Presented by: Dr. Satyajeet Rath

Guided by: Dr. Shantanu Sapru

Date: 28-10-16

Prudence A. Francis et al., N Engl J Med 2015;372:436-46

SOFT Trial

Olivia Pagani et al., N Engl J Med 2014;371:107-18

SOFT + TEXT Trial

Adjuvant Ovarian Supression in Premenopausal

Breast Cancer

Adjuvant Exemestane with Ovarian Supression

in Premenopausal Breast Cancer

Major controversial topics were, and still are:

1. Is Tamoxifen (TAM) alone an optimal treatment?

2. What is the role of ovarian function suppression (OFS)?

3. Is there a place for aromatase inhibitors (AIs)?

4. What is the optimal treatment duration?

Introduction :

• Adjuvant treatment for premenopausal women with ER+/PR+ disease is often a matter of physician and patient choice

• Current recommendations include treatment with TAM for at least 5 years

• 5 years of TAM reduces the odds of recurrence by 40% when added to adjuvant chemotherapy

• GnRH agonists show similar efficacy to chemotherapy in the absence of TAM in prememopausalwomen, but additional benefit from OFS for women who receive 5 years of TAM + adjuvant chemotherapy is uncertain

• AIs are equi-efficacious to TAM for postmenopausal women with endocrine-responsive breast cancer

• The value of therapeutic suppression of ovarian Estrogen production in premenopausal women who receive TAM is uncertain

• In 2003 the International Breast Cancer Study Group (IBCSG) started 3 trials

• SOFT - Suppression of Ovarian Function Trial

• TEXT - Tamoxifen and Exemestane Trial

• PERCHE - Premenopausal Endocrine-Responsive Chemotherapy

• They were designed to answer questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer, what is the role of:

1. Ovarian function suppression (OFS) for women who remain premenopausal and are treated with TAM?

2. AIs for women treated with OFS?

The SOFT trial was:

oDesigned to investigate the role of OFS and the role of the AI (Exemestane) in premenopausal women

oRandomised, 3-arm, phase III RCT with 1:1:1 allocation --

The TEXT trial was:

oDesigned to investigate the efficacy of AI (Exemestane)+OFS v/s TAM+OFS in premenopausal women

oRandomised, 2-arm, phase III RCT with 1:1 allocation --

Common to both SOFT & TEXT trials:

o Documented pre-menopausal status (using Estradiol levels)

o Operable breast cancer

o ER/PR +ve tumours (in ≥10% of the cells)

o BCS+RT or MRM±RT

o AxLND, or SLNBx –ve (or microscopically +ve only), or +ve SLNBx foll. by AxLND or Ax RT

Inclusion criteria

Inclusion (contd)

SOFT trial

o Enrollment:

(a)within 8 mth of the final dose of chemotherapy, or

(b)within 3 mth of definitive surgery if no adjuvant chemotherapy was planned.

o Trastuzumab was allowed.

TEXT trial

o Enrollment:

a) within 3 mth of Sx and excluded patients who had already received any prior chemotherapy or endocrine therapy.

o Chemotherapy use was optional and, if used, regimen was by investigator choice but had toto start at the same time as GnRH analog.

o Trastuzumab was allowed.

Exclusion Criteria

TEXT

• Patients who would be likely to have bilateral oophorectomy within 5 years (e.g., BRCA1/2 gene carriers) were not eligible. Patients could have received adjuvant oral endocrine therapy (but not GnRH analogs) for up to 8 months prior to randomization.

SOFT

• Patients who had already received any prior chemotherapy or endocrine therapy were excluded.

Exclusion Criteria common to both

• Previous B/L oophorectomy or ovarian RT

• Use of TAM or other SERM or HRT within one year prior to breast cancer diagnosis

• Previous or concurrent invasive malignancy cancer (other than stage Ia or Ib endometrioid endometrial cancer, borderline or stage I ovarian cancer)

Further design points

SOFT

• Stratification done by Nodal status, Prior chemo rcvd or not, and intended OFS method (GnRH analog, Oophorectomy or RT – by patient choice)

• Randomized in a 1:1:1 manner to 3 arms: TAM alone v/s TAM+OFS v/s AI+OFS

• OFS was mandatorily done using GnRHanalog for 6 mth, after which the pt. could choose to continue with this, or opt for RT or Sx. OFS was to be done for 5 yrs.

