Systemic Therapies for Breast Cancer

CHEMOTHERAPY

Algorithm for Adjuvant Systemic Therapy (DeVia 7th)

Stage ER/PR + ER/PR -
T1a, T1b N0 ±TAM ± Chemo
T1c-T2 N0 Chemo + TAM x 5 years Chemo
  • for patient > 70 y.o. give Chemotherapy if > 3 cm mass or node positive.

Survival and Local Recurrence Benefit

EBCTCG (Lancet 2005; 365:1687-1717).

Cancer Specific Mortality of polychemotherapy at 15 years by Age

Ages 15-Years
< 50 y.o. 10.0%
50-69 y.o. 3.0%

Local Control Benefit of polychemotherapy

5-LF 15-LF
Ages Node - Node + All Groups
< 50 y.o. 9.9% 14.6% 12.3%
50-69 y.o. 5.3% 5.9% 4.1%

LF: Local Failure Rate

  • Polychemotherapy is better than single agent
  • for < 50 year-old, Isolated local recurrence with polychemotherapy was 1.3%/yr vs 2.2%/yr without for a odd ratio of 0.63 which was significant
  • > 50 years-old, 1.7%/yr and 2.5%/yr .
  • chemotherapy reduces local recurrence rate by 30-40% or 0.8-0.9 % per year.

NSABP-06 and Milan

  • For node + pts, all got chemo and RT showed improved DFS and trend towards improved OS (p=0.08).

ESTROGEN RECEPTOR MODULATOR

Tamoxifen (Nolvadex®) is an oral estrogen receptor modulator

  • Indicated in Treatment of
    • Adjuvant treatment of breast cancer in ER or PR positive pre- or post-menopausal women
    • Metastatic breast cancer
    • Breast cancer prevention
  • Side-effects
    • endometrial cancer
    • thromboembolism
    • rapid increase in triglyceride
  • Results
    • Absolute survival benefit of TAM at 15-years = 9.2% (pretty much same for all groups)

Raloxifene (Evista®) is an oral selective estrogen receptor modulator

  • Indicated in Treatment of
    • prevention of osteoporosis in postmenopausal women.
    • prevention of breast cancer in post-menopausal women
    • no evidence for the use of raloxifene in the adjuvant treatment of breast cancer
  • Benefits over Tamoxifen
    • lower risk of thromboembolic events and cataracts
    • anti-estrogen like effect on uterus as well as in breast
  • Worse compared to Tamoxifen
    • Raloxifene a nonstatistically significant higher risk of noninvasive breast cancer.
  • NSABP-P-2 (STAR) trial of "postmenopausal" women [1]
    • Study of Tamoxifen and Raloxifene, or STAR, show that the drug raloxifene, currently used to prevent and treat osteoporosis in postmenopausal women, works as well as tamoxifen in reducing breast cancer risk for postmenopausal women at increased risk of the disease

Fulvestrant (Faslodex®) steroidal, ER downregulator with a mode of action distinct from that of tamoxifen

  • Indications
    • For patients getting AI or tamoxifen as first-line therapy, fulvestrant is a reasonable second-line choice.

TAMOXIFEN

NSABP B-21[2]

Eligibility

  • Invasive breast cancers 1 cm or less
  • ER test not required: ER+ (~55%), ER- (~13%) , ER unknown (~30%) patient

Results

8-IBTR 8-CBC 8-EFS 8-OS
L + TAM 13.5% 0.9 78.8% 93%
L + RT 6.9% 4.2% 81.6% 94%
L + RT + TAM 2.7% 3.0% 84.4% 93%
p-value < .01 .03 N.S. N.S.

L: Lumpectomy
TAM: Tamoxifen
RT: Radiation
IBTR: Ipsilateral breast Tumor Recurrence
CBC: Contralateral breast cancer

Conclusions

  • Adding RT to TAM reduces local recurrence by 10% at 8 years
  • Adding TAM to RT reduces local recurrence by 4% at 8 years

AROMATASE INHIBITORS (AI)

  • Function
    • Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.
  • Types of AI
Mechanism Examples
Type I Irreversible steroidal inhibitors exemestane
Type II Reversible non-steroidal inhibitors anastrozole, letrozole
  • Indicated in the treatment of
    • breast cancer in post-menopausal women.
    • (early adjuvant therapy), replacement of tamoxifen as adjuvant therapy for 5 years
    • (early sequential adjuvant therapy), sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years
    • (extended adjuvant therapy) following 5 years of tamoxifen .
    • in metastatic breast cancer.
  • Side-effects
    • osteoporosis (Zometa was shown Z-FAST study to help with osteoporosis)
    • sore muscles, joint pain, and arthritis. (3-4% increase over placebo)
    • increase in cholesterol levels (Letrozole and Anastrozole)
    • stomach upset and mild nausea. These symptoms usually occur in the first weeks of treatment and then slowly go away.

Exemestane (Aromasin®)
* A large trial (International Collaborative Cancer Group [ICCG] trial 96)
* switching to exemestane after 2 to 3 years of tamoxifen was significantly superior in disease-free survival compared with continuing on tamoxifen.

Anastrozole (Arimidex®)
* adjuvant trial (Arimidex, Tamoxifen Alone or in Combination [ATAC])
* superior to tamoxifen in reducing risk of disease recurrence

Letrozole (Femara®)
* Breast International Group (BIG) trial BIG 1-98 demonstrated the significant
* superior to tamoxifen in improving disease-free survival.
* Trial MA.17 evaluated extended adjuvant therapy with letrozole vs placebo following 5 years of tamoxifen.
* Superior Disease-free survival vs placebo, irrespective in both lymph node-positive or node-negative tumors.

HERCEPTIN (trastuzumab)

  • Function of HER2/neu receptor
    • HER2/neu is a membrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation.
    • increased cell proliferation and enhanced cell motility may be associated with overexpressed HER-2/neu
  • Epidemiology
    • 20% to 30% of breast tumors contain HER-2/neu overexpression
    • HER2/neu amplification is found in 28%-50% of DCIS cases (more than in invasive cancer). [Ref. Bartkova]
    • HER2/neu amplification is found in 50% of comedocarcinoma
  • Results
    • Two Randomized Trials - BIG 01-01 and NSABP B31 - show survival benefit ( > 50% reduction in recurrences ) with 1 year of Herceptin in HER-2 positive patient by IHC3+ or FISH.
    • BIG 01-01 (N Engl J Med. 2005 Oct 20;353(16):1659-72).
    • NSABP B31 (N Engl J Med 2005;353:1673–1684).
  • Herceptin can be given concurrent with radiation
    • but not with doxorubicin due to the potential for additive cardiac toxicity.
Bibliography
1. Vogel VG; Costantino JP; et. al.; for the National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA. 2006;295:2727-2741
2. Fisher B, Bryant J, Dignam JJ, Wickerham DL, Mamounas EP, Fisher ER, Margolese RG, Nesbitt L, Paik S, Pisansky TM, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol. 2002 Oct 15;20(20):4141-9. PMID: 12377957
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