI) were treated by BCT without breast irradiation(Rx). Patients with ER + were treated with endocrine therapy.Mean follow-up time was 74 months. Results: Of the 277 ILC cases , 55(19,8%) were treated by mastectomy and five patients palliatively because of distant metastases. 217 ILC (79%) were treated with BCT (T1:108/48%;T2:45(21%);T3:67/31% ; NO:135/62%; ER+: 295/94%). 6 patients(2,8%) had local recurrence(LR). 161 ILC (T1 38%; T2 22%; T3 39%; N0 55%) were treated with BCT with Rx. Patients mean age was 57 years. 6(3,7%) of the patients had local recurrence (4 LR only, 2 LR and distant metastases). 56 ILC (T1 69%; T2 15% T3 22% ; NO 81%) were treated with BCT without Rx. Mean age 66 years. There were no LR , 2 patients had distant metastases. Conclusions: Using strict selecting criteria with a standardized breast conserving surgical procedure, thorough histological examination and using all breast imaging possibilities risk adapted BCT for ILC are not more likely to fail than BCT of other types of breast cancer. These results support the use of BCT for ILC patients.

No significant financial relationships to disclose.
Biweekly nonpegylated liposomal doxorubicin (M) and docetaxel (T) as neoadjuvant treatment in patients with stage II-III breast cancer
Authors: Alvarez I. , Modolell A. , Mayordomo J. I. , Janariz J. , Centelles M. , García J. M. , Puerto P. , Diego C. , Madroñal C. , Burillo-R Andres M. A.
Published: March 2020

11049

Background: We have previously reported (ASCO 2006) the efficacy and toxicity of 4 courses of M (75mg/m2) and T (75mg/m2) with G-CSF support in a 21 day schedule as neoadjuvant treatment in patients with resectable breast cancer. Aim: To evaluate the clinical and pathological response rate (RR) and toxicity of biweekly M and T given prior to surgery in patients with breast cancer. Methods: Patients with histological confirmation of breast cancer (stage II-III and inflammatory), age >18 years, left ventricular ejection fraction > 45% and adequate bone marrow, renal and hepatic function were included in the study. Prior systemic therapy, radiotherapy or surgery for breast cancer were not allowed. The treatment was: M (60 mg/m2) and T (60mg/m2) each in 1 hour infusion, with subcutaneous G-CSF (5 mcg/kg) support on days 4–9. Courses were repeated every 14 days. Patients received 6 courses prior to surgery. Results: To date 45 patients have been enrolled; 20 who have completed therapy and underwent surgery (except for patients with progression) were included in this interim analysis. Median age: 48 years (38–63), ECOG PS 0: 90%, ECOG PS1: 10%, postmenopausal: 35%. Histology was infiltrating ductal carcinoma in 80%. Patients received a total of 110 courses (median 6, range 2–6). Efficacy: Of 19 evaluable patients, 4 achieved a clinical complete response (cCR) (21%), 12 partial response (cPR) (63%), 1 stable disease (cSD) (5%) and 2 progressive disease (cPD) (10%), resulting in a clinical response rate (cRR) of 84%. Surgery was performed in 17 (85%) patients, 4 (23%) of them had pathological complete response (pCR), 12 (70%) partial response (pPR), 1 (6%) stable disease (pSD), resulting in a pathological RR of 93%. Median time to progression and overall survival have not been reached. Toxicity: Hematological grade III/IV toxicities per patient were neutropenia (10%), febrile neutropenia (10%) and thrombocytopenia (5%). Non-hematological grade III/IV toxicities per patient were mucositis (10%), nausea/vomiting (10%) and epigastralgia (10%) Conclusions: Six courses of T and M every 14 days with G- CSF support as induction treatment in stage II and III breast cancer are active and well tolerated.

