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CLINICAL TRIALS IN BREAST CANCER

DR. SUMIT GOYAL

ASSISTANT PROF

DEPT OF RADIATION ONCOLOGY,

Level Ia evidence: prospective randomized surgical trials in breast cancer

1. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation.

Fisher B, Jeong JH, Anderson S, et al. N Engl J Med 2002;347:567–75.

Hypothesis: Less radical surgery with or without RT is as effective as the Halstead radical mastectomy (RM) in primary operable breast cancer.

BACKGROUND: In women with breast cancer, the role of radical mastectomy, as compared with less extensive surgery, has been a matter of debate.

This report 25-year findings of a randomized trial initiated in 1971 to determine whether less extensive surgery with or without radiation therapy was as effective as the Halsted radical mastectomy.

METHODS: A total of 1079 women with clinically negative axillary nodes underwent radical mastectomy, total mastectomy without axillary dissection but with postoperative irradiation, or total mastectomy plus axillary dissection only if their nodes became positive.

A total of 586 women with clinically positive axillary nodes either underwent radical mastectomy or underwent total mastectomy without axillary dissection but with postoperative irradiation.

Kaplan-Meier and cumulative-incidence estimates of outcome were obtained

RESULTS: No significant differences were observed among the 3 groups of women with negative nodes or between the 2 groups of women with positive nodes with respect to disease-free survival, relapse-free survival, distant disease-free survival, or overall survival.

Among women with negative nodes, the hazard ratio for death among those who were treated with total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.08 (95% confidence interval, 0.91 to 1.28; P = .38), and the hazard ratio for death among those who had total

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NSABP B-04 Trial Results

No. of Patients Randomized

Study Groups Stratification Significance Demonstrated

% Change Identified in Trial

1079 with clinically negative nodes

RM n = 362TM+RTn=352TM obs=365

N/A No, in survival N/A

586 with clinically palpable nodes

RM n = 292TM+RTn=294

N/A No, in survival N/A

CONCLUSIONS: The findings validate earlier results showing no advantage from radical mastectomy.

Although differences of a few percentage points cannot be excluded, the findings fail to show a significant survival advantage from removing occult positive nodes at the time of initial surgery or from radiation therapy

Editor's summary and comments: The NSABP B-04 trial compared less extensive operations (TM) with or without RT to traditional RM in women with primary operable breast cancer, and with long-term follow-up, no differences in any survival outcomes were observed.

NSABP B-04 has been fundamental in shaping the approach to breast cancer treatment for the last 35 years as its findings supported the “systemic” disease hypothesis, which proposed that alterations in local therapy were unlikely to impact survival.

The proof of principle that more radical treatment did not increase cure rate opened the door for subsequent

Of note, 40% of the clinically node-negative patients in the RM arm of NSABP B-04 had nodal involvement on final pathology, but only 18% of those in the no axillary lymph node dissection (ALND) arm developed clinical axillary recurrence requiring delayed ALND.

This result, coupled with the lack of survival differences observed between arms, led to ALND being regarded as a staging rather than a therapeutic procedure.

For this reason, the role of completion dissection after a positive sentinel node biopsy (SLNB) is a source of debate, but when considering the role of B04 in

2. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.

Fisher B, Anderson S, Bryant J, et al. N Engl J Med 2002;347:1233–41

Hypothesis: BCT with RT is equivalent to TM.

BACKGROUND: In 1976, they initiated a randomized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer.

METHODS: A total of 1851 women for whom follow-up data were available and nodal status was known underwent randomly assigned treatment consisting of total mastectomy, lumpectomy alone, or lumpectomy and breast irradiation.

Kaplan-Meier and cumulative-incidence estimates of the outcome were obtained

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RESULTS: The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3% in the women who underwent lumpectomy and breast irradiation, as compared with 39.2% in the women who underwent lumpectomy without irradiation (P<.001).

No significant differences were observed among the 3 groups of women with respect to disease-free survival, distant disease-free survival, or overall survival.

