Axillary Node-positive Breast Cancer Research Articles

Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189.

The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P </=.01). Within the first 5 years of follow-up, mitotic index (P =.004), grade (P =.004), ploidy (P =. 006), and SPF (P =.05) were associated with time to recurrence; there was also a significant association with survival. The effect of mitotic index was largely a result of the difference between 0 to 2 mitoses/10 high-power fields (HPF; 5-year recurrence of 31%) and more than 2 mitoses/10 HPF (5-year recurrence of 52%). The 0 to 2 mitoses/10 HPF group was independently associated with improved prognosis at 5 years (P =.002) in regression models that included other standard prognostic factors. A subset of axillary lymph node-positive patients with improved prognosis may be identified using a lower (< 3 mitoses/10 HPF) mitotic count than is usually performed.

Taxanes for Breast Cancer: An Evidence-Based Review of Randomized Phase II and Phase III Trials

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early- or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n=1) or phase III (n=17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m 2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m 2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m 2 every 3 weeks) was given following 4 cycles of conventional doxorubicincyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/ne u, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease.

Estrogen replacement therapy and breast cancer survival in a large screening study.

Hormone replacement therapy has been associated in some studies with reductions in breast cancer mortality among women who develop this disease. It is unclear whether this association reflects the biologic activity of the hormones or the earlier detection of tumors among hormone users. We examined breast cancer mortality among women who were diagnosed with axillary lymph node-negative and node-positive breast cancer according to the currency of estrogen use at diagnosis. Vital status through June 1995 was determined for 2614 patients with postmenopausal breast cancer diagnosed during the period from 1973 to January 1981. We estimated adjusted hazard-rate ratios (adjusting for tumor size, age, race, Quetelet [body mass] index, and number of positive lymph nodes in women with node-positive disease) and unadjusted cumulative probabilities of breast cancer death over time since diagnosis. Among patients with node-negative disease, rate ratios for breast cancer mortality associated with current use compared with nonuse at diagnosis were 0.5 (95% confidence interval [CI] = 0.3-0.8) until 144 months after diagnosis and 2.2 (95% CI = 0.9-5.2) thereafter. Mortality was not statistically significantly lower in past users. The cumulative probabilities of breast cancer mortality at the end of follow-up were 0.14, 0.14, and 0.09 in nonusers, past users, and current users, respectively. Among women with node-positive disease, the rate ratios associated with current and past use were both 0.5 until 48 months after diagnosis (95% CI = 0.3-0.8 for current users; 95% CI = 0.3-0.9 for past users) and were 1.1 (95% CI = 0.7-1.7) and 1.8 (95% CI = 1.2-2.7), respectively, thereafter. The cumulative probabilities of breast cancer mortality were 0.32, 0.39, and 0.27 in nonusers, past users, and current users, respectively. Patients with breast cancer who were using replacement estrogens at the time of diagnosis experienced reductions in breast cancer mortality, which waned with the time since diagnosis.

Adjuvant chemotherapy for node-positive breast cancer: a retrospective comparison of two different regimens of cyclophosphamide, methotrexate and 5-fluorouracil

Adjuvant chemotherapy after surgery for early breast cancer has been shown to reduce disease recurrence and mortality. The effectiveness of ‘classical’ oral CMF (oral cyclophosphamide on days 1 to 14, combined with intravenous methotrexate and 5-fluorouracil given intravenously on days 1 and 8, repeated every 28 days) is well established. Modified protocols of CMF (where all three drugs are given as bolus intravenous injections once or twice every 3 or 4 weeks) have been used in many centres, because of a perceived greater convenience, better compliance, and reduced toxicity. Many such intravenous CMF (IV CMF) protocols deliver somewhat lower total drug doses, at a lower dose intensity, than classical oral CMF. It is important to know if there is any resultant reduction in efficacy with such regimens. This study compares the delivered dose intensity, efficacy and toxicity of the classical oral regimen with that of a modified CMF regimen delivered intravenously at 3-weekly intervals for six cycles. We performed a retrospective study of women with axillary node-positive breast cancer treated at our centre, between January 1980 and December 1991, in the adjuvant setting with either classical oral CMF ( n=70) or with an IV CMF protocol ( n=200). Although the mean delivered dose intensity was higher in the oral CMF than in the IV CMF group, we detected no difference in disease-free or overall survival at 5 years. Alopecia and weight gain were reported more frequently in the oral CMF group than in the IV CMF group. Nausea and emesis were also more severe in the oral group, although this may reflect, at least in part, the use of different antiemetics in the two cohorts. Although many patients are willing to tolerate quite severe side-effects for relatively small additional gains in survival, for others, reduced side-effects and fewer clinic attendances may make IV CMF an attractive option. Our data suggest that IV CMF remains a reasonable alternative for such patients.