No significant financial relationships to disclose.
Screening for clonal hematopoiesis as a predictive marker for development of t-AML following adjuvant therapy for breast cancer (S0012)
Authors: Slovak M. L. , Bedell V. , Lew D. , Albain K. S. , Ellis G. K. , Livingston R. , Martino S. , Perez E. , Sher D. , Stock W.
Published: March 2020

11051

Background: A serious complication associated with breast cancer treatment is the increased risk for development of therapy-related acute myeloid leukemia (t-AML). To evaluate and possibly identify patients (pts) at high risk for development of t-AML, the Southwest Oncology Group asked whether dose-intensive adjuvant regimens for high risk breast cancer pts induced genetic damage to hematopoietic stem cells (HSC), defined by the emergence of clonal hematopoiesis, an early marker of HSC damage. Methods: 274 pts consented to the clonal hematopoiesis study objective of S0012, a randomized clinical trial of standard doxorubicin and cyclophosphamide followed by weekly paclitaxel (arm 1, 129 pts) vs. weekly doxorubicin and daily oral cyclophosphamide plus G-CSF followed by weekly paclitaxel (arm 2, 145 pts) as neoadjuvant therapy for inflammatory and locally advanced breast cancer. Two different clonality assays were used: the HUMARA (HUMan Androgen Receptor) Assay to estimate the incidence of early genetic damage by clonal proliferation and microsatellite instability (MSI) testing at 5 loci (Bat 26, Bat 40, APC, Mfd, D2S123), common ‘hotspots‘ in t-AML, to screen for loss of heterozygosity or defective DNA mismatch repair mechanisms. Blood samples were evaluated prior to treatment and at 6 and 12 mos post-surgery for emergence of clonal hematopoiesis. Results: Of the 274 pts enrolled, follow-up clonal hematopoiesis samples were available for 195 pts; 96 pts on arm 1 and 99 pts on arm 2. Both HUMARA and MSI results were negative for clonal hematopoiesis in 96% of samples analyzed. In 14 cases, the HUMARA assay suggested that a clonal population was present, but MSI analysis was negative. No cases were HUMARA+/MSI+. With a median follow-up of 19.6 mos, only one pt has developed t-AML 3 yr 5 mos post randomization. Her clonal hematopoiesis test samples at 6 and 12 mos following treatment were negative. Conclusions: Clonal hematopoiesis assays performed within the first year following neoadjuvant therapy and surgery on S0012 failed to identify an emerging clonal HSC population. Longer clinical follow-up will be necessary to define the positive predictive value of detecting clonal hematopoiesis in the 14 HUMARA+/MSI- cases as a harbinger of t-AML.

No significant financial relationships to disclose.
Costs and benefits of dose-dense chemotherapy scheduling in Hong Kong Chinese patients with primary breast cancer
Authors: Tsang J. , Yau T. , Chan A. T. , Liang R. H. , Yeo W. , Epstein R. J.
Published: March 2020

11054

Background: Routine prophylactic administration of recombinant granulocyte colony-stimulating factor (G-CSF, filgrastim) has enabled more frequent scheduling of adjuvant cytotoxic drugs in primary breast cancer. Dose-dense chemotherapy of this kind has become popular in recent years, but few studies have compared the costs and benefits of this treatment approach. Methods: We conducted a retrospective comparison of 150 Hong Kong Chinese primary breast cancer patients treated with either conventional 3-weekly chemotherapy or G-CSF-supported 2-weekly (dose-dense) chemotherapy using similar cytotoxic regimens (four cycles of doxorubicin and cyclophosphamide, followed by four cycles of taxane) between April 2004 and May 2006 in two teaching hospitals. Assessments of treatment tolerance, toxicity, scheduling, and expense were applied to both patient cohorts. Results: Compared to conventionally treated patients (n = 117), dose-dense patients (n = 33) benefited from 52.3% fewer chemotherapy delays (21.2% vs. 44.4%; p = 0.02), 79.3% fewer hospital admissions for febrile neutropenia (3.0% vs. 14.5%; p = 0.07), and 54.8% enhancement of cytotoxic dose intensity (p < 0.001). Dose-dense patients also developed less nausea (p < 0.001) and stomatitis (p = 0.01) but more frequent bone pain (p < 0.001). After subtracting costs saved by fewer hospital admissions, dose-dense patients incurred higher total expenses approximating US$500 per cycle. Conclusion: Routine G-CSF administration to Hong Kong Chinese patients with primary breast cancer is associated with major improvements in cytotoxic drug delivery, which could plausibly translate into greater therapeutic efficacy in some patients. In addition, dose- dense treatment is shorter, safer, and more reliably scheduled, and is associated with unexpected improvements in nausea and stomatitis. The extent to which these gains justify the rise in net costs needs to be further defined in prospective randomized studies, both in different adjuvant patient subsets and in differently resourced socioeconomic contexts.

