Should premenopausal HR+ve breast cancer receive LHRH?

Should premenopausal HR+ve breast cancer receive LHRH? Hesham Elghazaly, MD Prof. Clinical Oncology, Ain Shams University President of the BGICS

Should premenopausal HR+ve breast cancer receive LHRH? NO? Side effects YES Efficacy Evidence

What is the evidence behind LHRH in HR+ve early breast cancer? OA vs No TTT OA + Tam vs Tam OA vs Chemo OA + Tam vs Chemo OA + AI vs OA +Tam vs Tam

Percentage OA vs No TTT Early Breast Cancer Trialists Group Overview 2005: Ovarian Ablation No Chemotherapy: Ovarian Ablation vs Not All Deaths 100 80 60 40 72.7% 62.7% 56.7% 66.6% 6.1% (SE 2.9) 54.3% 8.3% (SE 3.0) 46.3% 10.4% (SE 3.1) Reduction in the risk of Recurrence: 31% Death from BC: 31% Mortality: 28% 20 < 50 Actuarial estimate and SE - Allocated ABLATION - Allocated CONTROL 0 0 5 10 15 Years Early Breast Cancer Trialists Collaborative Group (EBCTCG). Lancet. 2005;365:1687-1717.

OA + Tam vs Tam ZIPP: Study Design Goserelin x 2 years Premenopausal ER+ and/or PgR+ Node positive Randomize N = 2631 Tamoxifen x 2 years Goserelin x 2 years plus tamoxifen x 2 years No further treatment Goserelin and tamoxifen administered for 5 years Rutqvist LE. ASCO 1999. Abstract 251.

ZIPP: Results Goserelin arms had significantly better DFS and trend toward better OS compared with no goserelin, particularly for ER+ patients HR: 0.77; 95% CI: 0.66-0.89; P <.001 Rutqvist LE. ASCO 1999. Abstract 251.

Ovarian Suppression vs Chemotherapy

OA vs Chemo DFS OS ZEBRA CMFx 6cycles Vs Goserline ND ND IBCSGVIII CMF Vs Goserline Vs CMF +Goserline ND Better in < 40 ys ND TABLE CMF x6 vs Leupron 2 years ND ND

Randomization ZEBRA: Study Design CMF x 6 cycles N = 1640; Premenopausal Lymph node positive ER+/ER- Goserelin 3.6 mg q 28 days x 2 yrs Median follow-up: 7.3 yrs Kaufmann M, et al. Eur J Cancer. 2003;39:1711-1717.

Proportion Alive and Disease Free ZEBRA: Disease-Free Survival (DFS) in ER+ Subgroup (a) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 591 598 537 559 470 486 0 1 2 3 4 5 6 7 8 9 10 HR: 1.05; 95% CI: 0.88-1.24 Patients at risk at the start of each year 427 429 380 397 333 342 Time (Years) 263 265 Reprinted from Kaufmann M, et al. Eur J Cancer. 2003;39:1711-1717, with permission from Elsevier. 187 181 126 112 59 60 Goserelin CMF

ZEBRA: Overall Survival in ER+ Subgroup No difference in overall survival between CMF and goserelin in ER+ subgroup HR = 0.94; 95% CI: 0.75-1.18 Kaufmann M, et al. Eur J Cancer. 2003;39:1711-1717.

Patients with amenorrhoea (%) ZEBRA: Effect of Treatment on Amenorrhoea Rates 100 90 80 70 60 50 40 30 20 10 0 ZOLADEX 3.6mg CMF 0 1 2 3 4 5 6 7 8 Time after entry (years) Jonat W, et al. J Clin Oncol 2002; 20: 4628 35

Percentage change from baseline Lumbar Spine Percentage change from baseline 0-2 p=0.00008 p=0.0005 NS -4-6 -8-10 -12-14 -16 ZOLADEX 3.6mg CMF 0 1 2 3 Years Fogelman I, et al. Osteoporosis Int 2003; 14: 1001 6

ZEBRA: Quality of Life (QoL) 86 centres: ZOLADEX 3.6mg, n=514; CMF, n=496 Early benefits (3 6 months) with ZOLADEX 3.6mg vs CMF treatment (p<0.00001) overall QoL score physical symptom distress score effort to cope with illness activity level No significant difference in overall QoL between groups after 6 months de Haes H, et al. J Clin Oncol 2003; 21: 4510 6

Randomization IBCSG VIII: Study Design CMF x 6 cycles (n = 360) N = 1063 Premenopausal Lymph node negative ER+/ER- Goserelin x 2 years (n = 346) CMF x 6 cycles followed by goserelin x 18 months (n = 367) Castiglione-Gertsch M, et al. J Natl Caner Inst. 2003;95:1833-1846.