Adjuvant Chemotherapy with a Combination of Mitoxantrone, Methotrexate, 5-Fluorouracil for Node-Positive Breast Cancer: Phase II Pilot Study

A phase II pilot study was carried out on 30 patients to ascertain the toxicity and efficacy of combination chemotherapy with mitoxantrone, methotrexate, 5-fluorouracil (NMF) in the adjuvant setting for axillary lymph node-positive breast cancer. The NMF regimen was mitoxantrone 10 mg/m2, methotrexate 40 mg/m2, and 5-fluorouracil 600 mg/m2 administered i.v. on day 1, repeated every 3-4 weeks for 6 cycles. The median nadir WBC count was 2,000/ml; grade 4 leukocytopenia occurred only in 1 patient. Nausea and vomiting appeared as grade 0 and 1 severity in 26/30 patients. Alopecia was extremely mild, appeared as grade 0 and 1 in 29/30 patients. The overall and relapsefree survival rates were 67.8% and 68.4% at the 82-month follow-up, respectively. The overall survival rate in premenopausal patients was significantly better than that in postmenopausal patients (P<0.05). NMF is a well-tolerated combination regimen, suitable as adjuvant chemotherapy for node-positive breast cancer.

Long-term follow-up of axillary node-positive breast cancer patients receiving adjuvant tamoxifen alone: patterns of recurrence

Purpose: To determine the patterns, incidence and risk factors for local-regional recurrence in patients with Stage II and III breast cancer treated with adjuvant tamoxifen alone, without adjuvant radiation. Material and Methods: The records of patients referred to the London Regional Cancer Centre with a diagnosis of breast cancer between 1980–1989 were reviewed. During this time period, it was the policy of the institution to omit local-regional radiation to patients receiving adjuvant systemic therapy. One hundred and fifty axillary node-positive Stage II and III breast cancer patients received adjuvant tamoxifen alone without postoperative local-regional radiation; these patients form the basis of this report. Results: Median follow-up was 67 months for the entire patient group and 85 months for the living patients. During this time, 42% of patients developed a recurrence, 22% first recurred in local-regional sites. The total incidence of local-regional recurrence (including those patients who first relapsed with systemic metastases) was 30%. Of the segmental mastectomy patients, 13% had recurrences in the intact breast. Of the modified radical mastectomy patients, 10% developed chest wall recurrences. Five percent of recurrences were first in the axilla and 6% in the supraclavicular nodes. Five-year actuarial survival for the entire patient group was 79% and disease-free survival was 60%, with a median disease-free survival time of 87 months. Five-year local-regional relapse-free survival was 76%. Five-year local-regional relapse-free survival was < 76% for those patients with 4 or more positive axillary nodes, regardless of tumor size. On univariable analysis, positive resection margins, number of positive axillary nodes, menopausal status, and negative estrogen and progesterone receptors were significant for isolated local-regional recurrence. On multivariable analysis, only positive resection margins and negative receptors remained significant. In terms of regional recurrence specifically, negative estrogen and progesterone-receptor status and positive resection margins were, again, prognostically significant. Conclusions: Postmenopausal women receiving adjuvant tamoxifen who have positive resection margins, ≥ 4 positive axillary nodes and/or negative estrogen and progesterone receptors, are at higher risk of local and regional recurrence and should, therefore, receive local-regional radiation.