No significant financial relationships to disclose.
Recurrence and morbidity in patients undergoing sentinel lymph node biopsy in Japanese breast cancer patients
Authors: Fujiwara I. , Nakajima H. , Mizuta N. , Sakaguchi K. , Hachimine Y.
Published: March 2020

11062

Background: Aim of this study was to determine the axillary lymph nodes recurrence rate in breast cancer patients with tumor less than 5 cm (T2), who did not have axillary node dissection with negative sentinel lymph node (SLN). Methods: SLN biopsies were performed in 403 consecutive patients with breast cancer up to 5 cm and clinically negative axillary node from May, 2000, to December, 2005. SLN were identified using the combined method with sulfan blue dye and technetium 99m-labelled stannous phytate. SLN were examined with H&E staining. In patinets with negative SLN, additional axillary nodes dissection were avoided. Results: The SLN identification rate was 99.8% (402 out of 403). Three-hundred forty-one (341) patients (84.8%) who were found to have no metastatic disease, were observed and followed without further axillary dissection. At a mean follow-up of 35.7 months (range, 12–79 months), five of these patients (1.5%) developed an axillary recurrence. SLN biopsy was not associated with morbidity such as arm lymph edema. Conclusion: With intermediate-term follow-up, the axillary recurrence rate was low and there was none of morbidity. We conclude that SLN biopsy is a promising alternative to axillary lymph node dissection in patients with breast cancer up to 5 cm in Japanese women.

No significant financial relationships to disclose.
Aromatase inhibitor-induced joint symptom in patients with breast cancer
Authors: Yamamoto Y. , Kawasoe T. , Ibusuki M. , Kai K. , Tomita S. , Iwase H.
Published: March 2020

11070

Background: Aromatase inhibitor (AI) are superior to tamoxifen (TAM) for postmenopausal women with estrogen receptor (ER)-positive breast cancer. Toxic profiles are different between AI and TAM. The frequency of bone fracture and joint symptom are high in AI compared with TAM. However, there is little report concerning a detailed joint symptom. Methods: From January 2002 to March 2006, 120 postmenopausal women with ER-positive breast cancer were treated with anastrozole 1mg or exemestane 25mg daily at our hospital. We studied retrospectively the incidence, onset, type, sites, grade, and change of joint symptom. We also investigated the incidence of discontinuation due to joint symptoms and correlation between patient’s characteristics and joint symptoms. Results: Median follow-up time is 590 days and median age is 63 years old. Forty-seven (39.1%) of 120 patients complained of joint symptom. Median onset time of the symptom was 90 days of starting AI. All cases with the symptom complained of joint stiffness and 33 (70.2%) of 47 patients with the symptom have joint pain. In decreasing order, the most commonly affected sites were hand, knee, wrist, ankle, shoulder and elbow. The joint symptom was mostly grade 1/2, and most symptom ware resolved with exercise. Most common feature is morning digital stiffness like initial symptom of rheumatoid arthritis. Some patients experienced severe joint symptom. Subsequently, 15 (12.5%) patients had to discontinue AI because of the severe symptom. Discontinuation of AI led to improvement of symptoms, and patients received TAM in stead of AI also led to resolution of symptoms. AI-induced joint symptom was significantly correlated with young age, prior chemotherapy and switching from TAM to AI. Conclusions: Most AI-induced joint symptom is modest, and this symptom can lead to resolution with exercise. However, some patients lead to discontinue AI because of AI-induced severe joint symptom. We should inform patients treated with AI about AI- induced joint symptom and observe patient’s symptom in detail because severe joint symptom can prevent maintenance of quality of life and compliance.