IBCSG VIII: DFS for ER+ N0 by Age 5-year DFS similar with all therapies in ER+ patients age 39 Years CMF + goserelin, 89%; goserelin, 85%; CMF, 85% (P =.90 5-year DFS significantly improves with CMF + goserelin in ER+ women 39 Years CMF + goserelin, 88%; goserelin, 63%; CMF, 62% (P =.04 Castiglione-Gertsch M, et al. J Natl Caner Inst. 2003;95:1833-1846.

N = 600, lymph node positive, ER+ CMF x 6 cycles or leuprolide x 2 years Ovarian suppression with leuprorelin acetate was as effective as standard chemotherapy in terms of Recurrence-free Overall survival Most common adverse events Leuprolide CMF TABLE Study Low-grade hot flashes, weight gain, and increased sweating Alopecia, nausea, and vomiting Schmid P, et al. Anticancer Res. 2002;22:2325-2332.

Ovarian Suppression plus Tamoxifen Compared With Chemotherapy

OA + Tam vs chemo TRIAL Study Population HR+ve Protocol DFS /OS ABCSG LN -ve CMFx6 vs Goserlinex3y+Tamx5y Better DFS GROCTA LN-ve or +ve CMFx6 vs Any OS+ Tam Same DFS and OS French Adj study group 1-3 LN +ve FEC vs LHRH + Tam Same DFS and OS ECOG5188/INTERG ROUP 0101 1500 pt LN+ve CAF vs CAF + Goserline vs CAF+ Goserline+ Tam betterdfs esp < 40y

ABCSG Trial 5 N = 1034, lymph node negative or positive, ER+ Regimens CMF x 6 cycles Goserelin x 3 years plus tamoxifen x 5 years Median follow-up: 60 months Results Goserelin plus tamoxifen better than CMF for DFS HR: 1.40; 95% CI: 1.06-1.87; P =.017 Jakesz R, et al. J Clin Oncol. 2002;20:4621-4627.

Relapse-Free Survival* (%) Overall Survival (%) Austrian Breast and Colorectal Cancer Study Group: Tam x 5 Yrs and OS x 3 Yrs vs CMF 100 Tamoxifen + Goserelin 100 Tamoxifen + Goserelin 90 90 CMF 80 80 70 CMF 70 60 0 12 24 36 48 60 Patients at risk Endocrine therapy Chemotherapy Months 511 476 410 329 272 207 523 464 379 309 244 179 * Kaplan-Meier estimates of RFS in the group assigned to endocrine therapy (taxoxifen and goserelin) and the group assigned to chemotherapy (CMF). Differences between groups were significant (P =.017, generalized Wilcoxon test; P =.037, log-rank test). Figures of patients at risk are included 60 Patients at risk Endocrine therapy Chemotherapy 0 12 24 36 48 60 Months 511 485 430 356 304 235 523 476 424 358 291 217 Kaplan-Meier estimates of OS in the group assigned to endocrine therapy (tamoxifen and goserelin) and the group assigned to chemotherapy (CMF). Differences between groups were not significant (P =.093, generalized Wilcoxon test; P =.195, log-rank test). Figures of patients at risk are included. Jakesz R, et al. J Clin Oncol. 2002;20(24):4621-4627. Reprinted with permission from the American Society of Clinical Oncology.

GROCTA 02 N = 244, lymph node negative or positive, ER+ Regimens OS (surgery, radiation, or goserelin x 2 years) + tamoxifen 30 mg x 5 years (n = 124) CMF x 6 cycles (n = 120) Results Median follow-up: 76 months Goserelin + tamoxifen comparable to CMF for DFS and OS Recurrence: HR: 0.94; P =.80 Death: HR: 0.69; P =.3 Boccardo F, et al. J Clin Oncol. 2000;18:2718-2727.

