LANDMARK CLINICAL TRIALS

IN BREAST CANCER

Dr. Aaditya Prakash,Radiation oncology, BMCHRC

PREVENTION TRIALS

Randomized data on chemoprevention

• Randomized study delivered placebo versus tamoxifen

• 13,388 females for 5 years• RR of invasive and non-invasive breast cancer

was reduced by 49 and 50%, respectively, with the use of tamoxifen

• After 7 years of follow-up, tamoxifen led to a 32% reduction in osteoporotic fractures.

• Side-effects such as endometrial cancer, deep-vein thrombosis, etc.

• The study concluded that tamoxifen use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease.

NSABP P1

Randomized data on chemoprevention

• Prospective, double-blind, randomized trial • Involved 19,747 postmenopausal females and

studied tamoxifen versus raloxifene in preventing breast cancer

• The final analysis initiated after at least 327 incident invasive breast cancers were diagnosed: 163 and 168 cases of invasive breast cancer in tamoxifen and raloxifene treated groups

• No differences were found for other invasive cancer sites, ischemic heart disease events, or stroke. Thromboembolic events occurred less often in the raloxifene group, and the number of osteoporotic fractures in the groups was similar

• Generally, tamoxifen is more often recommended in the premenopausal patients, and raloxifene for the postmenopausal patients

• .

NSABP P2

RADIATION THERAPY TRIALS

NSABP B-02

DCIS

• With a median follow up of 8.9  years, RT approximately halved the rate of ipsilateral breast events.

• RT was effective in all subgroups. There were 291 “low-risk” cases of DCIS that were low-grade, >20 mm in size, and with negative surgical margins identified.

• 10-year risk of an ipsilateral event in those allocated to lumpectomy alone was substantial at 30.1%, and even with this relatively small number of women, the effect of RT was highly significant.

Meta-analysis by the Early

Breast Cancer

Trialists’ Collaborativ

e Group (EBCTCG),

Breast Conservation

Trials2011

DCIS■ RTOG 9804 enrolled patients with smaller lesions, all

low- or intermediate-grade DCIS, and had a much higher rate adjuvant tamoxifen use (62%).

■ Recurrence rates were 6.7% in the observation arm, compared to 0.9% in the RT arm, after a median follow-up of 7.2 years (HR = 0.11; 95% CI = 0.03 to 0.47; p = 0.0003).

■ This suggests that even in low-risk DCIS, RT can lower the risk of in-breast recurrence.

DCIS

EARLY STAGE BREAST CANCER

NSABP-B06(1976–1980)

25-Year follow-up of a randomized trial of 590, 632, and 629 patients treated with mastectomy, lumpectomy alone, or lumpectomy followed by adjuvant RT Cumulative incidence of recurrence in the ipsilateral breast was 14.3 versus 39.2% after lumpectomy with or without RT, respectively (p < 0.001) No significant differences were observed with respect to DFS, DDFS, or OS OS was ~ 60% for all 3 groups (at 12 years follow-up)

Milan(1973–1980)

20-Year follow-up of a randomized trial of 349 patients and 352 patients treated with mastectomy vs quadrantectomy followed by adjuvant RT, respectively Cumulative incidence of same-breast recurrence was 8.8 versus 2.3%, respectively Overall survival 65 and 65% (p = NS) Rates of death from all causes was 41.7 versus 41.2% (p = 1.0) and rates of death from breast cancer were 26.1 versus 24.3% (p = 0.8) for the two groups No significant difference between the two groups in the rates of contralateral-breast carcinomas, distant metastases, or second primary cancers

NCI (1980–1986)

Randomized trial for stages I-II breast cancer patients treated with mastectomy (n=247) vs lumpectomy, followed by adjuvantRT (n=237) Node-positive patients on axillary dissection received adjuvantchemotherapy Overall survival was 75% versus 77% at 10 years No diffrence between OS (75 versus 77%) or DFS observed The probabilities of failure in the irradiated breast were 12 and 20% by 5 and 8 years, respectively