The hazard ratio for death among the women who

NSABP B-06 Trial Results

No. of Patients Randomized and Analyzed

Study Groups

Stratification

SignificanceDemonstrated

% ChangeIdentified in trial

1851 TM n = 589Lumpectomy n = 634Lumpectomy with RT n = 628

Nodal status

Yes,IBTR 39.2% Vs 14.3%in lumpectomy vs lumpectomy with RT at 20 y

CONCLUSIONS: Lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained.

Editor's summary and comments: NSABP-06 was designed to evaluate the efficacy of BCT with and without RT in women with tumors smaller than 4 cm in diameter.

The trial is one of several large studies evaluating the role of BCT and now reporting follow-up at 13 to 20 years after randomization.

The findings reported here are similar to those previously published; no differences in survival exist between the treatment groups.

The use of adjuvant RT did significantly reduce IBTR

Trials No of patients

Study groups

Stratification

Follow up Significance demonstrated

% change identified in trial

NSABP-06 1851 TM=589L=634L+RT=682

Nodal status

20 yr Yes,in local recurrence

39.2 Vs 14.3 % in L Vs L+RT

Milan 701 RM=349BCT+RT=352

Menopausalstatus

20 yr Yes,in local recurrence

2.3% Vs 8.8 % in RM Vs BCT and RT

EORTC10801

902 MRM=420BCT+RT=448

Stage I/IIPart centreMenopausalstatus

13.4 yr Yes,in local recurrence

12% Vs 20 % in MRM Vs BCT+RT

NCI 237 MRM=116BCT+RT=121

Age,clinical LN status

18.4 yr Yes,in local recurrence

0% Vs 22.4 % in MRM Vs BCT +RT

In NSABP B-06, only patients with positive axillary nodes received adjuvant chemotherapy.

This treatment combined with RT resulted in 50% fewer IBTRs (8.8%) than seen with RT alone in the lower risk node-negative patients (17%), indicating that chemotherapy can act synergistically with RT to prevent a subset of local recurrences.

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3. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group (EBCTG).

Lancet 2006;366:2087–106

Hypothesis: Differences in local regional recurrence (LRR) resulting from more versus less local therapy result in long-term survival differences.

BACKGROUND: In early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality.

To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomized trials that began by 1995.

METHODS: Information was available on 42,000 women in 78 randomized treatment comparisons (radiotherapy vs no radiotherapy, 23,500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300).

FINDINGS: About three-quarters of the eventual local recurrence risk occurred during the first 5 years.

In the comparisons that involved little (<10%) difference in 5-year local recurrence risk there was little difference in 15-year breast cancer mortality.

Among the 25,000 women in the comparisons that involved substantial (>10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44·6% versus 49·5% (absolute reduction 5·0%, SE 0·8, 2p<.001).

They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54.7% versus 60.1% (reduction 5.4%, SE 1.3, 2p = .0002; overall mortality reduction 4.4%, SE 1.2, 2p = .0009).

Radiotherapy produced similar proportionalreductions in local recurrence in all women (irrespective of age or tumor characteristics) and in all

To help assess the life-threatening side effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery.

There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0.06, 2p= .002) and a significant excess of non-breast cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2p = .001).

Both were slight during the first 5 years, but continued after year 15. The excess mortality was

INTERPRETATION: In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality.

Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every 4 local recurrences avoided, and should reduce 15-year overall mortality.

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Editor's summary and comments: The Early Breast Cancer Trialists' Collaborative Group (EBCTG) has centrally reviewed individual patient data every 5 years since 1985 to study the effects of RT and the extent of surgery on local control and cause-specific mortality in early breast cancer.

An important new finding in the 15-year review is that differences in local recurrence of greater than 10% at 5 years result in statistically significant differences in OS at 15 years.

The ratio of absolute effect is 4 to 1 (ie, for every 4 local recurrences prevented, 1 life is saved).

This principle is reflected in analyses addressing lumpectomy with or without RT, an adjuvant therapy resulting in an absolute risk reduction (ARR) of 19% in IBTR and 5.4% in breast cancer–specific mortality in this meta-analysis.

