Different responses to preoperative chemotherapy for invasive lobular and invasive ductal breast carcinoma.

AIM: Preoperative chemotherapy (PCT) is used in primary breast cancer, to facilitate breast conservative surgery (BCS). Clinical and pathologic responses are important prognostic parameters. Biologic markers are needed to individualize treatment. PATIENTS AND METHODS: One hundred and thirty-five patients with breast carcinoma were treated with PCT, followed by surgery and adjuvant therapy. Clinical response and pathological complete response (pCR), biological markers and type of surgery were compared between invasive ductal (IDC) and invasive lobular carcinoma (ILC). RESULTS: Overall response (OR) for IDC was 75% compared to 50% for ILC (P=0.0151). Pathological CR was 15% for IDC and 0% for ILC (P=0.0066). Fifty-six percent of the responding patients had BCS, in contrast with 16% of the non-responders. BCS was performed in 50% of patients with IDC, in 38% of the patients with ILC. Salvage surgery was more necessary in ILC (19%) compared to IDC (4%) (P=0.0068). Patients with ILC were more frequently ER-positive and HER-2 negative than patients with IDC. CONCLUSIONS: Clinical and pathological responses are lower in ILC compared to IDC. After PCT, patients with large ILC should preferably be offered mastectomy with immediate breast reconstruction. However, PCT still remains valuable to evaluate tumor response and biologic factors in vivo.     

Target and reality of adjuvant endocrine therapy in postmenopausal patients with invasive breast cancer

Previous research evaluating the use of adjuvant endocrine therapy among postmenopausal breast cancer patients showed with 15-50% wide ranges of non-adherence rates. We evaluated this issue by analysing an unselected study group comprising of 325 postmenopausal women, diagnosed from 1997 to 2003 with hormonal receptor-positive invasive breast cancer. The different clinical situations that led to the discontinuation of adjuvant endocrine therapy were clearly defined and differentiated: non-adherence was not simply the act of stopping medication, but rather the manifestation of an intentional behaviour of the patient. Of the 287 patients who initiated endocrine therapy, 191 (66.6%) fully completed this treatment. Thirty-one patients (10.8%) showed non-adherence to therapy. Patients who had follow-up with a general practitioner, rather than in an oncologic unit, were more likely to be non-adherent (P=0.0088). Of 25 patients who changed medication due to therapy-related adverse effects, 20 (80%) patients fully completed the therapy after drug change. In adjuvant endocrine therapy, a lowering of the non-adherence rate to 10.8%, the lowest reported in the literature, is realistic when patients are cared for by a specialised oncologic unit focusing on the individual needs of the patients.     

Invasive ductal carcinoma with lobular features: a comparison study to invasive ductal and invasive lobular carcinomas of the breast

Invasive ductal carcinoma with lobular features (IDC-L) is not recognized as a distinct subtype of breast cancer, and its clinicopathologic features and outcomes are unknown. In this retrospective study, we focused on characterization of clinicopathologic features and outcomes of IDC-L and compared them to invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). 183 cases of IDC-L from 1996 to 2011 were compared with 1,499 cases of IDC and 375 cases of ILC. Available slides of IDC-L (n = 150) were reviewed to quantify the lobular component (≤20, 21–50, 51–80, >80 %), defined as small cells individually dispersed, arranged in linear cords, or in loose aggregates without the formation of tubules or cohesive nests. E-cadherin immunostain was performed to confirm ductal origin. Compared to IDC, IDC-L was more likely to have lower histologic grade (p < 0.001), be positive for estrogen receptor (96 vs. 70 %; p < 0.0001) and progesterone receptor (84 vs. 57 %; p < 0.0001), and less likely to overexpress HER-2/neu (12 vs. 23 %; p = 0.001). Despite these favorable prognostic features, IDC-L had a higher frequency of nodal metastases (51 vs. 34 %; p < 0.0001) and a worse 5-year disease-free survival than IDC (hazard ratio = 0.454; p = 0.0004). ILC and IDC-L had similar clinicopathologic features and outcomes. The proportion of the lobular component in IDC-L had no impact on the size, nodal status, stage, or outcome. Our data suggest that although IDC-L may be a variant of IDC, with >90 % of cases being E-cadherin positive, the clinical and biological characteristics are more similar to that of ILC.     

Immunological subtypes in breast cancer are prognostic for invasive ductal but not for invasive lobular breast carcinoma

Background:

Classical patient and tumour characteristics are the benchmark of personalised breast cancer (BC) management. Recent evidence has demonstrated that immune and molecular profiling of BC may also play an important role. Despite evidence of differences between invasive ductal (IDC) and lobular (ILC) BC, they are infrequently accounted for when making treatment decisions for individual patients. The purpose of this study was to investigate the relevance of the tumour immune response in the major histological subtypes of BC. We also assessed the relationship between immune responses and molecular subtypes and their prognostic potential.