EORTC 10801 Randomized trial for stages II breast cancer (<5cm) patients treated with mastectomy (n=426) vs lumpectomy followed by adjuvant RT (n=456) At 10 years, OS (66 versus 65%) and DDFS (66 versus 61%) were not different statistically Locoregional recurrence after mastectomy was 12 versus 20% after lumpectomy and RT (p = 0.01)

BREAST-CONSERVING THERAPY

AcceleratedWhole-Breast Irradiation/Hypofractionated RT

• Randomized studied the efficacy of hypofractionated versus standard radiation dose regimen in whole breast irradiation for N- breast cancer after lumpectomy (margin negative)

• Radiation regimens were 42.5 Gy in 16 fractions versus 50 Gy in 25 fractions

• The risks of local recurrence at 10 years were 6.7 and 6.2 respectively, after standard or hypofractionated regimens

• Good or excellent cosmetic outcome was seen in 71.3 and 69.8% of patients after standard or hypofractionated regimens, respectively

• Thus, accelerated, hypofractionated whole-breast irradiation was not inferior to standard radiation treatment in women who had undergone breast-conserving surgery at 10 years.

Whelan et al

(Canada)

• Randomized trial studied standard versus hypofractionated adjuvant RT in 2,236 women with pT1–3a, pN0–1 breast cancer

• After surgery, patients were randomized to 50 Gy in 25 fractions vs 41.6 Gy in 13 Fractions vs 39 Gy in 13 fractions

• The rate of 5-year local-regional tumor relapse at 5 years was 3.6 versus 3.5% versus 5.2%, after 50, 41.6, and 39 Gy of radiation

• The Estimated Absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0.2% (95% CI, 1.3–6%) after 41.6 Gy and 0.9% (95% CI, 0.8–3.7%) after 39 Gy

• Lower rates of late adverse effects were reported with 39 Gy and 50 Gy

• Thus, a lower total dose in a smaller number of fractions offered similar rates of tumor control and side effects as the standard dose regimen for breast cancer

START A, (UK)

• Similar study setting as in START A but tested 50 Gy in 25 fractions versus 40 Gy in 15 fractions in 2,215 patients with pT1–3apN0–1 breast cancer

• The rate of locoregional tumor relapse at 6 years was 2.2 versus 3.3% in the 40- and 50-Gy groups, respectively.

• The estimated absolute differences in 6-year locoregional relapse rates compared with 50 Gy was 0-7% after 40 Gy

• Lower rates of late adverse effects after 40 than with 50 Gy were reported.

START B, (UK)

BREAST-CONSERVING THERAPY

AcceleratedPartial Breast Irradiation(APBI)

TARGIT-A TRIAL

TARGIT-A TRIAL

Randomized Trials of Whole-Breast Vs PBI

RANDOMIZED STUDIES FOR STAGE I BREAST CANCER COMPARING SURGERY & HORMONE THERAPY TO SURGERY, RADIATION THERAPY, & HORMONES

• 636 Stage T1N0 and ER+ breast cancer patients over 70 years of age were randomized to tamoxifen (TAM) alone(n = 319) vs RT plus TAM (n = 317)

• The 5-year LR rates were 1 and 7% (p <0.001), and favoured the RT plus TAM group

• No significant differences in mastectomy for LR, distant metastasis, or 5-year OS (86 versus 87%) were observed

CALGB/ECOG

trial

• 769 Early-stage breast cancer (tumor ≤

5 cm) patients were randomized to TAM alone (n = 383) or RT plus TAM (n = 386)

• The 5-year LR rates were 7.7 versus 0.6% (p < 0.001), with a corresponding 5-year DFS rates of 84 versus 91% (p = 0.004), favoring the irradiation group

• The 5-year axillary recurrence rates (0.5 versus 2.5%) also favored combined RT plus TAM (p = 0.049)

• Patients with stage T1 and ER positive disease also benefitted from RT (5-year LR rates of 0.4 versus 5.9%, p < 0.001)

• No significant differences in distant metastasis or OS rates were observed

PMH

• Randomized 1,099 patients with N negative invasive breast cancer (tumor ≤1 cm) to TAM alone (n = 336), RT plus placebo (n = 336), or RT plus TAM (n = 337)