Node-positive mastectomy patients similarly experienced large risk reductions in 5-year local recurrence with adjuvant RT (23% vs 6%), translating into a 15-year ARR in breast cancer–specific mortality of 5.4%.

Survival outcomes in node-negative patients treated with modified radical mastectomy (MRM) were not

Another finding of the meta-analysis was that adjuvant RT results in a small increase in long-term mortality related to contralateral breast cancer, heart disease, and lung cancer.

The increase in these events was 1.3% at 15 years and did not exceed the benefit of RT on breast cancer-specific survival.

The impact of modern chemotherapy and RT regimens on these outcomes requires further study.

Level Ia evidence: prospective randomized trials in evaluation and management of the axilla

4. Sentinel-lymph node biopsy as a staging procedure in breast cancer: update of a randomized controlled trial.

Veronesi U, Paganelli G, Viale G, et al. Lancet Oncol 2006;6:983–90

Hypothesis: SLNB is equivalent to ALND in node-negative patients.

BACKGROUND: In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favorable effect on quality of life.

Results of previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less.

They aimed to update this trial with results from longer follow-up.

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METHODS: Women with breast tumors of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group).

Analysis was restricted to patients whose tumor characteristics met eligibility criteria after treatment.

The major end points were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival

FINDINGS: Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; 8 of those with negative SLNs were found to have false-negative SLNs.

Of the 259 patients in the SLN group, 92 (36%) had a positive SLN and 167 (65%) had a negative SLN.

One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative).

After a median follow-up of 79 months (range 15–97), 34 events associated with breast cancer occurred: 18 in

Milan Institute Trial Results

No of patientsrandomized

Study Groups Stratification SignificanceDemonstrated

% change identified in trial

516 SLNB ± ALND n = 259ALND n = 257

Randomized patients whose SLN mapped on lymphoscintigraphy

None 31.7% Vs 15.7% at 12 yr.

INTERPRETATIONS: SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay.

The findings that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas 8 cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research.

Editor's summary and comments: SLN mapping in breast cancer was described by Giuliano and colleagues in 1994, and subsequently shown to predict axillary nodal status in 95.6% of patients.

In the NSABP B-32 trial of 5611 patients, more than 97% of patients had an SLN detected and removed using lymphoscintigraphy, blue dye, and palpation; accuracy was 97.1%, confirming feasibility of the technique.

In the ACOSOG Z10 trial involving a similar number of patients, no difference in SLN detection rate was observed when tracing was performed with blue dye

The Milan trial randomized 516 patients with T1 tumors undergoing quadrantectomy with planned adjuvant RT to either SLNB followed by ALND or to SLNB followed by completion ALND (cALND) only if the SLN contained metastases.

Concordant with earlier reports, the accuracy of SLN in patients undergoing ALND was 96.9%; in addition, patients in the SLNB group had a decrease in both short- and long-term morbidity. Quality of life benefits have been confirmed in subsequent trials designed to specifically address this question

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To date, oncologic outcomes appear identical in the 2 arms of the Milan Institute trial, although the relatively small size of the patient cohort limits its power to show small differences in survival.

Results of NSABP B-32, which enrolled a significantly larger number of patients than the Milan Institute or the underpowered Sentinella/GIVOM study, should, when mature, provide additional data regarding associated disease-free survival (DFS) and OS outcomes.

After a median follow-up of 79 months, only one case of overt clinical axillary metastasis was observed in the SLNB arm of the Italian study, although 8 false negatives would be expected based on technical outcomes.

This result demonstrated, as in NSABP-B04, that not all nodal metastases become clinically evident.

In addition, a subset analysis of the 60 patients with isolated micrometastatic disease in the SLN showed that only 17% of these patients had other axillary nodal metastases, providing additional evidence that cALND may not be warranted in all such cases.

THANK YOU.

Level Ia evidence: prospective randomized trials addressing adjuvant radiation of the breast

Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience.

Fisher B, Land S, Mamounas E, et al. Semin Oncol 2001;28:400–18

Hypothesis: RT after excision of ductal carcinoma in situ (DCIS) reduces IBTR.