No significant financial relationships to disclose.
In vivo response-adapted dose-dense (dd) doxorubicin and cyclophosphamide (AC) –> weekly carboplatin and albumin-bound paclitaxel (nab-TC)/trastuzumab (H)/bevacizumab (B) in large and inflammatory breast cancer (BC): A phase II study
Authors: Bernstein J. A. , Mehta R.
Published: March 2020

11078

Background: We showed high pathologic complete remission (pCR) rate with dd AC weekly (wkly) cremophor(c)-TCH in HER2+ BC in contrast to dd AC c-TC in HER2- BC (SABCS 2005). We substituted nab-T for c-T, and added B in HER2- BC to exploit the known synergy between the two in preclinical models. Methods: Pts received in vivo response-adapted 2–4 cycles of AC with G/GM-CSF followed by wkly 9–12 nab-T at 100 mg/m2 and C (AUC of 2), 3 wks on, 1 wk off. HER2+ patients (pts) received concurrent 12–16 wkly H (4mg/kg induction, 2mg/kg maintenance) and HER2- pts received 6–8 bi-wkly B (10 mg/kg). 37 of the proposed 43 pts with stage II-IV BC have been enrolled. Median age is 53 (range 32–76). Results: Median ejection fraction by echocardiogram was 67% (55–78) at baseline, 65% (55–80) after 2 cycles of dd AC and 66% (55–68) following nab-TCH. Additionally, no clinical cardiac dysfunction demonstrated. Adverse event with dd AC included neutropenic fever in 2 pts. 8 of 88 dd AC cycles administered were delayed by =1 wk. Of the 37 pts evaluated, 30 were switched to nab-TCH/TCB after 2 cycles of AC for less than 50% tumor reduction and 7 completed 4 cycles. Adverse event with nab- TCH/TCB included grade III arthralgia in 2 pts and TIA in 1 pt. pCR was documented in 5 of 8 HER2+ after nab-TCH, and 3 of 10 HER2- tumors after nab-TCB. Across the spectrum of stage II-IV, inflammatory and lobular carcinoma, tumors were reduced to ≤ 5 mm in first 7 of 8 (87.5%) HER2+ and 8 of 10 (80%) HER2- BC. Progression free survival at a median follow-up of 6 months (range 2–15 month) remains 100%. Conclusion: Induction chemotherapy with dd AC followed by wkly targeted chemotherapy is well tolerated. Additionally, limiting the exposure of AC to 2 cycles in resistant BC may reduce the known cumulative cardiac toxicity and yet allow the targeting of different clones in a heterogeneous BC population.

[Table: see text]
Combination chemotherapy with gencitabine and cisplatin in anthracycline and taxane pretreated metastatic breast cancer
Authors: Peria F. M. , Zola F. E. , Tiezzi D. G. , Carrara H. H. , Philbert P. M. , Marana H. R. , Andrade J. M.
Published: March 2020

1108

Background: Metastatic breast cancer (MBC) anthracycline (A) and taxane (T) resistant has a complicated management.Combination chemotherapy, even in 2nd line, may have advantages over single agent therapy. Gencitabine (G) - cisplatin (C) combinations have been used as synergistic salvage therapy in MBC and it’s another option for patients with important symptoms and aggressive visceral disseminated disease. Methods: This trial analyses the safety and efficacy of G-C in A-T pretreated MBC. Eligibility criteria include: confirmatory pathological analyses; measurable disease; adequate performance status, organ and hematological functions. It was not allowed patients with exclusive bone metastasis. They received IV G 750mg/m2 and C 30mg/m2, both d1 and d8 every three weeks for 6 cycles up to a maximum of 9 cycles. Response evaluation was performed every third cycle and in the end of treatment. Results: From February 2005 through December 2006, 31 patients have been evaluated for response and toxicity from G-C combination. For 20/31 patients this treatment was 2nd line palliative chemotherapy. 26/31 received at least 3 or more cycles (medium 4 cycles) and no one treatment was discontinued due to toxicity. The most frequent site of metastasis was lung (20/31), followed by hepatic in 13 patients, bone in 11, skin in 10, lymph nodes in 7, brain metastasis in 3 and pericardium in only one. Each patient had at least lung or hepatic metastasis and medium of 2 different metastatic sites. According to RECIST criteria, partial response were observed in 8/31, stable disease in 17/31 (55%) and progressive disease in 6 patients. 90% of cycles were given at full dose and at the right time. Hematological toxicity was modest with grade 2–3 (NCI-CTC) leucopenia in 58/140 cycles, grade 1–2 anemia in 40/140, grade 1–2 thrombocytopenia in 27/140 and was none febrile neutropenia. Non hematological toxicity: grade 2 fatigue in 4 patients and grade 2 nausea in 6/31. Following 22 months, global survival was at mean 4.8 months. Conclusions: Combination chemotherapy with gencitabine 750mg/m2 and cisplatin 30mg/m2 both d1 and d8 is feasible and effective in A-T pretreated MBC and demonstrated good tolerance with low intensity of collateral effects.

