Breast Carcinoma

Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

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The majority of patients with mammary carcinoma (approximately 90%) present with tumors that are clinically confined to the breast and neighboring axillary lymph nodes. Essentially, all these patients are rendered free of measurable disease after primary surgery.73 Despite this highly efficient locoregional therapy, 30 to 40% of these patients will develop clinically detectable metastases within 10 years if no further treatment is instituted.73 The chief reason for these relapses is that breast carcinoma cells disseminate throughout the body early in tumor development.74 To prevent the clinical progression of these micrometastases, about two thirds of the patients diagnosed with stage I to III breast cancer are candidates for adjuvant or neoadjuvant chemother-apy.75 It has been reported that approximately 36% of these women would remain free of disease using locoregional therapy alone. Routine adjuvant chemotherapy would subject these patients to unnecessary and toxic treatment. To better identify those patients who will benefit from adjuvant chemotherapy, several groups have attempted the detection of BM micrometastases by immunohistochemistry.77677 Some authors have indicated the prognostic significance of these sensitive immunocytochemical assays,777 but others failed to demonstrate such relevance.1114 Indeed, a significant minority of patients whose BM was positive by immunohistochemistry have remained free of clinically evident metastatic disease after relatively long intervals.73 These findings could be due to several factors. Some micrometastases may be incapable of developing into clinically significant lesions.73 Alternatively, the antibodies may have cross-reacted with normal marrow cells, leading to false positive results.

Table 13.4 RT-PCR and PCR Positivity Rate in Control Subjects Using Putative Markers for Breast Carcinoma

Ref.

Marker

(%)

Total

Eltahir et al.88

Muc1 mRNA

Bl

21 (91%)

23

CD44 variant

Bl

4 (40%)

10

Krisman et al.90

CK 19

Bl

13 (20%)

65

Mori et al.84

CEA

Bl

0 (0%)

22

Lopez-Guerrero et al.91

CK 19

Bl

0 (0%)

10

CEA

Bl

0 (0%)

4

Maspin

Bl

1 (20%)

5

De Graaf et al.92

EGP-2

Bl

10 (100%)

10

Ko et al.89

CEA

Bl

8 (33%)

24

Zach et al.102

Mammaglobin

Bl

0 (0%)

27

Silva et al.103

Mammaglobin

Plasma

3 (12%)

25

Bostick et al.87

Beta 1 4GalNAc-T

LN

0 (0%)

10

C-Met

LN

1/10 (10%)

10

P97

LN

1/10 (10%)

10

Note: Control subjects were defined as healthy volunteers only in all studies except Lopez-Guerrero's article. In this article,91 control subjects were defined as "healthy volunteers and patients without any type of solid tumors." In all articles, non-immunobead RT-PCR techniques were used. RT-PCR: reverse transcriptase-polymerase chain reaction; CK: cytokeratin; CEA: carcinoembryonic antigen; Bl: blood; LN: lymph nodes; Beta 1-4GalNAc-T: beta 1 4-N-acetylgalactosaminyltransferase.

Note: Control subjects were defined as healthy volunteers only in all studies except Lopez-Guerrero's article. In this article,91 control subjects were defined as "healthy volunteers and patients without any type of solid tumors." In all articles, non-immunobead RT-PCR techniques were used. RT-PCR: reverse transcriptase-polymerase chain reaction; CK: cytokeratin; CEA: carcinoembryonic antigen; Bl: blood; LN: lymph nodes; Beta 1-4GalNAc-T: beta 1 4-N-acetylgalactosaminyltransferase.

Several authors were able to detect tissue-specific transcripts in the PB, BM, and lymph nodes of patients with breast carcinomas using highly sensitive RT-PCR assays.2078-87 Unfortunately, almost all of the markers used were shown to have false positives (Table 13.4).86-92 These false positives could be due to illegitimate transcription, the presence of pseudogene, or sample contamination. In the hope of improving RT-PCR specificity, several authors have lately attempted variations on previously published PCR protocols including the use of real-time quantitative RT-PCR or novel markers.93-99

One of these "popular" novel markers is mammaglobin, a tissue-specific marker that has homology with a family of secreted proteins that includes rabbit uteroglobin. This marker was found to be present only in adult mammary tissue and in 80 to 95% of primary breast carcinomas where it is frequently overexpressed.100 According to one study, this marker was detectable by RT-PCR in breast carcinoma cell lines and absent in 20 normal lymph nodes.85 In a small group of patients with breast carcinoma, Aihara et al.101 found mammaglobin transcripts by RT-PCR in all histologically proven metastatic lymph nodes and in 31% of histologically negative lymph nodes. All their control lymph nodes were negative by mammaglobin RT-PCR. Zach et al.102 were able to detect mammaglobin mRNA in the PB of 28% of patients with breast carcinoma of various stages, 5% of patients with nonbreast carcinoma malignancies, and in none of 27 healthy volunteers. However, one study showed the presence of mammaglobin mRNA in the plasma of healthy individuals.103 Even the use of real-time quantitative RT-PCR did not eliminate the false positives encountered with the breast carcinoma-related markers. In one study, there was an overlap in the relative copies of cytokeratin 18 and 19 transcripts in BM between patients with benign tumors and those with breast carcinoma.97 Despite this persistent specificity problem, many recent articles have shown a statistically significant correlation between RT-PCR detection of breast carcinoma related transcripts and survival.9498 104-107 In node-positive patients, bone marrow mammaglobin RT-PCR positivity significantly increased the risk of recurrence at a distant site.94 The presence of cytokeratin 19 mRNA after surgery in the blood of patients with localized disease was a significant indicator of poor overall and disease-free survival.104 Using four markers including cytokeratin 19, Weigelt et al.96 were able to demonstrate that RT-PCR positivity in blood correlate with disease-free and overall survival in patients with distant metastases. These encouraging results demonstrate the potential clinical value of the detection of occult tumor cells in breast carcinoma. However, the use of these assays in the clinic awaits further improvement in specificity.

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