Published abstract: The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted 2 sequential randomized clinical trials to aid in resolving uncertainty about the treatment of women with small, localized, mammographically detected ductal carcinoma in situ (DCIS).

After removal of the tumor and normal breast tissue so that specimen margins were histologically tumor-free (lumpectomy), 818 patients in the B-17 trial were randomly assigned to receive either radiation therapy to the ipsilateral breast or no radiation therapy.

B-24, the second study, which involved 1804 women,

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The findings in this report continue to demonstrate through 12 years of follow-up that radiation after lumpectomy reduces the incidence rate of all IBTRs by 58%.

They also demonstrate that the administration of TAM after lumpectomy and radiation therapy results in a significant decrease in the rate of all breast cancer events, particularly in invasive cancer.

The findings from the B-17 and B-24 studies are related to those from the NSABP prevention (P-1) trial, which demonstrated a 50% reduction in the risk of invasive cancer in women with a history of atypical ductal

Editor's summary and comments: NSABP-17 is 1 of 4 major randomized controlled trials that address the role of adjuvant RT in local control of DCIS

Outcomes after 12 years demonstrated a 55% relative risk reduction in IBTR following RT.

Five years after randomization, the benefit of RT appeared greatest in reducing invasive recurrences, but with longer follow-up there was equal reduction in rates of intraductal and invasive cancers.

Radiation had no effect on the secondary survival end points in this study, which is not powered to identify

Similar themes are observed in the SweDCIS, EORTC 10853, and the UK-ANZ trials,also examining adjuvant RT in DCIS treatment.

All studies reported significant radiation-associated benefits on local control, and no subset analysis has been able to identify patients in whom RT does not affect rates of local recurrence.

Patient subsets were extensively evaluated in the EORTC trial, which looked at subgroups of patients younger than 40 years, high-grade tumors, patients with symptoms at presentation, cribriform and solid growth patterns, and doubtful margin status; benefit

This article by Fisher and colleagues also reviews most recent outcomes analysis from NSABP B-24, which sought to examine the role of adjuvant tamoxifen in patients with DCIS treated by lumpectomy and RT.

Patients were not required to have histologically negative margins to enroll in NSABP B-24.

After a mean follow-up of almost 7 years, event-free survival was 83% in patients treated with tamoxifen and only 77% in those treated with placebo.

Tamoxifen treatment resulted in a relative risk reduction of 47% in IBTR, but no effect of tamoxifen

2.Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial.

Ragaz J, Spinelli JJ, Phillips N, et al. J Natl Cancer Inst 2005;97:116–26

Hypothesis: Postoperative RT improves locoregional recurrence, DFS, and OS in premenopausal patients with high risk breast cancer.

BACKGROUND: The British Columbia randomized radiation trial was designed to determine the survival impact of locoregional radiation therapy in premenopausal patients with lymph node-positive breast cancer treated by modified radical mastectomy and adjuvant chemotherapy.

Three hundred eighteen patients were assigned to receive no further therapy or radiation therapy (37.5 Gy in 16 fractions).

Previous analysis at the 15-year follow-up showed that radiation therapy was associated with a statistically significant improvement in breast cancer survival but

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RESULTS: At the 20 year follow up (median follow up for live patients: 249 months) chemotherapy and radiation therapy, compared with chemotherapy alone, were associated with a statistically significant improvement in all end points analyzed, including survival free of isolated locoregional recurrences (74% versus 90%, respectively; relative risk [RR] = 0.36, 95% confidence interval [CI] = 0.18 to 0.71; P = .002), systemic relapse-free survival (31% versus 48%; RR = 0.66, 95% CI = 0.49 to 0.88; P = .004), breast cancer-free survival (48% versus 30%; RR = 0.63, 95% CI = 0.47 to 0.83; P = .001), breast cancer-specific survival (53% versus 38%; RR = 0.67, 95% CI = 0.49 to 0.90; P =

CONCLUSION: For patients with high-risk breast cancer treated with modified radical mastectomy, treatment with radiation therapy (schedule of 16 fractions) and adjuvant chemotherapy leads to better survival outcomes than chemotherapy alone, and it is well tolerated, with acceptable long-term toxicity.

