38 years old, premenopausal, had L+snbx. Pathology: IDC Gr.II T-1.9cm N+2/4sn ER+100%st, PR+60%st, Her2-neg, KI %

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Sarah Joseph
5 years ago
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1 38 years old, premenopausal, had L+snbx Pathology: IDC Gr.II T-1.9cm N+2/4sn ER+100%st, PR+60%st, Her2-neg, KI %

2 Question: What will you do now? 1. Give adjuvant chemotherapy 2. Send for Oncotype 3. Send for MammaPrint

If a patient has hormone receptor positive, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and a high clinical risk to

4 If a patient has hormone receptor positive, HER2-negative, node-positive breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and a high clinical risk to inform decisions on withholding adjuvant systemic chemotherapy. However, such patients should be informed that a benefit from chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node.

5 Question: MammaPrint=low risk What now? 1. Give adjuvant chemotherapy 2. Give XRT and endocrine therapy

6 At 5 years, patients who were at high clinical risk and low genomic risk who did not receive adjuvant chemotherapy (primary-test population) had a rate of survival without distant metastasis of 94.7% (95% confidence interval [CI], 92.5 to 96.2);

7 Among patients with node-negative disease, the rate of survival without distant metastasis was 95.7% (95% CI, 93.0 to 97.4) in the chemotherapy group and 93.2% (95% CI, 90.1 to 95.4) in the nochemotherapy group; Among patients with node positive disease, the rates were 96.3% (95% CI, 93.1 to 98.1) in the chemotherapy group and 95.6 (95% CI, 92.7 to 97.4) in the no-chemotherapy group. In the whole study 21% had positive nodes In the high clinical low mammaprint group Only 10% had 2 or more involved nodes, 52% had node negative disease.

8 MINDACT In the critical group of patients at high clinical risk and low genomic risk, the use of adjuvant chemotherapy led to a trend toward a higher rate of the 5-year outcome than that with no chemotherapy, which included a rate of survival without distant metastasis that was 1.5 percentage points higher, a rate of disease-free survival that was 2.8 percentage points higher, and a rate of overall survival that was 1.4 percentage points higher with chemotherapy than with no chemotherapy in the intention-to-treat population. The study was not powered to assess the statistical significance of these differences.

9 ABCSG-12: Study Design Key endpoints Primary: DFS at 5 yrs Secondary: relapse-free survival, OS, BMD, safety Treatment 3 yrs (median follow-up: 62 mos) 1803 premenopausal pts with stage I/II BC (30% N+) 80% > 40 yrs N+ 30% OFS: Goserelin Q 28 days OFS started concurrently with endocrine therapy R TAM 20 mg/day ANA 1 mg/day TAM + ZA 4 mg q6m ANA + ZA 4 mg q6m Long-term monitoring for 5 yrs for recurrence and survival (DFS, OS) Only 5% received Chemotherapy 3-yr BMD 5-yr BMD Gnant M, et al. N Engl J Med. 2009, Lancet 2011

10 ABCSG-12 (84 Months): DFS Tamoxifen vs AI Very good long term DFS and survival

11 St. Gallen Consensus 2017 Multi-gene testing Eric Winer if after accounting for stage, biological features, co-morbidities and patient preference, you & the patient are still ambivalent about choice of therapy that s the time to send an assay

12 Adjuvant chemotherapy in HR+/HER2-neg If IHC is used, which factors are a relative indication for inclusion of chemotherapy: Grade 3 LN+ High Ki67 Age <35 Extensive LVI Low HR staining Yes 91% 69% 85% 56% 68% 91% No 6% 32% 11% 44% 30% 9% Abstain Extensive LVI = in >2 blocks or >2 emboli in same block

13 Adjuvant chemotherapy in Luminal B Chemotherapy can safely be omitted for N+ (1-3LN) if Yes No Abstain Low Mammaprint Low PAM-50 ROR Low Endopredict Low Oncotype 55% 31% 20% 56% 35% 50% 66% 33%

14 Adjuvant chemotherapy in Luminal B Chemotherapy can safely be omitted for N+ (1-3LN) if Intermediate Oncotype RS: Yes - 6% No 88% Chemotherapy can safely be omitted for N0 if Intermediate Oncotype RS: Yes - 22% No 67%

15 38 years old premenopausal, had L+snbx. Pathology: IDC Gr.II T-1.9cm N+2/4sn ER+100%st, PR+60%int, Her2-neg KI67 10% Decided to get endocrine therapy, no chemo

16 Question: What would you recommend 1. Tamoxifen as long as the ovaries function, then switch to AI 2. OS + Tamoxifen 3. OS + AI 4. OS + AI + Zometa q 6 months