Methods:

Immunostains were done for HLA-I, HLA-E, HLA-G, Tregs, NK cells and CTLs for the composition of the immune profiles and Ki67, EGFR, CK5/6, ER, PR and HER2 for molecular profiles in 714 breast cancer patients who underwent primary surgery.

Results:

No significant association was found between IDC (90.6%) and ILC (9.4%) and tumour immune subtypes (P=0.4) and molecular subtypes (P=0.4). However, for the relapse-free period (RFP) tumour immune subtyping was prognostic (P=0.002) in IDC, but not ILC. Contrary to ILC, IDC patients frequently expressed higher cleaved caspase-3 and Ki67, which was prognostic. Intermediate immune-susceptible IDC expressing high cleaved caspase-3 or Ki67 showed worse RFP than those with low expression (caspase-3: P=0.004; Ki67: P=0.002); this was not seen for ILC or in high or low immune-susceptible tumour types for either IDC or ILC.

Conclusions:

Tumour immune characteristics and host immune responses are prognostic in IDC, but not ILC. In addition, tumour immune profiles are only prognostic in Luminal A tumours.     

Postmastectomy radiotherapy and concomitant adjuvant chemotherapy versus adjuvant chemotherapy alone in premenopausal breast cancer patients with positive axillary nodes

AIMS: To evaluate the efficacy of postmastectomy radiotherapy (RT) combined with adjuvant chemotherapy compared to adjuvant chemotherapy alone as regards overall survival (OS), overall disease-free survival (ODFS), local disease-free survival (LDFS) and distant disease-free survival (DDFS). METHODS: We reviewed retrospectively two non-randomized groups of premenopausal high-risk breast cancer patients treated from 1985 to 1990 in the following Institutions: Department of Radiation Oncology of Brescia University, "Istituto del Radio O. Alberti" (IRA), and Department of Oncology of Brescia Hospital "Beretta Foundation" (BF). A total of 163 patients was found to satisfy the criteria of the current analysis: 81 patients received adjuvant chemotherapy alone [6 cycles CMF(1-8)] at BF and 82 patients received postoperative radiotherapy and chemotherapy [8 cycles CMF(1-21)] at IRA. A modified CMF schedule was chosen at IRA to avoid the feared increase in toxicity due to the association with RT. Primary surgical treatment was modified radical mastectomy with axillary node dissection in both cases. RESULTS: A statistically significant improvement in OS was found in systemic adjuvant therapy patients compared to those also given RT (77.6% vs 59%; P = 0.0025). No statistically significant improvement in ODFS was found in the CMF(1-8) arm compared to the RT and CMF(1-21) stm: 51.6% vs 43.6%; P = 0.46. A statistically significant improvement in LDFS at 5 years was found in irradiated patients (89.3% vs 76.2%; P <0.05). The DDFS was also improved, although without evidence of statistical significance, in the CMF(1-8) group: at 5 years 65% vs 44% (P = 0.059). CONCLUSIONS: The study confirmed that RT reduces the risk of local recurrence but without a statistically significant reduction in mortality. The lack of a survival benefit may somehow reflect the dose reduction in CMF(1-21). The evidence that CMF(1-8) offers undoubtable advantages over the CMF(1-21) regimen in OS and, perhaps, in distant control suggests that the dose intensity of CMF in this setting may also be important. In fact, although many CMF(1-8) patients received a dose intensity lower than 100%, 95% of them received a dose intensity higher than the maximum one of the CMF(1-21) patients. Although our results should be interpreted with caution, they seem to provide further rationale for testing the association of postoperative radiotherapy and the CMF(1-8) regimen in stage II breast cancer with positive nodes and treated with demolitive surgery, as already done in the conservative management of breast cancer, also in view of the new support therapies now available (i.e. hematologic growth factors).     