Level Ia evidence: meta-analysis analyzing use of polychemotherapy in operable breast cancer

* Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: and overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group.

Lancet 2005;365:1687–717

Hypothesis: Adjuvant chemotherapy and endocrine therapy improve survival in patients with breast cancer.

BACKGROUND: Quinquennial overviews (1985–2000) of the randomized trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects.

METHODS: Collaborative meta-analyses were undertaken of 194 unconfounded randomized trials of adjuvant chemotherapy or hormonal therapy that began by 1995.

Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxorubicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modern aromatase inhibitors.

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FINDINGS: Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% for women younger than 50 years of age when diagnosed and by about 20% for those of age 50 to 69 years when diagnosed, largely irrespective of the use of tamoxifen and of estrogen receptor (ER) status, nodal status, or other tumor characteristics.

Such regimens are significantly (2p = .0001 for recurrence, 2p<.00001 for breast cancer mortality) more effective than CMF chemotherapy.

Few women of age 70 years or older entered these

For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% , largely irrespective of the use of chemotherapy and of age (<50, 50–69, > or = 70 years), progesterone receptor status, or other tumor characteristics.

5 years is significantly (2p<.00001 for recurrence, 2p = .01 for breast cancer mortality) more effective than just 1 to 2 years of tamoxifen.

For ER-positive tumors, the annual breast cancer mortality rates are similar during years 0 to 4 and 5 to 14, as are the proportional reductions in them by 5

Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments.

For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen.

For, if mortality reductions of 38% (age <50 years) and 20% (age 50–69 years) from such chemotherapy were

INTERPRETATION: Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.

Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18.

Wolmark N, Wang J, Mamounas E, et al. J Natl Inst Canc Monogr 2001;30:96–102

Hypothesis: Neoadjuvant chemotherapy improves survival in patients with operable breast cancer as compared with adjuvant treatment.

National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was initiated in 1988 to determine whether 4 cycles of doxorubicin/cyclophosphamide given preoperatively improve survival and disease-free survival (DFS) when compared with the same chemotherapy given postoperatively.

Secondary aims included the evaluation of preoperative chemotherapy in downstaging the primary breast tumor and involved axillary lymph nodes, the comparison of lumpectomy rates and rates of ipsilateral breast tumor recurrence (IBTR) in the 2

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There continue to be no statistically significant overall differences in survival or DFS between the 2 treatment groups.

Survival at 9 years is 70% in the postoperative group and 69% in the preoperative group (P = .80). DFS is 53% in postoperative patients and 55% in preoperative patients (P = .50).

A statistically significant correlation persists between primary tumor response and outcome, and this correlation has become statistically stronger with longer follow-up. Patients assigned to preoperative chemotherapy received notably more lumpectomies

Although the rate of IBTR was slightly higher in the preoperative group (10.7% versus 7.6%), this difference was not statistically significant.

Marginally statistically significant treatment-by-age interactions appear to be emerging for survival and DFS, suggesting that younger patients may benefit from preoperative therapy, whereas the reverse may be true for older patients.

Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis

Mauri D, Pavlidis N, and Ioannidis JP. J Natl Cancer Inst 2005;97:188–94

Hypothesis: Survival outcomes are equivalent in patients with operable breast cancer whether chemotherapy is administered before or after surgery

BACKGROUND: Interest in the use of preoperative systemic treatment in the management of breast cancer has increased because such neoadjuvant therapy appears to reduce the extent of local surgery required.

They compared the clinical end points of patients with breast cancer treated preoperatively with systemic therapy (neoadjuvant therapy) and of those treated postoperatively with the same regimen (adjuvant therapy) in a meta-analysis of randomized trials.

METHODS: They evaluated 9 randomized studies, including a total of 3946 patients with breast cancer, that compared neoadjuvant therapy with adjuvant therapy regardless of what additional surgery or radiation treatment was used.

Fixed and random effects methods were used to combine data.