No significant financial relationships to disclose.
Phase II study of primary chemotherapy with paclitaxel plus gemcitabine in patients with stage II and III breast cancer
Authors: Lee K. S. , Kwon Y. , Kang H. S. , Kim E. A. , Kim S. W. , Lee E. S. , Shin K. H. , Ro J.
Published: March 2020

11080

Background: Adding taxane in the preoperative therapy increases both clinical and pathologic responses in pts with early breast cancer (BC). Clinical outcomes were superior by adding gemcitabine (G) to paclitaxel (P) compared with P alone in metastatic BC. This study evaluated clinical and pathological response rates and adverse events by primary chemotherapy with P and G in stage II and III BC. Methods: Patients (pts) with histologically confirmed stage II and III BC with positve axillary nodes by PET or positive FNA under sono guidance, age = 18 years, adequate organ functions and good PS were eligible. No prior hormonal or chemo-therapy, radiation, or surgery was allowed. Pts received P 80 mg/m2 and G 1,200 mg/m2, intravenously, d1/d8 every 3 weeks x 4. Postoperatively, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2, intravenously, d1 every 3 weeks x 4 were given followed by radiation therapy. Assessment for clinical response was majorly done by ultrasound. Results: All planned 44 pts were enrolled between September 2005 and April 2006. The median age was 43 years (range, 30–72 years), the median primary tumor size was 5.5 cm (range, 2.1 to 12.4 cm) with 27%, stage II and 73%, stage III BC. Thirty three tumors (75%) were multiple and 25 %, single. Thirty tumors (68 %) were ER or PR positive and 32 %, HER2 IHC 3+. The median relative dose intensities were 0.97 for both P and G . Clinical responses were 1-CR (2%), 34-PR (77%), 7-SD (16%) and 1-PD (2%). One pt did not return after 1st cycle (2%). 43 pts underwent surgery with 28 (64%) breast conserving surgery. Eight pts achieved pathologic CR in primary tumors (18%), 11 in axillary nodes (25%), and 5 in combined tumor and axillary nodes (11%). Grade III/IV toxicities were neutropenia (57%), leucopenia (14 %), febrile neutropenia (2%), and headache (2%). Conclusions: Preoperative P and G combination therapy given on d1/d8 every 3 weeks for 4 cycles is well tolerable and effective for stage II and III breast cancer. Supported in part by NCC Grant No. 06102240 and SHIN POONG PHARM CO., LTD. which provided paclitaxel and gemcitabine.

No significant financial relationships to disclose.
Primary systemic chemotherapy for operable breast cancer with docetaxel followed by cyclophosphamide, epirubicin, and fluorauracil (DOC-CEF)
Authors: Kikawa Y. , Masai Y. , Hashimoto T. , Nakamoto Y. , Nishikawa H. , Takahara S. , Suwa H. , Tachibana T.
Published: March 2020