Long-term follow-up of axillary node positive breast cancer patients receiving adjuvant tamoxifen alone: Patterns of recurrence

Long-term follow-up of axillary node positive breast cancer patients receiving adjuvant tamoxifen alone: Patterns of recurrence

348 - Long-term survival in axillary node-positive breast cancer treated with locoregional therapy alone

348 - Long-term survival in axillary node-positive breast cancer treated with locoregional therapy alone

Long-term follow-up of axillary node-positive breast cancer patients receiving adjuvant systemic therapy alone: Patterns of recurrence

Prognostic factors for locoregional failure have been poorly documented. The purpose of this retrospective review is to examine the patterns of failure of 320 patients with Stage II or III axillary node-positive breast cancer who received adjuvant chemotherapy without locoregional radiation. The records of 735 patients who were referred to the London Regional Cancer Centre between 1980 and 1989 with a diagnosis of Stage II or III breast cancer were reviewed. Three hundred and twenty patients were identified who underwent segmental mastectomy with axillary dissection or modified radical mastectomy and adjuvant chemotherapy without adjuvant locoregional radiation. Seventy-one percent of these patients had undergone a modified radical mastectomy, 40% had T1 tumors, 49% T2, and 11% T3. Resection margins were positive in 13 patients. The median number of axillary nodes removed was 11. Fifty-four percent had one to three positive axillary nodes, 27% had four to seven positive nodes, and 19% had in excess of seven positive nodes. Median follow-up for the 320 patients was 77 months. One hundred and fourteen patients developed a locoregional recurrence as the site of first relapse (31 in the intact breast, 29 on the chest wall, 21 in the axilla, 22 in the supraclavicular fossa, 1 in the internal mammary chain, and 10 in multiple sites). Thirty-three percent of segmental mastectomy patients and 13% of modified radical mastectomy patients developed local recurrence. Seven percent of patients recurred in axillary or supraclavicular nodes each. Factors with regard to locoregional recurrence which on univariate analysis were significant included type of mastectomy (i.e., segmental vs. modified radical), size of primary tumor, positive resection margins, and percentage of ideal chemotherapy dose intensity (< 66% vs. > or = 66%). After multivariate analysis, only type of mastectomy, size of primary tumor, and percentage of ideal chemotherapy dose intensity retained significance. The number of positive axillary nodes was not a significant factor. Number of positive axillary nodes plus the above four clinical factors were analyzed in terms of regional recurrence specifically. By univariate and multivariate analysis, only size of primary tumor retained significance. Again, the number of positive axillary nodes was not a relevant factor. Patients receiving adjuvant chemotherapy who are at high risk of locoregional recurrence include those who undergo segmental mastectomy and those with larger tumors (> 5 cm in diameter). Breast or chest wall radiation is recommended for these groups. Supraclavicular radiation is recommended for patients with tumors larger than 5 cm in diameter. Axillary recurrences were relatively infrequent in patients who had undergone an adequate Level I and II axillary dissection, and therefore, axillary radiation was not recommended.

Is it time to develop an optimal endocrine therapy for premenopausal patients with axillary node positive and negative breast cancer?

One hundred years ago ovarian ablation was shown to be an effective treatment for advanced breast cancer in premenopausal women. Since that time many different treatment modalities have been advocated to improve patient survival. The value of adjuvant ovarian ablation, however, has recently been established in the overview of breast cancer clinical trials. In fact, comparison of the efficacy of combination chemotherapy with earlier trials of oophorectomy demonstrate the superiority of oophorectomy. The effectiveness of chemotherapy may largely be the result of partial ovarian ablation produced in premenopausal patients. Based on this position, we propose a clinical trial that would establish the optimal therapy for premenopausal breast cancer. In addition, the beneficial effects of long-term tamoxifen as it pertains to serum lipids and bone density are highlighted. The use of tamoxifen maintenance in oophorectomized women might provide an optimal therapy for the control of breast cancer recurrence.

Is it time to develop an optimal endocrine therapy for premenopausal patients with axillary node positive and negative breast cancer?