• Cumulative incidence of IBTR through 8 years was 16.5, 9.8, and 2.8% for TAM, RT alone, and RT plus TAM, respectively

• RT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status

• TAM provided a significant reduction in contralateral breast cancer (p = 0.039)

• OS rates were 93, 94, and 93% in the 3 groups (p = 0.93)

NSABP B21

POST-MASTECTOMY RADIATION THERAPY

• Randomized 318 premenopausal

breast cancer patients to PMRT versus observation

• RT fields included chest wall, supraclavicular, and internal mammary lymph node regions versus no PMRT

• The 20-year LR rates were 13 versus 39%, and favored adjuvant RT (p = 0.0005)

• The 20-year OS rates were 47 versus 37%, and favoured PMRT (p = 0.03)

British Columbia

trial

• Randomized 1,708 premenopausal

patients with stage II and III breast cancer to PMRT versus observation

• RT fields included chest wall, supraclavicular, and internal mammary lymph node regions

• All patients received adjuvant chemotherapy

• The 10-year LR rates were 9 versus 32%, and favored adjuvant RT (p < 0.0001)

• The 10-year OS rates were 45 versus 54%, favored adjuvant RT (p < 0.0001)

DBCG 82b trial

• Randomized 1,375 postmenopausal patients with stage II and III breast cancer to PMRT versus observation

• RT fields included chest wall, supraclavicular, and internal mammary lymph node regions

• All patients received hormonal therapy with tamoxifen

• The 10-year LR rates were 8 versus 35%, and favored PMRT (p < 0.0001)

• The 10-year OS were 45 versus 36%, and favored adjuvant RT (p = 0.03)

DBCG 82c trial

Re-analysis of theDanish trials after 15-years of follow-up

LOCOREGIONAL RECURRENCE AND OVERALL SURVIVAL AT 15 YEARS IN PATIENTS WITH 1–3 POSITIVE VERSUS >= 4 POSITIVE

LYMPH NODES

NEOADJUVANT THERAPY TRIALS

CHEMO-THERAPY

Neoadjuvant Vs Adjuvant AC

■ Neoadjuvant AC effectively downstaged both the primary tumor (36% complete clinical response rate) and the axillary lymph nodes (73% complete clinical nodal response in patients with clinically positive lymph nodes).

■ No differences in 5-year disease-free (67% both groups, P = .99) and overall survival rates (80% both groups, P = .83) were observed between treatment groups.

■ Recently updated outcome results from the B-18 study continue to demonstrate that the equivalence between preoperative and postoperative chemotherapy, and the significant correlation between pCR and outcome has persisted through 9 years of follow up.

Neoadjuvant AC Plus Docetaxel

AC ACT P-VALUE

Clinical Response AC (n=1502) AC -> T (n=687) PValue

Complete response rate, % 40 65 < .001

Overall response rate, % 85 91 < .001

Pathologic Response AC (n=1492) AC -> T (n=718) PValue

Pathologic complete response rate, %

13.7 25.6 < .001

Histologically positive nodes, %

48.5 40.5 < .01

Surgical Procedure      

Lumpectomy, % 61% 63% .70

NSABP B-27 Randomized 2411 operable cancers to AC versus AC Dversus AC S D Breast conservation rate was same between arms. The pCR rate favored AC D over AC (p < 0.001)

MDACC trial Randomized 258 patients with stages I-IIIa Weekly P FAC versus every 3 week P FAC Breast conservation 47 versus 38% favor weekly P-FAC (p = 0.05) The pCR rate favored weekly P FAC (p = 0.02)

ECTO trial Randomized 1,355 patients with stages T2-T3, N0-N1 AP CMF S versus S APCMF versus S A CMF Breast conservation 65 versus 34% in favor of AP CMF S (p <0.001)

Gerpar–DUO trial Randomized 913 patients with stages T2-T3, N0-N2 Dose dense AD S versus AC D S Breast conservation 63 vs 58% in favor of AC D S (p = 0.05) The pCR rate favored AC D S ( p < 0.001)

NEOADJUVANT THERAPY TRIALS

TARGET THERAPY

HER2 Targeted Therapy

The results were that 45.8% of patients receiving dual HER2-targeted therapy with docetaxel achieved a pCR compared with29.0% (95% CI, 20.6%-38.5%) of patients receivingtrastuzumab and docetaxel alone.