Primary outcomes were death, disease progression, distant disease recurrence, and loco-regional disease recurrence. Secondary outcomes were local response and conservative local treatment.

RESULTS: They found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms associated with death (summary risk ratio [RR] = 1.00, 95% confidence interval [CI] = 0.90 to 1.12), disease progression (summary RR = 0.99, 95% CI = 0.91 to 1.07), or distant disease recurrence (summary RR = 0.94, 95% CI = 0.83 to 1.06).

However, neoadjuvant therapy was statistically significantly associated with an increased risk of loco-regional disease recurrences (RR = 1.22, 95% CI = 1.04 to 1.43), compared with adjuvant therapy, especially in

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CONCLUSIONS: Neoadjuvant therapy was apparently equivalent to adjuvant therapy in terms of survival and overall disease progression.

Neoadjuvant therapy, compared with adjuvant therapy, was associated with a statistically significant increased risk of loco-regional recurrence when radiotherapy without surgery was adopted.

Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. Romond, E.H., Perez EA, Bryant J, et al. N Engl J Med 2005;353(16):1673–84.29

Hypothesis: Trastuzumab given concurrently with adjuvant chemotherapy improves DFS in patients with operable breast cancer overexpressing HER2.

Published abstract: They present the combined results of 2 trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer.

METHODS: The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2).

The North Central Cancer Treatment Group trial N9831 compared 3 regimens: doxorubicin and

RESULTS: By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis.

Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12% at 3 years.

Trastuzumab therapy was associated with a 33% reduction in the risk of death (P = .015). The 3-year

CONCLUSIONS: Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer.

Similar results were reported from the HERA trial, an international, multicenter trial that examined 5102 patients with HER2-positive tumors who, after completion of standard chemotherapy, were randomized to observation, for 1 or 2 years of traztuzumab.

The 1- versus 2-year comparison is not yet mature, but these results are awaited with great interest.

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Significant risk of cardiac complications was seen with administration of trastuzimab in all reports; 4.1% of patients in NSABP B-31 developed congestive heart failure or died of cardiac disease while enrolled in the study.

Cardiotoxicity caused 4.3% of patients in the HERA trial to discontinue the drug during trial despite stringent entry requirements.

Drug reduction schemes such as that presented in the FinHer trial seem to reduce this risk without compromising efficacy

Level Ia evidence: prospective randomized trials addressing the role of endocrine therapy in breast cancer prevention and treatment

Published abstract: Initial findings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor positive tumors and osteoporotic fractures in women at increased risk for breast cancer.

Side effects of varying clinical significance were observed.

The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial findings.

METHODS: Women (n = 13,388) were randomly assigned to receive placebo or tamoxifen for 5 years.

Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs).

Estimates of the net benefit from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk.

Statistical tests were 2-sided.

RESULTS: After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5

Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92).

Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported.

Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically significant. The net benefit achieved with tamoxifen varied according to

CONCLUSIONS: Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all beneficial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboembolic events and endometrial cancer. Readily identifiable sub sets of individuals comprising 2.5 million women could derive a net benefit from the drug.

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Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial.

Fisher B, Dignam J, Bryant J, et al. J Natl Cancer Inst 2001;93:684–90

Hypothesis: More than 5 years of adjuvant tamoxifen therapy does not improve outcomes when compared with 5 years of therapy.

Published abstract: BACKGROUND: Previously reported information from B-14, a national Surgical Adjuvant Breast and Bowel Project (NSABP) randomized, placebo-controlled clinical trial, demonstrated that patients with estrogen receptor (ER)-positive breast cancer and negative axillary lymph nodes experienced a prolonged benefit from 5 years of tamoxifen therapy.

When these women were rerandomized to receive either placebo or more prolonged tamoxifen therapy, they obtained no additional advantage from tamoxifen through 4 years of follow-up.

METHODS: Patients (n = 1172) who had completed 5 years of tamoxifen therapy and who were disease free were rerandomized to receive placebo (n = 579) or tamoxifen (n = 593).

Survival, disease-free survival (DFS), and relapse-free survival (RFS) were estimated by the Kaplan-Meier method; the differences between the treatment groups were assessed by the log-rank test.