Is it time to develop an optimal endocrine therapy for premenopausal patients with axillary node positive and negative breast cancer?

2001 Longterm follow-up of axillary node positive breast cancer patients receiving adjuvant systemic therapy alone: Patterns of recurrence

2001 Longterm follow-up of axillary node positive breast cancer patients receiving adjuvant systemic therapy alone: Patterns of recurrence

305Longterm follow-up of axillary node positive breast cancer patients receiving adjuvant systemic therapy alone: Patterns of recurrence

305Longterm follow-up of axillary node positive breast cancer patients receiving adjuvant systemic therapy alone: Patterns of recurrence

Prognostic value of bcl-2 expression in invasive breast cancer.

Expression of the bcl-2 proto-oncogene was studied immunohistochemically in 251 invasive ductal breast carcinomas (median follow-up time 91 months, range 24-186 months) and the results were correlated with clinicopathological data and prognostic variables. Sixty-three (25%) tumours were scored bcl-2 negative and 188 (75%) tumours were bcl-2 positive. No relationship could be observed between bcl-2 status and tumour grade, pTNM staging or menopausal status. A strong positive relationship was demonstrated between bcl-2 immunoreactivity and oestrogen receptor status (P < 0.001) and progesterone receptor status (P < 0.001). No prognostic value was demonstrated for bcl-2 expression on disease-free survival and overall survival in axillary node-negative breast cancer patients. However, in axillary node-positive breast cancer patients multivariate analysis demonstrated absence of bcl-2 expression to be independently related to shortened disease-free survival (P = 0.003) and shortened overall survival (P < 0.001). Our results suggest a potential important role for bcl-2 expression as a modulator of response to adjuvant therapy in breast cancer.

Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organization for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. Cooperating Investigators.

To investigate whether treatment with prolonged low-dose adjuvant chemotherapy could improve survival of patients with axillary node-positive breast cancer. Four hundred fifty-two patients with axillary node-positive breast cancer who received postoperative irradiation were prospectively randomized in a trial (European Organization for Research and Treatment of Cancer [EORTC] 09771) that compared surgery followed by prolonged low-dose chemotherapy versus surgery alone. Chemotherapy was given for a period of 2 years and consisted of monthly courses of cyclophosphamide 50 mg/m2 orally on days 1 to 14, methotrexate 15 mg/m2 intravenously on days 1 and 8, and fluorouracil 350 mg/m2 intravenously on days 1 and 8 (CMF). At a median follow-up time of 10 years, the overall survival duration was significantly prolonged in the chemotherapy arm (hazards ratio, 0.75; 95% confidence interval, 0.56 to 0.99; P = .04). Ten-year overall survival rates (+/- SE) were 59% (+/- 3.6%) for the chemotherapy arm and 50% (+/- 3.7%) for the control arm. Time to local relapse was significantly prolonged in the chemotherapy arm (hazards ratio, 0.63; 95% confidence interval, 0.42 to 0.94; P = .02). Patients with one to three positive axillary nodes and patients with estrogen receptor-negative tumors especially benefited from chemotherapy. Toxicity was observed in 93% of patients. We conclude that prolonged low-dose adjuvant CMF can significantly prolong overall survival in patients with node-positive breast cancer. However, considering the fact that toxicity was still considerable despite reducing the dose of chemotherapy by 50%, we believe that conventionally dosed short-term regimens are preferable in the treatment of node-positive breast cancer.

Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive, node positive breast cancer: A randomized study

370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 mg/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.