17 Current Standard Options for Adjuvant Endocrine Therapy Menopausal Status at Diagnosis Pre / perimenopausal Initial Therapy Extended Therapy Tamoxifen 5 Tamoxifen 5 Tamoxifen 5 Postmenopausal AI 5 What about ovarian suppression? AI 5 (*if post-menopausal) Tamoxifen 2-3 AI 2-3 What about AI + OFS in premenopausal women? Tamoxifen 5 AI 5 Tamoxifen 5 Tamoxifen 5 Adapted from ASCO Guidelines Available at:

18 SOFT/TEXT SOFT: SUPPRESSION OF OVARIAN FUNCTION TRIAL TEXT: TAMOXIFEN AND EXEMESTANE TRIAL Both Phase III Trials; Exemestane Plus gonadotrophin-releasing hormone (GnRH) Analogue as adjuvant therapy for premenopausal women with hormone receptor positive breast cancer Question: is temporary ovarian function suppression with GnRH analogues (ovarian ablation permanent with surgery or radiation) useful when combined with AI or TAM. Goserelin (zoladex 3.6 sc monthly), leuprorelin (lupron 3.75 im monthly), buserelin, triptorelin (3.75 im monthly) DFS event rate much lower than anticipated combined analysis (4690 patients)

19 SOFT & TEXT trials

20 TEXT & SOFT Tamoxifen + OFS vs. Exemestane + OFS TEXT Premenopausal, HR+ BC 12 wks after surgery N = 2672 Stratified by trial, use of chemotherapy, nodal status Tamoxifen 20 mg/day + OFS* (n = 1338) Exemestane 25 mg/day + OFS* (n = 1334) Joint Analysis Tamoxifen + OFS* N = 2344 Premenopausal HR+ BC 12 wks after surgery (if no chemo) or 8 mos after chemo if premen status confirmed N = 3066 SOFT Tamoxifen 20 mg/day + OFS* (n = 1024) Exemestane 25 mg/day + OFS* (n = 1021) Tamoxifen 20 mg/day Median follow up: 68 months 42% N+ Neo/Adjuvant chemotherapy: 58% Exemestane+ OFS* N = 2346 *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 Pagani O, et al. NEJM July 2014.

21 Contribution of OFS / ablation

22 Contribution of OFS / ablation

23 Contribution of OFS / ablation

24 Contribution of EXEMESTANE

25 SOFT/TEXT: Exemestane + OFS better DFS Median f/u 5.7 years

27 SOFT/TEXT: selected AEs QOL not different Early cessation of treatment 16 vs 11%

28 When to initiate ovarian suppression? Effect on disease outcome? Ovarian protection?

29 Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT. DESIGN AND METHODS: OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). CONCLUSION: Regann MM et al. Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected. Ann Oncol Sep 1;28(9):

30 Ovarian protection

31 METHODS We randomly assigned 257 premenopausal women with operable hormonereceptor negative breast cancer to receive standard chemotherapy with the GnRH agonist goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy- alone group). RESULTS Among the 218 patients who could be evaluated, pregnancy occurred in more women in the goserelin group than in the chemotherapy-alone group (21% vs. 11%, P = 0.03); women in the goserelin group also had improved disease-free survival (P = 0.04) and overall survival (P = 0.05). CONCLUSIONS Although missing data weaken interpretation of the findings, administration of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility.

32 Ovarian Suppression With Triptorelin During Adjuvant Breast Cancer Chemotherapy and Long-term Ovarian Function, Pregnancies, and Disease-Free Survival A Randomized Clinical Trial INTERVENTIONS Patients were randomized to receive adjuvant or neoadjuvant chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group). RESULTS A total of 281 women (median age, 39) were randomized. Median follow-up was 7.3 years years). The 5-year cumulative incidence estimate of menstrual resumption was 72.6% among the 148 patients in the LHRHa group and 64.0% among the 133 patients in the control group (hazard ratio [HR], 1.28 [95%CI, ]; P =.07; age-adjusted HR, 1.48 [95%CI, ]; P =.006). Lambertini M et al. JAMA 2015 Volume 314, No 24 Eight pregnancies occurred in the LHRHa group and 3 in the control group (HR, 2.56 [95%CI, ]; P =.14; age-adjusted HR, 2.40 [95%CI, ]; P =.20). Five-year DFS was 80.5% in the LHRHa group and 83.7% in the control group (LHRHa vs control: HR, 1.17 [95%CI, ]; P =.52) CONCLUSIONS AND RELEVANCE Among premenopausal women with either hormone receptor positive or hormone receptor negative breast cancer, concurrent administration of triptorelin and chemotherapy, compared with chemotherapy alone, was associated with higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate. There was no statistically significant difference in DFS for women assigned to triptorelin and those assigned to chemotherapy alone, although study power was limited.

33 Thank you

Adjuvant endocrine therapy (essentials in ER positive early breast cancer)

Adjuvant endocrine therapy (essentials in ER positive early breast cancer) Giuseppe Curigliano MD, PhD Breast Cancer Program Division of Experimental Therapeutics Outline Picking optimal adjuvant endocrine