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CTSU IBCSG 25-02 - "A Phase III Trial Evaluating the Role of Exemestane Plus GnRH Analogue as Adjuvant Therapy for Premenopausal Women with Endocrine Responsive Breast Cancer"

NOTE:  Pts can be enrolled concurrently on CTSU N063D (ALTTO).

Treatment Plan    (Supplied Drug:  Triptorelin, Exemestane)

Arm A

(+/- Chemo)*

Triptorelin x  5 yrs + Tamoxifen** x  5 yrs

Arm B

(+/- Chemo)*

Triptorelin x  5 yrs + Exemestane** x  5 yrs

*   If used, should begin at same time as Triptorelin.  Use of chemo determined by investigator/pt choice.

** Start after adjuv chemo has been completed or 6 wks after initiation of Triptorelin, whichever is later.

Treatment Schedules

RT:  RT to conserved breast is required.  RT to chest wall following mastectomy is optional (may also include nodal fields).  May be given either after all chemo or integrated into chemo.  May be concurrent w/trial hormonal therapy.

Chemo:  Planned duration of > 2 mos if anthracycline is included (e.g., 4 cycles of EC or AC) or > 4 mos if no anthracycline is given (e.g., 6 cycles of CMF) is recommended.  If anthracycline is used, an epirubicin-containing regimen is recommended.

Adjuv Endocrine Therapy

Triptorelin:  3.75mg, IM, q 28 days, x 5 yrs (unless relapse, intolerance, surgical oophorectomy, or ovarian RT subsequently performed)

Tamoxifen:  20mg, PO, QD, x 5 yrs (unless relapse or intolerance)

Exemestane:  25mg, PO, QD, x 5 yrs (unless relapse or intolerance)

Translational Investigations

Pts randomized prior to 1/1/08:  Whole blood for DNA isolation is required at pt's next visit, after appropriate informed consent

Pts randomized after 1/1/08:  Whole blood for DNA isolation required at baseline (prior to start of tx, but <14 days pre-randomiz)

Eligibility

• Premenopausal women (should have E2 in premenopausal range following surgery).  Only pts who do not require E2 testing are those who have been menstruating regularly during 6 mos pre-randomiz and have not used any hormonal contraception or any hormonal txs during 6 mos pre-randomiz.  Must be randomized w/i 12 wks after definitive surgery.

• Histol-proven, resected breast cancer.  Path material must be available for central path review.

• Must have hormone receptor positive tumors.  If >1 breast tumor, each tumor must be hormone receptor positive.  Hormone receptors must be determined using immunohistochemistry.  ER &/or PgR must be >10% of tumor cells positive by immunohistochemical eval.  Biochemical determination alone is not acceptable. 

• Tumor must be confined to breast and axillary nodes w/o detected mets w/exception of tumor detected in internal mammary chain nodes by sentinel node procedure.  Pts who received neoadjuv therapy must have had operable disease prior to neoadjuv tx.  Pts who had a path eval w/tru-cut or core bx of invasive breast cancer prior to neoadjuv therapy and had no invasive tumor in path specimen from definitive surgery are eligible.  For these pts, pre-neoadjuv tumor characteristics will be used for defining eligibility.  In persistent disease, path findings from definitive surgery should be used.

• Must have had proper surgery for prim breast cancer w/no known clinical residual loco-regional disease:

  • A total mastectomy.  RT is optional after mastectomy OR

  • A breast-conserving procedure (lumpectomy, quadrantectomy, or partial mastectomy w/margins clear of invasive cancer and DCIS) w/RT planned.  Local pathologist must document negative margins of resection in path report.  If all other margins are clear, a positive posterior (deep) margin is permitted, if surgeon documents that excision was performed down to pectoral fascia and all tumor has been removed.  If all other margins are clear, a positive anterior (superficial; abutting skin) margin is permitted if surgeon documents all tumor removed.  RT to conserved breast is required.

• Either axillary lymph node dissection (path exam of > 6 nodes recommended) or a negative axillary sentinel node bx (pN0[sn]) is required.  Pts w/negative or microscopically axillary positive sentinel nodes (pN1mi:  micromets none >2.0mm) do not require further axillary therapy.  Pts w/positive sentinel nodes must have either an axillary dissection or RT of axillary nodes.

• Pts must complete the Quality of Life portion of the study.

• Must be accessible for follow-up.

• Must agree to data and tissue material transfer and handling.

• No locally advanced inoperable breast cancer including inflammatory breast cancer or supraclavicular node involvement or w/enlarged internal mammary nodes (unless path negative). 

• No positive final margins (refers only to DCIS and invasive cancer, not LCIS).  Except as noted above, DCIS at a margin is allowed if a complete mastecomy has been performed.

• No clinically detectable residual axillary disease.

• No hx of prior ipsilateral or contralateral invasive breast cancer.  Pts w/bilat synchronous invasive breast cancer (diagnosed histologically w/i 2 mos) are eligible if bilat disease meets all other eligibility criteria. 

• No previous or concomitant invasive malignancy except the following (previous or concomitant; only if adequately treated):  non-melanoma skin cancer, in situ  non-breast cancer w/o invasion, contra- or ipsilateral in situ  breast cancer, or non-breast invasive malignancy diagnosed >5 yrs ago and w/o recurrence (Stg I papillary thyroid cancer; Stg Ia cervical carcinoma; Stg Ia or Ib endometriod endometrial carcinoma; borderline or Stg I ovarian cancer).

• No other non-malignant systemic diseases to preclude prolonged follow-up.  Pts w/previous thrombosis &/or embolism may be included only if medically suitable.

• No bilat oophorectomy or ovarian RT.

• No hx of non-compliance to medical regimens or potentially unreliable pts.

• No pregnant or lactating women or those who desire pregnancy w/i 5 yrs from randomiz.  No pts planning additional hormonal therapy apart from randomized tx during next 5 yrs (includes all types of hormonal contraception).  Pregnancy test recommended, if applicable.

• No neoadjuv or adjuv endocrine therapy after breast cancer dx.

• No pts taking Tamoxifen or other SERM or HRT w/i 1 yr prior to breast cancer dx.  Prior oral contraceptives are allowed.

• No prior neoadjuv or adjuv chemo (neoadjuv or adjuv Trastuzumab is allowed).

• No psychiatric, addictive, or other disorder to preclude protocol compliance.

• PRESTUDY REQUIREMENTS:

  • H&P, wt (up to 2 mos pre-randomiz)

  • Pregnancy test (recommended, if applicable)

  • Estradiol (following surgery to confirm premenopausal status)

  • Adverse events

  • Hematology*

  • Blood chemistry* (LFTs w/alk phos)

  • Bilat mammo**

  • CXR (PA & Lat) or chest CT**

  • Bone scan (recommended)**

  • Abdominal US, CT, or liver scan (if LFTs significantly abnormal or if medically indicated)

  • GYN exam (per standard local practice)**

  • Bone mineral densitometry** (by DEXA)

  • Quality of Life (recommended)

  • Whole blood for DNA isolation***

  *   Within 2 mos pre-randomiz

  **  Within 1 yr pre-randomiz

  *** Pts randomized prior to 1/1/08:  Whole blood for DNA isolation is required at pt's next visit, after appropriate informed consent

         Pts randomized after 1/1/08:  Whole blood for DNA isolation required at baseline (prior to start of tx, but <14 days pre-randomiz)

         10ml EDTA whole blood (contact KCCOP for kit).  Send to CALGB PCO; Ohio State Univ.; Columbus, OH.  Ship Mon-Fri via overnight delivery     

        (mark "For Saturday Delivery" if applicable).

• Signed informed consent (including translational research).