A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer

A multicentre pilot study has been conducted to determine an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil which was tolerable and acceptable to patients with node positive breast cancer. Consecutive patients with operable axillary node positive breast cancer (T1–3, N1–2, M0), 266 patients, or locally advanced breast cancer (T4), 22 patients, were treated with cyclophosphamide post-operatively for 14 days and epirubicin and flourouracil, both intravenously on days 1 and 8. Each cycle was repeated monthly for 6 months. Dosages were increased accoring to predetermined guidelines. Outcome measures were admission to hospital for febrile neutropenia and change in cardiac function as assessed by radionucleide angiography. The first 46 patients were treated at the doses of cyclophosphamide = 75 mg/m 2, epirubicin = 50 mg/m 2, fluorouracil = 375 mg/m 2 (level 1), then 42 patients at cyclophosphamide = 75 mg/m 2, epirubicin = 50 mg/m 2 and fluorouracil = 500 mg/m 2 (level 2), 69 patients at cyclophosphamide = 75 mg/m 2, epirubicin = 60 mg/m 2, and fluorouracil = 500 mg/m 2 (level 3), and 42 patients at cyclophosphamide = 75 mg/m 2, epirubicin = 70 mg/m 2, and fluorouracil = 500 mg/m 2 with concurrent antibiotics (level 4). The rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4), respectively, P = 0.002. Accrual to level 4 was discontinued according to study guidelines and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between levels 3 and 3a was statistically significant. There were no toxic deaths and 2 cases of heart failure. In conclusion, through a careful dose-finding study in patients with operable or locally advanced breast cancer, an intensive epirubicin-containing adjuvant regimen has been established which is presently being compared with standard CMF (cyclophosphamide,methotrexate, 5-fluorouracil) chemotherapy in a randomised trial. In addition, this study suggests that antibiotic prophylaxis reduces the risk of febrile neutropenia in breast cancer patients receiving intensive chemotherapy.

Loccregional reciimence and extranodal extension in patients receiving systemic therapy for axillary node positive breast cancer

Loccregional reciimence and extranodal extension in patients receiving systemic therapy for axillary node positive breast cancer

Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial.

Between 1976 and 1985, 391 patients (202 premenopausal, 189 postmenopausal) with operable breast cancer and positive axillary lymph nodes were randomized after total mastectomy and axillary clearance to receive cyclophosphamide, methotrexate, and fluorouracil (CMF) (n = 193) or no adjuvant therapy (n = 198). After a median follow-up of 8 years, both relapse-free survival (RFS) and survival (S) were significantly prolonged in premenopausal patients receiving CMF (RFS, P less than .001; S, P = .003). Treatment with CMF resulted in a significant improvement in RFS in premenopausal patients both with steroid receptor-positive and steroid receptor-negative tumors and also in subgroups of premenopausal patients defined by the number of axillary nodes involved. Premenopausal patients who developed permanent amenorrhea following CMF had a significantly better RFS than those who continued to menstruate. Induction of amenorrhea following CMF was related to age, with almost all patients over 40 years becoming amenorrheic. For patients less than or equal to 40 years, development of amenorrhea following CMF did not influence outcome. No difference was detected between control and CMF groups (RFS, P = .9; S, P = .9) in postmenopausal patients nor in any subgroup of these patients. The results of this trial of the efficacy of CMF for improving RFS and S have strengthened with longer follow-up.

A randomized trial comparing 12 weeks versus 36 weeks of adjuvant chemotherapy in stage II breast cancer.

A randomized trial has been performed in which women with axillary node-positive breast cancer were allocated to either a short intensive 12-week chemohormonal treatment consisting of cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and tamoxifen (CMFVP plus AT) or 36 weeks of CMFVP. The median follow-up is 37 months. Of the 222 women randomized to the 12-week treatment, 113 (50.9%) have experienced either recurrence or death as compared with 90 patients (41.9%) in the 36-week treatment group. The corresponding 3-year relapse-free survivals are 55% and 64%, respectively, P = .003. Fifty-nine (26.6%) of the patients in the 12-week group have died compared with 46 (21.4%) of the 36-week group. The corresponding 3-year survival rates are 78% and 85%, respectively, P = .04. A Cox regression analysis showed an associated increased risk ratio for recurrence or death of 1.7, P = .003, and for death of 1.8, P = .017 in the 12-week treatment group compared with the 36-week group. Thus, this 12-week regimen of adjuvant chemohormonal therapy is inadequate treatment for women with axillary node-positive breast cancer; possible explanations for this inferiority are its shorter duration and/or a negative interaction of tamoxifen on the chemotherapy.