Percent Surviving Overall and Disease-Free Survival Curves 1.0 Overall Survival.5 Disease Free 0 1 2 Boccardo F, et al. J Clin Oncol. 2000;18:2718-2727. Reprinted with permission from the American Society of Clinical Oncology. Copyright American Society of Clinical Oncology 0 CMF TMX+OS Overall Survival CMF TMX + OS Disease-Free Survival CMF TMX + OS 3 4 5 6 7 8 9 10 Patients at risk 116 121 101 106 94 94 74 73 Years 53 58 36 42 24 16 10 9

French Adjuvant Study Group Trial 06 Premenopausal women, N = 333, 1-3 positive nodes, ER+ Regimens Tamoxifen 30 mg plus triptorelin 3.75 mg IM every month x 3 years (n = 164) FEC x 6 cycles (n = 169) Results 54 months of median follow-up Tamoxifen plus triptorelin vs chemotherapy DFS: 91.7% vs 80.9% (NS) OS: 97.0% vs 92.9% (NS) Roche HH, et al. ASCO 2000. Abstract 279.

ECOG 5188/Intergroup Trial 0101 CAF N = 1503 Lymph node positive Hormone receptor positive Randomize CAF + goserelin CAF + goserelin + tamoxifen Goserelin and tamoxifen administered for 5 years Davidson NE, et al. J Clin Oncol. 2005;23:5973-5982.

E5188/INT 0101: DFS for Women < 40 Years of Age Improvement in 9-year DFS with CAF plus goserelin over CAF in women < 40 years of age Tamoxifen + CAF + goserlein 9-year DFS: 64% CAF + goserelin 9-year DFS: 55% CAF 9-year DFS: 48% Suggests possible treatment benefit in younger women with addition of ovarian suppression Davidson NE, et al. J Clin Oncol. 2005;23:5973-5982.

E5188/INT 0101: Survival No difference in overall survival when tamoxifen added to CAF plus goserelin compared with CAF or CAF plus goserelin Tamoxifen + CAF + goserlein 9-year OS: 76% (P = NS) CAF + goserelin 9-year OS: 73% (P = NS) CAF 9-year OS: 70% Significance not achieved after 9 years Davidson NE, et al. J Clin Oncol. 2005;23:5973-5982.

Chemotherapy regimen Reported Amenorrhoea Rates for Chemotherapy Regimens % of women becoming amenorrhoeic Women aged 30 39 years Women aged 40 years CMF (6 months) 1 CAF or FEC (3 6 months) 1 AC (3 months) 1 CEF (6 months) 2 30 40 10 25 13 48 80 95 80 90 57 63 86.5 1. Burstein HJ, Winer EP. N Engl J Med 2000; 343: 1086 94; 2. Parulekar W, et al. Proc Am Soc Clin Oncol 2001; 20: 25a, Abstr 97

OA + AI vs OA +Tam vs Tam

Adjuvant Ovarian Suppression in Premenopausal Breast Cancer ( SOFT trial) N Engl J Med 2015;372:436-46. DOI: 10.1056/NEJMoa1412379 Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer (TEXT trial) N Engl J Med 2014;371:107-18. DOI: 10.1056/NEJMoa1404037

TEXT SOFT Designs TEXT (N=2672) Enrolled: Nov 03-Apr11 Premenopausal > 12 weeks after surgery planned OFS NO planned Chemo OR planned Chemo. SOFT (N=3066) Premenopausal > 12 weeks after surgery planned OFS NO planned Chemo OR remain premenopausal > 8 months after chemo. R A N D O M I Z A T I O N R A N D O M I Z A T I O N Tamoxifen + OFS 5Y Exemestane + OFS 5Y Tamoxifen 5Y Tamoxifen + OFS 5Y Exemestane + OFS 5Y Joint Analysis (N=4690) Tamoxifen + OFS 5Y Exemestane + OFS 5Y Median follow up 5.7 Y Adapted from Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