11085

Background: Primary systemic chemotherapy (PSC) for breast cancer has been considered to be useful controlling the micrometastasis and shown to increase the breast conserving surgery rate, result in similar survival rate as usual post-operative adjuvant chemotherapy. Recently, doxorubicin based regimen followed by taxan regimen in neoadjuvant chemotherapy has shown a high response rate and sequential administration is supposed to be important. However, taxan regimens sequentially followed by doxorubicin are not so common. The purpose of this study is to evaluate the efficacy of primary systemic chemotherapy with docetaxel followed by cyclophosphamide, epirubicin and fluoraouracil (DOC-CEF) in breast cancer. Methods: Since 2003, 80 women histologically proven as the primary breast cancer, measurable lesion >= 2cm or inflammatory breast cancer, age 20–75, PS 0–1 were enrolled. The patients received 4 cycles of DOC (75mg/m2) every 3 weeks followed by CEF (500mg/m2, 75mg/m2, 500mg/m2) every 3 weeks as the primary systemic chemotherapy. After administrations, clinical responses and tumor vascularities were recorded by ultrasonography and pathological responses were examined after surgery for all patients. Results: 57 out of 80 patients (T2: 45, T3 6, T4 6) were analyzed at this time. Clinical response rate recorded by ultrasonography and pathological response rate were 82.4% (47/57) and 91.2% (52/57) respectively. Pathological CR rate was 26.3% (15/57). 8 pCR cases showed ER/PR-negative tumors of which 3 cases showed ER/PR-negative/Her2-negative (triple negative pattern). Breast conservative surgery was underwent in 51 patients (89.5%). Among the response group, the tumor vascularities were almost remarkably decreased in the early phase (mostly until 2–3 cycles) of the chemotherapy. Grade 4 neutropenia was observed in 16% (9/57) and 4% (2/57) had febrile neutropenia. Conclusion: This regimen is well tolerated and has good feasibility because most patients have experienced the early reduction of tumor by high response rate of docetaxel.

No significant financial relationships to disclose.
HER2 overexpression is associated with shorter disease-free survival (DFS) following neoadjuvant systemic therapy (NST) of primary breast cancer (PBC) patients with gemcitabine (G), epirubicin (E) and docetaxel (Doc)
Authors: Marmé F. , Rom J. , Schütz F. , Eichbaum M. , Sinn P. , Sohn C. , Schneeweiss A.
Published: March 2020

11087

Background: To evaluate prognostic factors for disease-free survival (DFS) following NST with G, E and Doc of patients with PBC. Methods: From 1/02 to 12/04 113 patients with T2–4 N0–2 M0 PBC received either six cycles of GEDoc (G 800 mg/m2 day (d) 1+8, E 60–90 mg/m2 d 1, Doc 60–75 mg/m2 d 1 every three weeks; 63 patients) or five cycles of GE (1,250 mg/m2 d 1, E 90–100 mg/m2 d 1 every two weeks) sequentially followed by four cycles of Doc (80–100 mg/m2 d 1every two weeks) with prophylactic filgrastim. 71% of tumours were hormone receptor positive, 24% HER2 positive (3+ by immunohistochemistry), 46% grade 3. 28 patients (25%) achieved a pathologic complete response (pCR) defined as no invasive tumour residue in the removed breast tissue at surgery. 9 of these patients had non-invasive cancer residues in the breast, one patient showed persisting axillary lymph node involvement. Results: With a median follow up of 3.2 years there is no statistically significant difference in DFS, distant DFS (DDFS) and overall survival (OS) rates between patients with and without pCR (DFS 79 versus (vs) 81 %, p=0,61; DDFS 82 vs 84 %, p=0.69; OS 86 vs 91%, p=0.33). In a Cox proportional hazards model HER2 3+ before NST (hazard ratio (HR)= 4.7; 95% confidence interval (CI) 1.9 - 11.3; p=0.0006), positive hormone receptors before NST (HR=0.27; 95% CI 0.11 - 0.65; p=0.003) and clinically nodal involvement before NST (HR=3.3; 95% CI 1.2–9.1; p=0.02) were statistically significant prognostic factors for recurrence whereas tumour size and grade before NST, the achievement of pCR, nodal status at surgery and response after 6 weeks of NST did not reach statistical significance. Thus far, in multivariate analysis only Her2 3+ before NST retained its prognostic significance (HR= 2.8; 95% CI 1.03 - 7.5, p=0.04). Conclusions: With a median follow-up of 3.2 years in multivariate analysis only HER2 3+ is associated with shorter DFS following NST containing G, E and Doc for PBC. Thus far, there is no statistically significant prognostic value for pCR.