HER2 Targeted Therapy

■ The majority of patients achieved pCR in the breast (61.6% in arm A, 57.3% in arm B, and 66.2% in arm C), with pCR including lymph nodes in 50.7% (arm A), 45.3% (arm B), and 51.9% of patients (arm C).

■ 11 patients had declines in left ventricular ejection fraction to less than 50%, and diarrhea was the most common adverse event.

HER2 Targeted Therapy■ Gepar Quinto trial- EC(4) D + Trastuzumab pCR – 30.3% D + Lapatinib pCR – 22.7%

■ Neo ALTTO trial- Lapatinib + Pacli pCR – 24%

Trastuzumab + Pacli pCR – 29%

T + L + Pacli pCR – 51.3%

■ NeoSphere trial – Pertuzumab + Trastuzumab + paclitaxel

pCR – 45.8%

■ Tryphaena trial – Pertuzumab + trastuzumab + Doce + Carbo

(in early & LABC) pCR – 66.2%

NEOADJUVANT THERAPY TRIALS

ENDOCRINE HR+ THERAPY

ADJUVANT THERAPY TRIALS

When to offer adjuvant therapy

COMPARISON OF PROSPECTIVE TRIALS UTILIZING MULTIGENE TESTS

FOR PROGNOSTIC AND PREDICTIVE FACTORS

ADJUVANT CHEMOTHERAPY

ADJUVANT TREATMENT AND SURVIVAL IMPROVEMENT OVER PAST 40 YEARS

q4w

C: 100mg/m2/d, D1-14M: 40mg/m2, D1,8F: 600mg/m2, D1,8

386 ptsLN: positiveMenopausal: bothHormone: N/A None

CMF x 12

RFS OS

20 yrs follow-up

New England Journal of Medicine 1976; 294: 405-410 New England Journal of Medicine 1995; 322: 901-966

Classic CMF

Istituto Nazionale Tumori, Milan, ItalyGianni Bonadonna et al. 1973-1975

20yr

RR ↓Risk

Recur 65% 35%

OS 76% 24%

2194 ptsMenopausal: bothLN: positive*TAM non-responder

AC x 4

CMF x 6

A: 60mg/m2, D1C: 600mg/m2, D1 q3

w

C: 750mg/m2, D1M: 40mg/m2, D1,8F: 600mg/m2, D1,8

q4w

NSABP B-151984-1988

Journal of Clinical Oncology 1990;8:1483-1496

AC x 4 6m period CMF x 3

C: 100mg/m2/d, D1-14M: 40mg/m2, D1,8F: 600mg/m2, D1,8

q4w

Follow-up: 3 yrs

• Comprehensive meta‐analysis of randomized controlled trials of chemotherapy showed that 6 months of anthracycline‐based chemotherapy reduced mortality by 38% in women aged <50 years and by 20% in women aged 50–69 years, irrespective of ER status, nodal status and other tumour characteristics

• Similarly, 5 years of tamoxifen reduced mortality by 31% after ER‐positive breast cancer irrespective of age, chemotherapy and tumour characteristics

• Oophorectomy or ovarian suppression, when given as the only adjuvant systemic therapy, reduced mortality by about 13%

• Impact of oophorectomy was attenuated when chemotherapy was also given

EBCTCG meta‐

analysisfor

chemother-apy and hormonetherapy (2005) Lancet

• Combined analyses of several trials of anthracycline versus anthracycline plus taxane chemotherapy showed a signifi cant survival advantage for adding a taxane to the treatment of HER2‐positive and ER‐negative early‐stage breast cancers

• A meta‐analysis of taxane‐containing adjuvant regimens showed a 15% survival advantage for the addition of taxanes, either sequentially or concurrently, to anthracyclines in the treatment of node‐positive disease