• OFS was started only after pts. had completed their chemo (within 8 mth of chemo completion).

• Oral ET (TAM) was permitted even before randomization.

TEXT

• Stratification done by Nodal status, and Chemo planned or not (chemo regimen & use was by investigator choice)

• Randomized in a 1:1 manner to 2 arms: TAM+OFS v/s AI+OFS

• OFS was mandatorily done using GnRHanalog for 6 mth, after which the pt. could choose to continue with this, or opt for RT or Sx. OFS was to be done for 5 yrs.

• OFS started concurrently with Chemo

• Oral ET was to start after adjuvant chemotherapy was completed, or approximately 6-8 weeks after initiation of GnRH analog, whichever was later.

• OFS was done for 5 years. Initially, mandatorily, by the GnRH analog Triptorelin 3.75mg IM administered 4-weekly. After 6 mth, patients were allowed to choose to continue Triptorelin, or choose between B/L oophorectomy or B/L ovarian RT.

• In either case, biochemical confirmation of cessation of ovarian function was done 2 mthafter therapy.

Trial Design

Original statistical design :

• Each trial’s statistical design assumed uniform accrual, exponential distribution of DFS, and two-sided log rank tests with trial wise 0.05-level α-error.

• Each analysis would implement stratified log rank tests and Cox proportional hazard regression, and Kaplan Meier estimates of the DFS distribution.

• Four interim and the final analysis were planned using O’Brien-Fleming boundaries.

• From the outset, the protocols planned to combine the data of TEXT with the two arms of SOFT comparing AI+OFS vs TAM+OFS.

• Primary end point of both RCTs was disease-free survival (DFS), defined as the time from randomization to the first onset of the following events: invasive recurrence at local, regional, or distant sites; new invasive cancer in the contralateral breast; secondary (non-breast) malignancy; or death without prior cancer event

• Secondary end points for both included the following:

• Time interval without breast cancer, defined as the time from randomization to the recurrence of invasive breast cancer (local, regional, or distant) or invasive contralateral breast cancer;

• Time interval before a recurrence of breast cancer at a distant site, defined as the time from randomization to the recurrence of breast cancer at a distant site; and

• Overall survival, defined as the time from randomization to death from any cause.

End Points:

SOFT

• Primary end point – DFS

• Secondary end point –

• Interval without breast cancer

• Time interval before recurrence of breast cancer at a distant site

• Overall survival

SOFT + TEXT

• Primary end point – DFS

• Secondary end point –

• Interval without breast cancer

• Time interval before recurrence of breast cancer at a distant site

• Overall survival

Derivations of 5-yr DFS estimates

• A 40% reduction in risk of relapse by adding TAM was assumed, resulting in an estimated 5-year DFS of 67% among patients treated with TAM in the SOFT control arm.

• A 25% reduction in hazard by adding OFS to TAM (74.1% 5-year DFS) and a further 25% reduction in the hazard with AI + OFS (79.8% 5-year DFS) were hypothesized.

Statistical analysis :

TEXT

• Planned enrollment was 2672 patients for

the 2 arms

• The design projected that 4.5 years of

uniform accrual, plus 2.4 years of

additional follow-up would be sufficient

to observe the target of 396 DFS events

to provide 80% power to detect 25%

reduction in hazard with AI + OFS

versus TAM + OFS (hazard ratio (HR) -

0.75; 79.8% vs 74.1% 5-year DFS,

respectively).

SOFT

• Planned enrollment was 3066 patients for

the 3 arms.

• The design projected that 5 years of

uniform accrual, plus 1.9 years of

additional follow-up would be sufficient

to observe the target of 783 DFS events

(522 per pairwise comparison) to have

80% power to detect a 25% reduction in

hazard relative to control 5-year DFS of

67% (HR - 0.75; 74.1% vs 67.0% 5-year

DFS; 2-sided α-0.0167).