One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer

PurposeWe report the long-term results of a randomised trial comparing tamoxifen with tamoxifen plus cyclophosphamide, methotrexate and fluorouracil (CMF) in postmenopausal high-risk breast cancer patients. In addition, we analyse the prognostic and predictive value of centrally assessed subtypes.MethodsPostmenopausal patients with breast cancer and positive nodes, deep invasion or size exceeding 5 cm were randomly assigned to 1 year of tamoxifen, or cyclophosphamide 600 mg/m², methotrexate 40 mg/m² and fluorouracil 600 mg/m² intravenously on day 1 every 4 weeks for nine cycles plus tamoxifen (CMFT). Tissue microarrays were constructed retrospectively and oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and proliferation-related Ki-67 antigen (Ki67) status were assessed.ResultsFrom October 1982 through March 1990 we randomised 1445 patients and 969 (67%) were eligible for the biomarker analysis. At 10-years 936 women had suffered a disease-free survival (DFS) event (tamoxifen, 495 events in 686 patients; CMFT, 441 events in 642 patients). The addition of CMF to tamoxifen significantly improved DFS (adjusted hazard ratio 0.82; 95% confidence interval (CI) 0.71–0.93; P = 0.003) but not overall survival (adjusted hazard ratio 0.95; 95% CI 0.85–1.08; P = 0.44). DFS was superior in Luminal A tumours (ER or PgR positive, HER2 negative and Ki67 ?14%) when compared to Luminal B or non-luminal (ER and PgR negative) tumours. There was no statistical evidence of heterogeneity by subtype in the benefit from CMF (P_interaction = 0.45).ConclusionCMF added to 1 year of tamoxifen reduces the risk of a DFS event. The benefit from CMF was not significantly different in Luminal A and B subtypes.     

Femoral fractures in postmenopausal breast cancer patients treated with adjuvant tamoxifen

Summary The anti-estrogen tamoxifen is the prevalent endocrine treatment in postmenopausal breast cancer patients. However, nothing is known about the long-term effects of the drug on the skeleton as assessed by the occurrence of fractures.We investigated the occurrence of fractures of the femur in patients from a Danish Breast Cancer Cooperative Group (DBCG) trial initiated in 1977 by a linkage of data from the Danish National Registry of Patients with data from the DBCG registry. 1716 postmenopausal women with high-risk breast cancer were randomized to local radiotherapy with or without tamoxifen, 30 mg daily for 1 year.Fifty-one patients in the control group had one femoral fracture and 64 tamoxifen treated patients had one femoral fracture. Eleven patients in the control group had one trochanteric fracture compared to 27 patients in the tamoxifen group (logrank = 5.28, P = 0.022; hazard ratio = 2.12, 95% CL 1.12, 4.01).The results could not be explained by a longer survival in the tamoxifen group nor by bone metastases with pathological fractures.In conclusion, our study suggests that tamoxifen does not seem to offer protection against fractures in old age and may even increase the risk of fractures at particular sites. This hypothesis needs to be disproved or confirmed in other trials.     

Randomized trial of adjuvant tamoxifen combined with postoperative radiation therapy or adjuvant chemotherapy in postmenopausal breast cancer

From 1976 to 1984, 427 postmenopausal women with high-risk breast cancer (pN + or pT greater than 30 mm) were randomized between postoperative radiation therapy (RT), radiation therapy plus tamoxifen (RT-TAM), adjuvant chemotherapy (CT), or chemotherapy plus tamoxifen (CT-TAM). Surgery was a modified radical mastectomy in all cases. The radiation therapy was given with high-voltage techniques and included the chest wall and regional nodes. The dose was 4600 cGy/4 1/2 weeks. Tamoxifen was given at a dose of 40 mg daily for 2 years. The adjuvant chemotherapy consisted of 12 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (or chlorambucil, methotrexate, and 5-fluorouracil [LMF] for patients entered before 1978). At a median follow-up time of 6 1/2 years the recurrence-free survival was significantly better for patients allocated to radiation therapy compared to chemotherapy and for patients allocated to tamoxifen compared to no adjuvant endocrine treatment (P less than 0.01). At 10 years the recurrence-free survival for patients in the RT-TAM, RT, CT-TAM, and CT groups was 63%, 57%, 47%, and 31%, respectively. A significant reduction of treatment failures with tamoxifen was only observed among patients with estrogen receptor-positive tumors. The overall survival difference in favor of patients allocated to radiation therapy or tamoxifen was not significant: the respective survival percentage at 10 years in the RT-TAM, RT, CT-TAM, and CT group was 65%, 62%, 52%, and 50%. The results indicate that postoperative radiation therapy continues to play an important role in the primary management of postmenopausal women with high-risk breast cancer and that the addition of tamoxifen may further improve the results among ER-positive patients.     

Inflammatory infiltrate in invasive lobular and ductal carcinoma of the breast.