Role of adjuvant taxanes

according to biomarker

profile and nodal status

Hayes et al . (2007) N Engl J

Med ;De Laurentiis et

al. (2008) J Clin

Oncol

DOSE DENSE THERAPY

ADJUVANT ENDOCRINE HR+ THERAPY

NSABP B-14• Tumors With ER 10 fmol/mg• Histologically Neg. Axillary Nodes,N-• TM or Lump. + Ax. Diss. +XRT

Stratification• Age• Clinical Tumor

Size• Quantitative ER• Type of

Operation

Placebo TAM

NSABP B-14: NODE NEGATIVE PATIENTS

Tamoxifen Placebo p Value

DFS 56% 46% < 0.0001

OS 71% 65% = 0.0015

No advantage in continuing tamoxifen beyond 5 yrs*Through 15 years in 2871 patients

NSABP B-21

NSABP B-21: OUTCOMES■ Cumulative incidence of IBTR over an 8

year period was 16.5% with tamoxifen alone, 9.3% with radiation and placebo, and 2.8% with radiation and tamoxifen

■ Radiation reduced IBTR below the level achieved with tamoxifen alone, regardless of estrogen receptor status

■ Distant treatment failures were infrequent and not significantly different among the three groups (P=.28)

■ When tamoxifen-treated women were compared with those who received radiation and placebo, there was a significant reduction in contralateral breast cancer (hazard ratio, 0.45; P=.039).

■ Survival in the three groups was 93%, 94% and 93%, respectively

■ Tamoxifen was not as effective as breast radiation in controlling the disease in the breast

PATIENTS(n)

TREATMENT

F/u(years)

% IBTR

% RISKREDUCTION

334 TAM 7 16.5 --

332 RT + Placebo -- 9.3 49

334 TAM + RT -- 2.8 81/63

• Comprehensive meta‐analysis of randomized controlled trials of chemotherapy showed that 6 months of anthracycline‐based chemotherapy reduced mortality by 38% in women aged <50 years and by 20% in women aged 50–69 years, irrespective of ER status, nodal status and other tumour characteristics

• Similarly, 5 years of tamoxifen reduced mortality by 31% after ER‐positive breast cancer irrespective of age, chemotherapy and tumour characteristics

• Oophorectomy or ovarian suppression, when given as the only adjuvant systemic therapy, reduced mortality by about 13%

• Impact of oophorectomy was attenuated when chemotherapy was also given

EBCTCG meta‐

analysisfor

chemother-apy and hormonetherapy (2005) Lancet

AROMATASE INHIBITORS

• A meta‐analysis of trials of adjuvant hormone therapy in menopausal women showed a 23% risk reduction in recurrence by replacing 5 years of tamoxifen with 5 years of an aromatase inhibitor as adjuvant therapy for ER‐positive breast cancer, but no overall survival benefit with a median follow‐up of 6 years

• Combining 2–3 years of tamoxifen with 2–3 years of an aromatase inhibitor reduced recurrence by 40% and mortality by 21%

• However, the absolute benefit was just a 3% improvement in recurrence‐free survival in either strategy  

Impact of adjuvant AI

hormone receptor

+ve breast cancer

Dowsett et al. (2009) J Clin

Oncol

OVARIAN SUPPRESSION/ABLATION TRIALS

NSABP B-03

SOFT/TEXT

■ SOFT: SUPPRESSION OF OVARIAN FUNCTION TRIAL

■ TEXT: TAMOXIFEN AND EXEMESTANE TRIAL (at NYU)

■ Both Phase III Trials; Exemestane Plus gonadotrophin-releasing hormone (GnRH) Analogue as adjuvant therapy for premenopausal women with hormone receptor positive breast cancer

■ Goserelin (zoladex 3.6 sc monthly), leuprorelin (lupron 3.75 im monthly), buserelin, triptorelin (3.75 im monthly)

