Breast Cancer is a common malignancy encountered in the US .Despite advancements in
the field of chemotherapy, radiotherapy and other forms of breast conserving therapies, mastectomy (surgical removal of breast tissue) remains the primary method of treatment for breast cancer. According to Kaae and Johansen (1962, as cited in Carreno et al, 2007), one common problem after mastectomy is local recurrence (LR) of the tumor, which can develop in about 10-18% of patients. This can occur despite the achievement of negative surgical margins by mastectomy. Local recurrence was defined by Carreno et al (2007), in their study as the development of adenocarcinoma, confirmed by biopsy and similar to the initially resected tumor, in one or more of the following locations: skin, subcutaneous tissues or muscles of the ipsilateral chest wall, axilla, supraclavicular fossa or internal mammary group of lymph nodes. At present, it is not possible to determine the cause of an isolated LR. It could be due to an incomplete initial removal of the tumor or it could be a sign of an already disseminated cancer at the time of mastectomy (Carreno et al, 2007).
Significance of development of LR
Presence of LR significantly decreases the period of survival in such patients by
promoting development of distant metastases within a short period of time. In a study by Bedwinek, Lee, Fineberg and Ocwieza (1981), the development of distant metastases in patients suffering from LR after mastectomy was seen in 81% of subjects. The treatment of LR consists of complete excision of gross disease followed by local radiation (Chu, Lin, Kim, Huh & Garmatis, 1976). However radiotherapy has no effect on five year survival rate and most of these patients eventually die of metastasis. Chu et al in their study have shown a five-year survival rate of only about 21%, in these patients, even after radiotherapy. However radiation therapy does help in improving quality of survival by controlling these locally recurring lesions.
Role of Clinical, Pathological and Biological Prognostic Parameters
It has been seen that within the population of cancer patients suffering from LR after
mastectomy, there exist subsets of patients which show wide variations in prognosis after development of LR (Carreno et al 2007).Some subgroups of patients show a much more favorable prognosis and higher survival rates as compared to others. These subgroups can be identified based on certain parameters: clinical, pathological and biological. The study by Carreno et al (2007) aimed at identifying and analyzing these potential prognostic factors at the
time of occurrence of LR. Carreno et al (2007) also compared the expression of these several parameters between the primary breast carcinoma and isolated local recurrences which developed post-mastectomy in these patients. This journal review aims at discussing the results of the study by Carreno et al (2007) in light of increasing research that has been carried out to discover the parameters of breast cancer which could predict the prognosis of LR, post-mastectomy. The results of such research are particularly important as presence of these parameters in a patient would alert the physician regarding the prognosis of LR in that patient. This would enable them to implement aggressive therapeutic strategies in patients with poor prognosis in order to improve their survival (Carreno et al, 2007). Patients with poor prognostic factors who are at a greater risk of LR following mastectomy are most likely to benefit from post mastectomy radiotherapy (Zellars et al, 2000). Borner et al (1994) have also reported that patients with ER (estrogen receptor) positive local recurrence who also received tamoxifen along with radiation showed a significantly more favorable disease-free survival rate as compared to those who did not receive the drug tamoxifen. On the other hand, Haffy at al, 2004 observed that patients suffering from LR which were positive for H2N (HER-2/neu) receptors could show high survival rates when treated with monoclonal antibodies to H2N. However much research is still required before implementing this treatment strategy in clinical practice. Bedwinek, Lee, Fineberg and Ocwieza (1981) in their study showed that the time taken for appearance of distant metastases in patients who had LR after radical mastectomy was significantly longer in the group of patients with good prognostic factors (clinical parameters like size of the largest recurrence being less than 1 cm, and a disease-free interval of longer than 24 months) compared to the group of patients with poor prognostic factors.
Clinical and Pathological Parameters
Some clinical parameters have been found to be directly related with the development of
local recurrence post -mastectomy. In the study by Carreno et al (2007), these clinical parameters included: size of the primary tumor, lymph node involvement prior to the surgery, histological grade of primary malignancy and disease free interval. Carreno et al (2007) found that incidence of local recurrence after mastectomy was significantly more common among those who had larger tumors, more poorly differentiated tumors on histological examination or lymph node-positive status at the time of primary diagnosis. The factors like: smaller tumor size, well differentiated tumor, lymph-node negative status and a longer disease-free interval from the time of original diagnosis of the cancer to development of LR (> 12 months) were seen to be significantly associated with overall improved survival amongst patients who developed LR post-mastectomy. They thus can be identified as good prognostic factors for post-recurrence outcome. It was also seen in this study that these clinical parameters, which had a strong, affect on prognosis after the primary diagnosis too retained their effect after LR as well. Carreno et al, 2007 from their study also reached a conclusion that under-treatment with adjuvant therapy (in form of adjuvant radiotherapy, chemotherapy or hormone therapy like tamoxifen) in patients undergoing mastectomy could be an important factor leading to the development of LR.
