Combination Chemotherapy and Trastuzumab in Treating Women With Stage I, Stage II, or Stage III HER2-Positive Breast Cancer

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known which regimen of combination chemotherapy given together with trastuzumab is most effective in treating breast cancer. PURPOSE: This randomized phase III trial is comparing two different regimens of combination chemotherapy given together with trastuzumab to see how well they work in treating women with HER2-positive stage I, stage II, or stage III breast cancer.

Sex

Female

Minimum age

18 Years

Maximum age

75 Years

DISEASE CHARACTERISTICS:

* Diagnosis of infiltrating primary breast cancer

  * Stage I-IIIA disease
  * Resected tumor with free margins (i.e., no neoplastic cells on the resected margin)

    * Must have node-negative sentinel node or complete axillary clearance

      * Axillary clearance required for micrometastasis (between 0.2 and 2 mm) in the sentinel node but not for isolated tumor cells
    * Treatment is scheduled to begin within 10 weeks from the date of surgery

      * Date of the last surgery will be taken into account for patients undergoing re-excision of positive margins or axillary lymph node dissection after positive sentinel node biopsy
* Node positivity or node negativity AND ≥ 1 of the following:

  * T \> 2 cm
  * Grade 3
  * Presence of lymphovascular invasion
  * Ki 67 \> 20%
  * Age 35 years
  * Hormone receptor negativity (\<10%)
* HER2-positive tumor (3+ by IHC or FISH+ according to the American Society of Clinical Oncology guidelines \[i.e., \> 2.2; in case of polysomy, with ≥ 6 gene copies\])
* Estrogen receptor-positive and/or progesterone receptor-positive disease

PATIENT CHARACTERISTICS:

* Female
* Pre- or postmenopausal status

  * Postmenopausal status defined by ≥ 1 of the following:

    * At least 60 years of age
    * Less than 60 years of age and amenorrheic for ≥ 12 months prior to day 1
    * Less than 60 years of age and amenorrheic for \< 12 months prior to day 1 with luteinizing hormone and follicle-stimulating hormone values within postmenopausal range OR without a uterus
    * Prior bilateral oophorectomy
    * Prior radiation castration with amenorrhea for ≥ 6 months
* ECOG performance status 0-1
* Suitable for adjuvant chemotherapy
* WBC \> 3,000/mcL
* ANC \> 1,500/mcL
* Platelet count \>100,000/mcL
* Total bilirubin normal
* AST and ALT 2.5 times upper limit of normal
* Creatinine normal
* Cardiac ejection fraction normal as measured by ECHO or MUGA scan
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for ≥ 3 months after completion of study therapy
* No contraindication to anthracycline, cyclophosphamide, fluorouracil, paclitaxel, or trastuzumab (Herceptin®) treatment
* No uncontrolled intercurrent illness including, but not limited to, the following:

  * Ongoing or active infection
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Cardiac arrhythmia
  * Psychiatric illness/social situations that would limit compliance with study requirements

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* See Patient Characteristics
* No prior chemotherapy, endocrine therapy, or radiotherapy
* No other concurrent investigational agents

• RESULTGuarneri V, Frassoldati A, Bruzzi P, D'Amico R, Belfiglio M, Molino A, Bertetto O, Cascinu S, Cognetti F, Di Leo A, Pronzato P, Crino L, Agostara B, Conte P. Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER2- positive breast cancer (Short-HER Trial; NCT00629278). Clin Breast Cancer. 2008 Oct;8(5):453-6. doi: 10.3816/CBC.2008.n.056. PMID 18952561
• DERIVEDConte P, Bisagni G, Piacentini F, Sarti S, Minichillo S, Anselmi E, Aieta M, Gebbia V, Schirone A, Musolino A, Garrone O, Beano A, Rimanti A, Giotta F, Turletti A, Miglietta F, Dieci MV, Vicini R, Balduzzi S, D'Amico R, Guarneri V. Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial. J Clin Oncol. 2023 Nov 10;41(32):4976-4981. doi: 10.1200/JCO.23.00790. Epub 2023 Sep 25. PMID 37748109
• DERIVEDDieci MV, Bisagni G, Bartolini S, Frassoldati A, Vicini R, Balduzzi S, D'amico R, Conte P, Guarneri V. Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial. NPJ Breast Cancer. 2023 Feb 4;9(1):6. doi: 10.1038/s41523-023-00509-2. PMID 36739285
• DERIVEDDieci MV, Bisagni G, Brandes AA, Frassoldati A, Cavanna L, Giotta F, Aieta M, Gebbia V, Musolino A, Garrone O, Donadio M, Rimanti A, Beano A, Zamagni C, Soto Parra H, Piacentini F, Danese S, Ferro A, Cagossi K, Sarti S, Gambaro AR, Romito S, Bazan V, Amaducci L, Moretti G, Foschini MP, Balduzzi S, Vicini R, D'Amico R, Griguolo G, Guarneri V, Conte PF. Validation of the AJCC prognostic stage for HER2-positive breast cancer in the ShortHER trial. BMC Med. 2019 Nov 21;17(1):207. doi: 10.1186/s12916-019-1445-z. PMID 31747948
• DERIVEDConte P, Frassoldati A, Bisagni G, Brandes AA, Donadio M, Garrone O, Piacentini F, Cavanna L, Giotta F, Aieta M, Gebbia V, Molino A, Musolino A, Ferro A, Maltoni R, Danese S, Zamagni C, Rimanti A, Cagossi K, Russo A, Pronzato P, Giovanardi F, Moretti G, Lombardo L, Schirone A, Beano A, Amaducci L, Bajardi EA, Vicini R, Balduzzi S, D'Amico R, Guarneri V. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER studydouble dagger. Ann Oncol. 2018 Dec 1;29(12):2328-2333. doi: 10.1093/annonc/mdy414.