TEXT & SOFTTAMOXIFEN + OFS VS. EXEMESTANE + OFS

Tamoxifen 20 mg/day+ OFS* (n = 1338)Premenopausal, HR+ BC

≤ 12 wks after surgeryN = 2672

Stratified by trial, use of chemotherapy, nodal status

*OFS TEXT: triptorelin 3.75 mg IM every 28 days for 6-8 weeks prior to

initiation of HT or concurrently with chemotherapy. SOFT: triptorelin, bilateral oophorectomy or Ovarian irradiation

TEXT

Exemestane 25 mg/day+ OFS* (n = 1021)

Tamoxifen 20 mg/day

• Premenopausal HR+ BC≤ 12 wks after surgery

(if no chemo) or• ≤ 8 mos after chemo if premen status confirmed • N = 3066

SOFT

Tamoxifen + OFS*

Tamoxifen 20 mg/day+ OFS* (n = 1024)

N = 2346

Exemestane 25 mg/day+ OFS* (n = 1334)

Joint Analysis

Median follow up: 68 months

42% N+ Neo/Adjuvant

chemotherapy: 58%

Pagani O, et al. NEJM July 2014.

N = 2344

Exemestane+ OFS*

SOFT/TEXT: Exemestane + OFS better DFS

Median f/u 5.7 years

SOFT/TEXT: selected AEs

QOL not differentEarly cessation of treatment 16 vs 11%

SOFT/TEXT

• Exemestane with ovarian function suppression is a new evidence based treatment option for premenopausal women with HR+ early breast cancer

• Some premenopausal women diagnosed with HR+ breast cancer have an excellent prognosis with highly-effective endocrine therapy alone (>97% BC free at 5 yrs)

• Need longer f/u, esp OS

Randomized trials of adjuvant CT versus Ovarian ablation/suppression with or without Tamoxifen

HER2 Targeted Therapy

TARGET THERAPY TRIALS

• This pooled analysis of 5 randomized trials reported a 48% reduction in mortality with the addition of trastuzumab to chemotherapy for HER2‐positive early‐stage breast cancer

• Cardiac toxicity was 2.5 times greater in patients who received trastuzumab, but overall rates were low (4.5% in the trastuzumab groups)

Impact of adding

trastuzumab to adjuvant

chemotherapy for HER2

positive breast cancer

Viani et al. (2007) BMC

Cancer

OTHER TARGETED THERAPIES TRIALS

■Response rates and clinical benefit rates (patients with complete response, partial response, or stable disease for greater than six months) were higher in the combination arms (12.0% vs. 1.3% and 50.5% vs. 25.5%; P<0.0001), respectively.

■Patients with only bone metastases benefited from the combination.

■These results are similar to the benefit seen with chemotherapy (without their toxicity). For instance, the median PFS with capecitabine, taxanes or anthracyclines also ranges between 6.2 months and 8.2 months.

■ PALOMA-1 trial demonstrated a statistically significant improvement in PFS when palbociclib was added to letrozole in the treatment of postmenopausal women with metastatic ER+/HER2-breast cancer who had not previously received any systemic treatment for their advanced disease.

■ With a median follow-up of approximately 30 months for the palbociclib plus letrozole group and 28 months for the letrozole alone group, the median PFS was 20.2 months (95% CI 13.8–27.5) and 10.2 months (95% CI 5.7–12.6), respectively, (HR 0.488, 95% CI 0.319–0.748; one-sided p = 0.0004).

SURGERY TRIALS

NSABP B-04

■ Between 1971-74, 1765 patients from 34 institutions across USA and Canada participated

■ Objective - whether reducing the extent of surgery might not compromise outcome

■ Two companion trials conducted in parallel –one for those with clincally node negative patients and other for clinically node positive patients.

■ Radical Mastectomy served as control arm for both

Operable Breast Cancer

Clinic. Negative Node Clinic. Positive Node

RadicalMast.

TotalMast.

Total Mast.+

XRT

RadicalMast.

Total Mast.+

XRT

NSABP B-04: LOCO-REGIONAL

Opened : July 1971Closed : September 1974

Fisher, B. et al., NEJM 2002;347(8):567-575.