Adaptations in the statistical design and analysis plans

1. OFS question : the primary analysis from SOFT would focus on the unique comparison of TAM + OFS versus TAM alone, tested at the two-sided α - 0.05 level .

IBCSG estimated power to be at least 80%, 69%, 52% and 34% to detect 33.5%, 30%, 25% and 20% reductions in hazard, respectively, with TAM + OFS.

1. AI question : the primary analysis comparing AI + OFS versus TAM + OFS would implement the originally planned combined analysis of TEXT and SOFT.

The power of such a combined comparison (two-sided α-0.05 level) would be at least 95%, 84% and 63% to detect a 30%, 25% and 20% reduction in hazard, respectively, with TAM + OFS.

SOFT - 2014

Prudence A. Francis et al., N Engl J Med 2015;372:436-46.

Results

Adverse events :

Summary – SOFT Trial

SOFT Tamoxifen-OFS Tamoxifen P value

5-yr DFS 86.6% 84.7% 0.10

5-yr OS 96.7% 95.1% 0.13

5-yr BC freedom rate 88.4% 86.4% 0.09

• In the low risk subpopulation of patients who did not receive chemotherapy

(predominantly women >40 years, with small, node-negative [N-] tumors of low to

intermediate grade), >95% remained free from BC and without distant recurrences at 5

years with TAM alone. In this cohort of patients TAM alone is very effective and can still

be considered the standard of care.

SOFT + TEXT Trial - 2014

Olivia Pagani et al., N Engl J Med 2014;371:107-18.

Results

P<0.001 P<0.001

P=0.02 P=0.37

P<0.0001

TEXT-SOFT combined

analysis

Tamoxifen-OFS Exemestane-OFS P-value

5-yr DFS 87.3% 91.1% P<0.001

5-yr BC free interval 88.8% 92.8% P<0.001

Freedom from recurrence of

breast cancer at a distant site

92% 93.8% P=0.02

5-yr OS 95.9% 96.9% p=0.37

5-yr OS > 95% in both groups, not significantly different according to assignment, but not

considered mature

Selected adverse events of Grade

3 or 4

29.4% 30.6%

• Median follow-up : 68 months

Among patients who received chemotherapy, the absolute improvement in the 5-year BC-free rate with

Exemestane-OFS as compared with tamoxifen- OFS was 5.5% in TEXT and 3.9% in SOFT.

• Median FU – 68 mth

• 60.1% of first events involved distant sites

• 13.6% were second, non-breast, invasive cancer

• Among patients who did not receive chemotherapy and were assigned to receive

Exemestane plus ovarian suppression, 97.6% of the patients in TEXT and 97.5% of those

in SOFT remained free from breast cancer at 5 years

• Recurrence of breast cancer at a distant site was reported in 325 patients (6.9%)

• Among patients who received chemotherapy, the rate of freedom from distant recurrence at

5 years was 2.6 percentage points higher among those who were assigned to AI + OFS than

among those who were assigned to TAM + OFS in TEXT and 3.4 percentage points higher

in SOFT

Side effects

• Exemestane+OFS : Fractures, musculoskeletal symptoms, vaginal dryness, decreased libido, and dyspareunia were reported more frequently

• Tamoxifen +OFS : thromboembolic events, hot flushes, sweating, and urinary incontinence more frequent

• Osteoporosis was reported in 13.2% of the patients assigned to Exemestane + OFS and in 6.4% of those assigned to TAM + OFS

The events of grade 3 or 4 that were reported most frequently were hot flushes, musculoskeletal symptoms, and hypertension.

Conclusion :

• TAM alone is still the preferred agent in low-risk patients

• OFS should be considered in patients at sufficient risk to deserve adjuvant chemotherapy and particularly when very young

• When OFS is indicated, AI further improves short-term outcomes

• The 5-year median follow-up and the low event rate are insufficient to assess whether the significant improvement in DFS with AI+OFS will translate into an overall survival benefit

Thank You