Eligibility Premenopausal women with HR+ (ER and/or PgR <10%) Proper Local-regional treatment with no residual disease. Randomized within 12 weeks of surgery for all women in TEXT & SOFT who didn t receive Chemotherapy. Women in SOFT who received prior (neo)adjuvant chemotherapy randomized >8 months of chemotherapy completion when premenopausal status demonstrated. These patients were permitted to receive oral endocrine therapy prior to rendomization. Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

Treatment Protocol treatment was for 5 Years from randomization. Ovarian Function Suppression TEXT SOFT All women started with GnRH agonist triptorelin (IM q28d). Triptorelin initiated concurrently with chemotherapy, if it was given. Bilateral oophorectomy or irradiation as alternative to triptorelin(decapeptyl, Diphereline and Gonapeptyl ) after 6 months. Choice of OFS Method. Oral Endocrine therapy Exemestan 25mg daily, or Tamoxifen 20 mg daily. In TEXT Started 6 to 8 weeks after initiation of OFS, or After Chemotherapy if given. Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

Study Procedures Adjuvant Trastuzumab allowed, if indicated. Annual mammography and bone densitometry recommended. Targeted A.Es and other grade 3-5 A.Es (CTCAE v3.0) QOL Self assessment of Global & Sympto-Specific Indicators. Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

Primary: Disease Free Survival (DFS) Endpoints o Invasive recurrence (Local, Regional, Distant) o Invasive Contralateral Breast Cancer. o Second (non-breast) invasive malignancy. o Death without prior cancer event. Secondary Breast Cancer Free interval (BCFI) o Invasive recurrence or contralateral Breast Cancer. Distant recurrence free interval (DRFI) o Distant Recurrence. Overall Survival (OS) o Death from any cause. Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

Characteristics No Chemo TEXT (N=1053) No Chemo SOFT (N=943) Chemo TEXT (N=1607) Prior Chemo SOFT (N=1087) Overall (N=4690) Age < 40 Y 16% 9% 30% 49% 27% LN + 21% 8% 66% 57% 42% T-Size > 2 cm 19% 15% 53% 47% 36% Surgery to Random (median) HER2 + 5% 3% 17% 19% 12% 1.5 mo 1.8 mo 1.2mo 8.0 1.6 mo Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

4% absolute improvement in 5-Y freedom from breast cancer for exemestane + OFS No Significant difference in Overall survival Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

Some Women have excellent prognosis with highly effective endocrine therapy alone >97% breast cancer-free at 5 years when treated with exemestane + OFS Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

Absolute improvement with exemestan + OFS 5 Y freedom from breast cancer: 5.5% in TEXT and 3.9% in SOFT 5 Y freedom from distant recurrence: 2.6% in TEXT and 3.4% in SOFT Supplementary appendix of, Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

Pagani O, Regan MM, Walley BA, et al. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer. This article was published on June 1, 2014, at NEJM.org.

The DFS was RESULTS 92.8% in the exemestane plus ovarian S group, 88.8%in the tamoxifen + ovarian suppression (HR for recurrence, 0.66;95% CI,0.55-0.80;P<.001) The OS did not differ significantly between groups. Women at high risk of recurrence who received prior chemotherapy had improved outcome with ovarian suppression their chance to be disease free at 5 years 78% with Tamoxifen alone, 82% with tamoxifen and ovarian suppression, 85.7% with exemestane and ovarian susupression. In the cohort of women with no prior chemotherapy, no meaningful benefit was seen from ovarian suppression as women who received tamoxifen alone has 95% chance of remaining disease free for 5 years

GUIDELINES

Ovarian Ablation in Early Breast Cancer: an overview of the randomized trials ( I ) TABLE 6. Meta-analysis of the Effect of Ovarian Ablation Reduction in Reduction Annual Odds Annual Odds Group of Recurrence (%) of Death (%) Ovarian ablation vs. no adju- 25 + 7 24 + 7 vant therapy (age < 50) Ovarian ablation + chemo- 10 + 9 8 + 10 therapy vs chemotherapy Adapted from EBCTCG Lancet 1996;348:1189-96

Dr. Heba plz save my life.. Don t say NO Reversible side effect Efficacy DFS