NSABP B-04: LOCO-REGIONAL

RFS (25 yrs)Negative Node

P = .46

RFS (25 years)

Positive Node P = .40

Radical mastectomy 53% 36%

Total mastectomy + XRT 52% 33%

Total mastectomy 50% --

• No difference in overall survival among 3 arms in clinically node negative patient - 25% for RM arm, 19% for TM/radiation arm, 26% for TM

• In node positive patients overall survival 14% in each arm

• 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=0.38)

NSABP- 06

OBJECTIVE :

■ To find whether LUMPECTOMY & AXILLARY DISSECTION with or without RADIOTHERAPHY is better than TOTAL MASTECTOMY with AXILLARY DISSECTION in early stage breast cancer (stage I & II with tumour size < 4 cm,N0/N1)

NSABP B-06: LOCO-REGIONAL

All patients with histologically positive axillary nodes receive L-PAM + 5 FU

Total mastectomy performed in event of ipsilateral breast tumor recurrence

Clinical Tumor Size 4.0 cm

Stratification Clinical Nodal Status Clinical Tumor Size

TotalMastectomy+ Ax. Diss.

Lumpectomy+ Ax. Diss.

Lumpectomy+ Ax. Diss.

+ XRT

NSABP B06 Results

Fisher, et al N Engl J Med,Vol. 347, No. 16 · October 17, 2002

NSABP B06 Results

■ No difference in survival at 20 years

■ Lumpectomy without postoperative irradiation higher local recurrence 39.2% vs. 14.3%

■ Radiation therapy was associated with a marginally significant decrease in deaths due to breast cancer

■ However, this decrease was partially offset by an increase in deaths from other causes

■ BCS New standard of care for Stage I/IIFisher, et al N Engl J Med

Vol. 347, No. 16 · October 17, 2002

Local control and survival in early breast cancer: Milan trial■ Int J Radiat Oncol Biol Phys. 1986 May;12(5):717-20. Veronesi U, Zucali R, 

Luini A.

■ From 1973 to 1980, 701 patients with breast cancer measuring less than 2 cm in pathological diameter and with no palpable axillary lymph nodes were randomized to Halsted mastectomy (349) or to "quadrantectomy" with axillary dissection and radiotherapy to the ipsilateral breast tissue (QUART) (352)

■ The two groups were comparable in age distribution, size and site of primary tumor; menopausal status; and frequency of axillary metastases

■ At 8 years, the disease-free survival was 77% for the Halsted patients and 80% for the "quadrantectomy" patients, while overall survival was 83% and 85%, respectively.

■ Breast cancer of small size (less than 2 cm) may be safely treated with conservative treatment.

■ Mutilating operations are not justified.

AXILLARY DISSECTION VS SENTINEL NODE BIOPSY TRIALS

NSABP B-32■ 5,611 women with operable, clinically

N0, invasive breast cancer were randomized to SNR + AD (Group 1) or to SNR alone with AD only if SNs were positive (Group 2).

■ 3,989 (71.1%) of 5,611 patients were SN negative, and 3,986 (99.9%) of these SN negative patients had follow-up information.

■ 1,975 women had SNR + AD (Group 1) and 2,011 women had AD alone (Group 2).

■ Median time on study was 9.4 years.

■ SN Identification rate 97%

■ 26% had positive node

■ 9.7% false negative rate ; less common with >1SN,

■ OS, DFS, Regional Control statistically equivalent

Enrollment 1999-2004

NSABP B-32■ No significant difference in OS between patients who received

SNR + AD versus SNR alone (HR: 1.11, p = 0.27) at 10 years.

■ 10 year Kaplan-Meier (K-M) estimates for OS are 87.8% for SNR alone and 88.9% for SNR + AD.

■ There continues to be no significant difference in DFS between the two groups (HR: 1.01, p=0.92).

■ 10 year K-M estimates for DFS were 76.9% for both groups.

■ There was no significant difference in the rates of local-regional recurrence between the two groups (HR: 1.09, p=0.29).

ACOSOG Z0010■ SN biopsy (SNB) with immunohistochemistry (IHC) of histologically

negative SN identifies metastases (mets) not seen by standard histology.

