Cytokine Expression During Radiation for Breast Cancer

It is well recognized that the diagnostic and therapeutic gains made in the management of
breast cancer over the last 2 decades are not fully realized by all groups. African American
women with breast cancer have greater risk of recurrence, shorter overall survival, shorter
survival after relapse, worse toxicity and worse cosmetic outcome than their Caucasian
counterparts.(1-5) These differences in outcome persist even when controlling for age, and
stage at presentation.(1, 6, 7) Being similarly treated with modern breast conserving therapy
(lumpectomy and adjuvant whole breast irradiation) at recognized centers of excellence does
little to alleviate the disparities in outcomes.(5, 8) Controlling for socioeconomic factors
decreases the severity of these disparities, but it does not completely explain them.(4)
Theories abound as to the cause of outcome inequality. Many of these theories take either a
psychosocial, or biologic bent. One potential biologic cause may be chemokine and cytokine
expression.

Chemokines and cytokines (chemo/cytokines) are proteins and peptides used for cell signaling.
Primarily secreted by T cells and macrophages, they influence cellular activation,
differentiation, and function and act as mediators for inflammatory and immune responses.(9)
There has been substantial research linking some of these chemo/cytokines (TNFα, PDGF, TGFβ,
Il-6,and IL-8) to tumor promotion and progression. For example, TNFα has been linked to
greater cell survival despite genomic injury which in turn leads to greater genetic
alterations and malignant transformation. TNFα has been associated with breast cancer
progression and metastases.(10) Blocking the receptor for PDGF appears to decrease the
metastatic potential of breast cancer cell lines.(11, 12) TGFβ inhibits T cell and B cell
lymphocytes and natural killer cell cytotoxicity.(13) This immuno-suppression has been shown
to promote tumor progression in mammary cancer cells lines.(13, 14) The ability of TGFβ to
promote tumor progression is so well recognized that it has become a therapeutic target by
some researchers.(15, 16) IFNγ has been shown to inhibit mammary cancer cell proliferation
and angiogenesis in vitro and in vivo.(17) Clinically, Lyon et al reported significantly
higher circulating levels of TNFα, Il-6, and IL-8 in women with breast cancer compared to
women with a negative breast biopsy.(18) Additionally, researchers have directly correlated
increased levels of IL-6 with the development and progression of breast cancer, and decreased
overall survival (OAS).(19) Conclusion: Expression of certain chemokines and cytokines is
associated with development and progression of breast cancer.

- Patient must be 18 years of age or older

- Patients must have histologically confirmed (by routine H&E staining) adenocarcinoma
of the breast any T or N No M disease Patients with squamous carcinomas or sarcomas of
the breast cancer are NOT eligible

- Patients must have undergone a segmental mastectomy SM with a level I and ll axillary
dissection or sentinel lymph node biopsy Surgical margins at time of local surgery
must be negative greater or equal to 2mm for both invasive carcinoma and for
non-invasive ductal carcinoma Patients who have post-operative margins which are
negative but less than 2mm will be considered eligible if the surgeon states that the
margin in question cannot be improved. Patients treated with a mastectomy are NOT
eligible

- Patients must be registered such that radiation therapy begins within 10 weeks of last
surgery

- Patients must have a performance status 0 or 1 by ECOG criteria or a 80-100 Karnofsky
Performance Scale at time of consult

- Patients must not have received prior radiation therapy to the breast at any time for
any reason

- Any patient with active local-regional disease prior to registration is not eligible

- No other prior malignancy is allowed except for adequately treated basal cell or
squamous cell skin cancer, in situ cervical cancer, or any other cancer from which the
patient has been disease-free for at least 5 years

- Patients must not be pregnant due to the potential for fetal harm as a result of this
treatment regimen. Women of child-bearing potential must use effective non hormonal
contraception while undergoing radiation therapy

- Patients must not have a serious medical or psychiatric illness which prevents
informed consent or compliance with treatment

- All patients must be informed of the investigational nature of this study and give
written informed consent in accordance with institutional and federal guidelines

- Women of all races and ethnic groups are eligible for this trial