No significant financial relationships to disclose.
Primary invasive breast cancer in 104 women: A single-center experience in the years 1995–2005
Authors: Beda M. , Ghiotto C. , Basso U. , Stefani M. , Lonardi S. , Bonavina M. , Monfardini S.
Published: March 2020

11093

Background: To assess clinical, genetic and biological characteristics of breast cancer (BC) in women £ 35 years followed in a single Institution, along with patterns of disease recurrence and survival. Materials and Methods: All consecutive women £ 35 years with invasive BC registered at our Medical Oncology Department between 1995 and 2005 were enrolled in this retrospective analysis. Genetic testing for BRCA1/2 and P53 started in the year 2000. Results: Out of 4.120 cases, a total of 104 pts were identified, median age 32 years (range 22–35). Median age at menarche was 13 years, 48% were nulliparous. Approximately on third reported oral contraceptive use, while 23% reported a family history of BC. Almost 90% had a self -diagnosis of disease. Modified radical mastectomy was performed in 48%, conservative surgery in 46%, 6 metastatic pts were not operated. Axillary lymph node involvement was present in one half of cases. The prevalent histology was ductal carcinoma, 78% G2-G3, 26% hormone-receptor negative, 43% HER-2 positive. TNM stage was 29% I, 39% II, 22% III, 10% IV. Neo-adjuvant or adjuvant anthracycline based chemotherapy was administered to 86.7% of patients, combined with taxanes in 23% of cases. Twenty-four patients developed amenorrhea after stopping chemotherapy, the other ER/PgR positive patients received LH-RH analogues for 2 years. Tamoxifen was given to all ER/PgR positive patients. Genetic mutational analysis was available in 43 patients, and 9 mutations of BRCA 1 and 4 of BRCA 2 were found; two patients had a p53 mutation and one of them had an overt Li-Fraumeni syndrome. After a median follow-up of 5.5 years, 29 patients (28%) have recurred and 13 (12.5%) have died, with an estimated 5 year-DFS and OS of 82.4% and 87.5%, respectively. Conclusions: Our data confirm the aggressive biological features of BC in very young women. Intensive chemotherapy produces amenorrhea in 31% of cases. The 35% rate of BRCA1/2 or p53 mutation justifies a broader use of genetic testing in such patients in order to evaluate prophylactic measures for the female relatives.

No significant financial relationships to disclose.
HER2 status of patients with invasive breast cancer in a population at a single UK centre: Correlation with tumor characteristics
Authors: Saleh B. , Jader S. , Singer J. , Jenkins S. , Bradpiece H. , Patel A.
Published: March 2020

11094

Background: The human epidermal growth factor receptor 2 (HER2) overexpression, has been correlated with higher histological grade, increased tumour size, positive lymph node status, and negative or lower oestrogen receptor (ER) expression. Our aim was to look at the association between HER2 status, patient age and tumour histopathologic characteristics. Methods: We analysed retrospectively 735 cases of invasive breast cancer treated between the years 2000 and 2004. HER2 was measured by immunohistochemistry (IHC) and all IHC 2+ tumours were also tested by fluorescent in situ hybridisation (FISH). All information was collected from pathology reports in patient case records. Results: A total of 143 (19.5%) tumours were HER2 positive (120 IHC 3+ and 23 IHC 2+/FISH+). Of the 66 tumours that were IHC 2+, 23 (34.8%) were FISH-positive. The age of most patients (75.8%) was over 50 years but there was a higher incidence (28%) of HER2 overexpresion in the 40–49 age group compared to all other age groups, the incidence of HER2 overexpression was still at least 17–18% in all age groups, including patients aged =70 years. Although, a high proportion of patients (62.2%) had tumours less than 2 cm in size, comparison of tumours less than 2 cm with those greater than 2 cm showed no predictive effect of size on HER2 expression. Over half of the patients had lymph node-negative disease (55.2%) and despite some association of HER2 expression with lymph node involvement (odds ratio of 1.23 for comparison of lymph node-positive versus negative), 19% of lymph node-negative tumours overexpressed HER2. Most tumours were high grade (32.8% grade 3, 44.1% grade 2 ) and although the proportion of HER2 overexpression increased with increasing tumour grade, some grade 1 tumours still overexpressed HER2. A higher proportion (28%) of ER-negative tumours was HER2 positive compared to ER-positive tumours (18%); however, co-expression of HER2 and ER occurred in 14% (105/735) of all primary cancers. Conclusions: In conclusion, it is not possible to predict which patients will be HER2 positive. Therefore, it is essential that HER2 status should be determined in all patients with invasive breast cancer to allow a decision on the use of trastuzumab and guide the choice of chemotherapy.

No significant financial relationships to disclose.