■ 5,539 patients (pts) were entered into this prospective multicenter observational study to determine the clinical significance of SN and Bone Marrow (BM) micromets. 

Methods Patients underwent lumpectomy and SNB with bilateral iliac crest

BM aspiration.

■ BM and histologically negative SN were evaluated with IHC in a central laboratory

■ Overall survival (OS), disease-free survival, and locoregional recurrence were determined.

ACOSOG Z0010Results:

■  SN were successfully identified in 5,184 of 5,485 pts (94.5%)

■ Histologic SN mets were found in 1,239 pts (23.9%).

■ IHC detected an additional 350 pts (10.5%) with SN mets.

■ BM mets were identified by IHC in 105 of 3491 examined (3.0%).

■ BM IHC positivity significantly predicted decreased OS (p=0.015).

■ A multivariable analysis that included SN and BM status, ER, PR, grade, size, and age showed that neither IHC detected mets in SN (p=0.66) or BM (p=0.08) were independent predictors of OS 

Conclusions: 

■ The detection of BM mets by IHC in pts with clinical T1/2 N0M0 breast cancer identifies those pts at significantly increased risk for death

■ In this study, SN IHC-detected mets appear to have no significant impact on OS.

■ The routine examination of SN by IHC is not supported in this patient population by this study. 

Positive Sentinel Node (891 patients)Axillary

Dissection (445)

No axillary

Dissection (446)

Objective To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer•All patients with +nodes received WBI and adjuvant systemic therapy•Original goal = 1900•End Points: Overall & Disease Free Survival and Local-Regional Failure

Positive Sentinel Node ACOSOG -Z0011 Trial Giuliano AE, et al

JAMA 2011;305:569-75

ACOSOG Z11 Results

■ 1999 to 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section

■ Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected.

■ Closed early due to slow accrual and lower mortality than anticipated

■ No difference in OS or DFS

■ 70% vs. 25% (AXND vs. SNB) surgical morbidity: wound infections, axillary seromas, paresthesias

■ Lymphedema 13% vs. 2%;

■ In patients with limited SN disease who receive BCS with WBI and systemic therapy, SNB alone does not result in inferior survival

Randomized Multicenter Trial of Sentinel Node Biopsy Versus Standard Axillary Treatment in Operable Breast Cancer: The ALMANAC Trial

■ Multicenter randomized trial to compare quality-of-life outcomes between patients with cN0 invasive breast cancer who received SLNB V/S standard axillary treatment

■ The primary outcome measures were arm and shoulder morbidity and quality of life

■ From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516)

■ Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution)

■ Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented

ALMANAC■ The relative risks of any lymphedema and sensory loss for the

sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval [CI] = 0.23 to 0.60;

■ absolute rates: 5% versus 13% respectively

■ Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P<.001), and axillary operative time was reduced (P = .055).

■ Overall patient-recorded quality of life and arm functioning scores were statistically significantly better in the sentinel lymph node biopsy group throughout (all P≤.003).

NSABP 32 & ALMANACConclusion: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes.

AMAROS trialMethods

■ Patients with T1–2 primary breast cancer and no palpable lymphadenopathy were enrolled

■ Randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node,

■ The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group.

Findings

■ Between Feb 19, 2001, and April 29, 2010, 4806 patients were enrolled at 34 centres from nine European countries,

■ 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy

■ Median follow-up was 6·1 years (IQR 4·1–8·0) for the patients with positive sentinel lymph nodes

AMAROS trial■ In the axillary lymph node dissection group, 220 (33%) of 672 patients who

underwent axillary lymph node dissection had additional positive nodes.

■ Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group.

■ 5-year axillary recurrence was 0·43% (95% CI 0·00–0·92) after axillary lymph node dissection versus 1·19% (0·31–2·08) after axillary radiotherapy.

■ The planned non-inferiority test was underpowered because of the low number of events

■ Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years.

Interpretation

■ Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1–2 primary breast cancer and no palpable lymphadenopathy.

■ Axillary radiotherapy results in significantly less morbidity.

ONGOING PHASE 3 TRIALS

THANKS