Relative risks of failure (with 95% confidence intervals) were determined by the Cox proportional hazards model. P values were 2-sided.

RESULTS: Through 7 years after reassignment of tamoxifen-treated patients to either placebo or continued tamoxifen therapy, a slight advantage was observed in patients who discontinued tamoxifen relative to those who continued to receive it: DFS = 82% versus 78% (P = .03), RFS = 94% versus 92% (P = .13), and survival = 94% versus 91% (P = .07), respectively.

The lack of benefit from additional tamoxifen therapy was independent of age or other characteristics. CONCLUSION: Through 7 years of follow-up after rerandomization, there continues to be no additional

Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group, Forbes JF, Cusick J, Budzar A, et al. Lancet Oncol 2008;9:45–53.

Hypothesis: Five years of adjuvant anastrozole treatment improves survival compared with tamoxifen therapy, and has an improved side effect profile

BACKGROUND: Little data exist on whether efficacy benefits or side-effects persist after 5 years of adjuvant treatment with an aromatase inhibitor.

They aimed to study long-term outcomes in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial that compares anastrozole with tamoxifen after a median follow-up of 100 months

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METHODS: They analyzed postmenopausal women with localized invasive breast cancer.

The primary endpoint disease-free survival (DFS), and the secondary endpoints time to recurrence (TTR), incidence of new contralateral breast cancer (CLBC), time to distant recurrence (TTDR), overall survival (OS), and death after recurrence were assessed in the total population (intention to treat; ITT: anastrozole, n = 3125; tamoxifen, n = 3116; total 6241) and the hormone-receptor-positive subpopulation, the clinically important subgroup for which endocrine treatment is now known to be effective (84% of ITT:

FINDINGS: At a median follow-up of 100 months (range 0–126), DFS, TTR, TTDR, and CLBC were improved significantly in the ITT and hormone-receptor-positive populations.

For hormone-receptor-positive patients: DFS hazard ratio (HR) 0.85 (95% CI 0.76–0.94), P = .003; TTR HR 0.76 (0.67–0.87), P = .0001; TTDR HR 0.84 (0.72–0.97), P = .022; and CLBC HR 0.60 (0.42–0.85), P = .004.

Absolute differences in time to recurrence increased over time (TTR 2.8% [anastrozole 9.7% vs tamoxifen 12.5%] at 5 years and 4.8% [anastrozole 17.0% vs tamoxifen 21.8%] at 9 years) and recurrence rates

Fracture rates were higher in patients receiving anastrozole than in those receiving tamoxifen during active treatment (number [annual rate]: 375 [2.93%] vs 234 [1.90%]; incidence rate ratio [IRR] 1.55 [1.31–1.83], P<.0001), but were not different after treatment was completed (off treatment: 146 [1.56%] vs 143 [1.51%]; IRR 1.03 [0.81–1.31], P = .79).

They did not note any significant difference in risk of cardiovascular morbidity or mortality between anastrozole and tamoxifen treatment groups.

INTERPRETATION: These data show long-term safety findings and establish clearly the long-term efficacy of anastrozole compared with tamoxifen as initial adjuvant treatment for postmenopausal women with hormone-sensitive, early breast cancer, and provide statistically significant evidence of a larger carryover effect after 5 years of adjuvant treatment with anastrozole compared with tamoxifen.

CONCLUSION

RT after excision of DCIS reduces IBTR- NSABP-17

RT after MRM &adjuvant CT improves LRR,OS,DFS.-British columbia TRIAL.

Adjuvant CT & ET improve survival in Breast cancer.

Neoadjuvant chemotherapy improves survival in patients with operable breast cancer as compared with adjuvant treatment- NSABP-18.

Trastuzumab given concurrently with adjuvant chemotherapy improves DFS.

Five years of adjuvant anastrozole treatment improves survival compared with tamoxifen therapy, and has an improved side effect profile-ATAC

More than 5 years of adjuvant tamoxifen therapy does not improve outcomes when compared with 5 years of therapy.-NSABP-14.

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