Bedwinek et al (1981) also observed similar results in their study showing that the
factors like: number of recurrences (multiple recurrences vs. single recurrence), the size of the largest recurrence (size of ? 1 cm vs. size >1cm) and the time interval between mastectomy and recurrence (disease-free interval of less than 24 months vs. disease free interval of longer than 24 months) had definite prognostic significance for predicting post-recurrence outcome. In their study Bedwinek et al showed that a single recurrence, the size of the largest recurrence being ? 1 cm and a disease-free interval of longer than 24 months were factors associated with a good prognosis. On the other hand, multiple recurrences, the size of the largest recurrence being >1 cm, and a disease-free interval of less than 24 months were factors associated with a poorer prognosis. However the factors like: the clinical stage of the primary malignancy at the time of initial diagnosis, the number of histologically positive nodes at mastectomy, menopausal status of woman at the time of diagnosis and the location of the recurrence (chest wall vs. nodal) had no significant effect on survival or disease-free survival in such patients. In another study Haffy et al (2004) found disease free time interval (?24 months vs. > 24 months) between diagnosis to development of local recurrence to be the most significant predictor of outcome. According to Beenken et al (2003), patients with axillary lymph node involvement at the time of primary disease showed a significantly higher rate of local recurrence and significantly lower rates of overall survival as compared to those with no axillary nodal involvement at the time of diagnosis. In 2005, Truong, Berthelet, Lee, Kader and Olivotto conducted a study in order to further define the effect of the percentage of positive lymph nodes involved in the primary cancer on risks of local recurrence following mastectomy. Truong et al, 2005 found that presence of more than 25% positive lymph nodes was associated with more than 30% incidence of local recurrence.
Biological and Molecular Parameters
Continuing research in the field of molecular biology has led to discovery of numerous
genes and their products which can be associated with the transformation of cells into a malignant growth. Presence of such biological and molecular markers plays an important role in the diagnosis, staging, and management of cases of breast cancer. Some of these markers may even serve as prognostic factors. A growing body of research studies supports the potential of using these molecular and genetic factors in predicting the prognosis of cases of local recurrence following mastectomy. The biological parameters studied by Carreno et al (2007) included: steroid receptors [estrogen receptors (ER), progesterone receptors (PR) and Androgen receptors (AR)], the oncoprotein (c-erbB-2), the tumor suppressor protein (p53), the proliferative marker (ki67) and the apolipoprotein D. Carreno et al (2007) demonstrated a significant concordance in the expression of ER, PR and p53 between primary tumors and their local recurrences. However, they found no significant concordance for AR, c-erbB-2 and ki67. These results suggest that LRs do not maintain all the biological characteristics similar to that of primary tumors. Carreno et al (2007) observed that absence of estrogen and progesterone receptors and presence of altered p53 in the LRs were significantly associated with a poorer overall survival. This result coincides with the previous reports by Borner et al (1994) which indicated that a positive ER status significantly implied a longer disease-free survival as well as a longer overall survival. This has been made possible due to Systemic therapy with Tamoxifen (an anti-estrogen) after locoregional recurrence of breast cancer. According to Diez-Itza, et al (1994, cited in Carreno et al, 2007) apolipoprotein D is the major protein component of breast secretions in non lactating women and a marker associated with a favorable prognosis in breast cancer.
Zellar et al (2000) have shown that a mutation in the p53 gene acts as a significant
poor prognostic factor for local recurrence in mastectomy treated cases of breast cancer. This is so as the tumor suppressor gene, p53 also known as “guardian of the genome” plays an important role in keeping DNA mutations in the body under control. Alterations in p53 gene can thus lead to increased frequency of DNA mutations. These unchecked DNA mutations can lead to an increase in development of human cancers. Presence of altered p53 would therefore be associated with a worse clinical outcome.
In 2004, Haffy et al conducted a study to evaluate the prognostic value of molecular
markers like: ER status, PR status, HER-2/neu (H2N) receptor, p53, and cyclin D1. Their results were similar to that by Carreno et al (2007). Haffy et al (2004) also observed that negative ER and PR and altered p53 in the LRs were significantly associated with a poorer overall outcome. PR status had a much stronger predictive value as compared to other markers. H2N status was found to be a very powerful predictor of subsequent local-regional disease progression in patients following mastectomy. Patients who had positive ER status tended to have positive PR status as well. Patients with negative ER status were significantly more likely to be positive for H2N.Cyclin D–positive patients were more likely to have a late local recurrence compared with cyclin D–negative patients. Bandic et al (2006) suggested that the MAGE-A4 (a type of tumor-associated antigen) may be used as a tumor marker for predicting the prognosis of LR in post mastectomy patients. Mohammad et al, 2006 in their study showed an elevated expression of enzymes: cox-2 (cyclooxygenase-2) and 12-lipooxygenase in patients with breast carcinoma. They also observed an inverse association between cox-2 expression and hormonal receptor status (ER and PR). They concluded that presence of these two enzyme markers (cox-2 and 12-lipooxygenase) in LR were indicators of poor prognosis.
Various studies regarding both the clinical-pathological factors as well as molecular and
biological parameters in relation to local-regional relapse following mastectomy in patients with breast cancer have presented with conflicting results. The data presented in the study by Carreno et al (2007) suggests that classical clinical-pathological factors as well as newly discovered biological and molecular parameters may help in identifying the prognosis of patients with LR after mastectomy. Even though the role of radiation and systemic therapy for LR has not been clearly defined, discovery of these prognostic markers would help in identifying potential candidates that might benefit from further therapeutic strategies. This study can serve as basis for designing larger clinical trials in future in order to discover therapeutic strategies to increase survival rate and quality of life in patients suffering from LR after mastectomy. With continuing development in the field of molecular biology and technology, further research studies defining the role of various biological and molecular markers, in future may play an important role in determining the plan of therapy for patients suffering from post-mastectomy recurrence.
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