The significance of inflammation in carcinoma of the breast is controversial. Little attention has been paid to different patterns of inflammation or inflammation associated with different histological types of carcinoma. We have looked at the pattern of inflammation in 123 invasive mammary carcinomas (including 46 lobular), and characterised the inflammatory cells with immunohistochemistry in 21. We found different patterns of inflammation in ductal and lobular carcinoma. Diffuse inflammation was seen more in ductal carcinoma, particularly of high grade, and was predominantly composed of macrophages and T cells. It was associated with necrosis, but the correlation was weak, suggesting that other factors are important. Perilobular inflammation was seen most frequently in lobular and high-grade ductal carcinomas, particularly at the tumour edge. Perivascular inflammation was also largely at the tumour edge, but was not more common in any tumour type. In contrast to the diffuse inflammation, the perivascular and perilobular inflammation was composed of T and B cells. Normal lobules at the tumour edge showed consistent expression of HLA-DR, whereas lobules away from the tumour were negative. A combination of perilobular and perivascular inflammation composed of B and T cells with epithelial expression of HLA-DR mimicking lymphocytic lobulitis was seen more frequently in lobular than ductal carcinoma.     

淋巴结阳性乳腺癌的术后辅助化疗研究进展

大规模随机临床试验和荟萃分析证明,绝大多数淋巴结阳性乳腺癌病人需要辅助化疗.合适的化疗方案、剂量强度和周期数都是影响疗效的重要因素,剂量密度化疗进一步提高了疗效.分子标志物不仅可预示淋巴结阳性乳腺癌病人的预后,在将来还可以指导乳腺癌的个体化治疗.     

Feasibility of adjuvant chemotherapy for breast cancer patients

To evaluate the feasibility of adjuvant chemotherapy, we analyzed the toxicities of chemotherapy for primary breast cancer in Japanese women. Since the opening of the National Cancer Center Hospital East, 180 female breast cancer patients have received adjuvant chemotherapy or chemo-hormonal therapy following surgical treatment between June 1992 and December 1995. On the basis of informed consent about prognosis and adjuvant therapy, most patients decided to choose the type of cytotoxic chemotherapy themselves. Adjuvant chemotherapy consisted of oral fluoropyrimidine compounds (OFP), cyclophosphamide + adriamycin +/- 5-fluorouracil [CA(F)] or cyclophosphamide + methotrexate + 5-fluorouracil (CMF). Toxicity was determined using the Toxicity Grading Criteria of the Japan Clinical Oncology Group (JCOG). Sixty-six patients received OFP, 59 CA(F) and the rest 55 CMF. The toxicity grading of leukocytes and neutrophils was significantly higher in patients treated with CA(F) or CMF than in those treated with OFP. Similar results were also seen relating to the toxicity of nausea/vomiting and alopecia. There was no statistical difference in the toxicity grading of hemoglobin, glutamic oxaloacetic transaminase/glutamic pyruvic transaminase (GOT/GPT) and stomatitis/ gastritis between the three groups of patients. Interestingly, the number of patients that were forced to discontinue chemotherapy was higher in those receiving OFP than in those receiving CA(F) or CMF. Cytotoxic chemotherapy of CA(F) or CMF results in greater toxicity than OFP, but is tolerated and feasible in the adjuvant setting used in Japanese breast cancer patients from the viewpoint of toxicities by anticancer chemotherapy.      

Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy

BACKGROUND:

Population‐based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy.

METHODS:

Adjuvant chemotherapy trials coordinated by the Eastern Cooperative Oncology Group that accrued patients between 1978 and 2002 were reviewed. Survival after distant disease recurrence was estimated for progressive time periods, and adjusted for baseline covariates in a Cox proportional hazards model.

RESULTS:

Of the 13,785 patients who received adjuvant chemotherapy in 11 trials, 3447 (25%) developed distant disease recurrence; the median survival after recurrence was 20 months (95% confidence interval, 19 months‐21 months). Factors associated with inferior survival included a shorter distant recurrence‐free interval (DRFI), estrogen receptor‐negative and progesterone receptor‐negative disease, the number of positive axillary lymph nodes present at the time of diagnosis, and black race (P < .0001 for all). When the time period of recurrence was added to the model, it was not found to be significantly associated with survival for the general population with disease recurrence. Survival improved over time only in those patients with hormone receptor‐negative disease with a DRFI ≤ 3 years, both among the 5 most recent and the entire trial data sets (P = .01 and P = .05, respectively).

CONCLUSIONS:

In contrast to reports from population‐based studies, no general improvement in survival was observed over the last 30 years for patients who developed distant disease recurrence after adjuvant chemotherapy after adjusting for DRFI. Improved survival for patients with hormone receptor‐negative disease with a short DRFI suggests a benefit from trastuzumab. Cancer 2013. © 2012 American Cancer Society.