are her2+ (and/or EGFR+) tumors more radioresistant (ie radiation therapy doesn't

[Lani]

work as well)? This article doesn't think so!:

RESULTS Go to:
For the whole group of 352 patients with known HER-2 status, the median follow-up was 5.4 years, for the HER-2-positive group it was 5.5 years, and for the HER-2-negative group it was 5.5 years. The overall percentage of HER-2-negative tumors was 76% and of HER-2-positive tumors was 24%, which is consistent with the expected range. Overall the percentage of HER-2-negative patients per year over the study period ranged from 53% to 97%, which is likely due to sampling error among relatively small numbers of patients tested in any given year.

Outcomes analysis was performed to assess local recurrence, overall survival, cause-specific survival, relapse-free survival, and distant disease-free survival (Table 2). In this series there was no statistically significant difference between the two groups for any of the outcomes. Local recurrences have been seen in 7 of the 266 (3%) HER-2-negative patients, for an actuarial rate of local recurrence of 2% at 5 years. There have been no local recurrence events to date in the HER-2-positive group (p = 0.15).

Due to these local recurrences, as well as two isolated regional failures in the HER-2-negative group, the relapse-free survival appears somewhat lower than in the HER-2-positive group, although this difference is not significant. Relapse-free survival for the HER-2-negative group at 5 years was 92%, compared to 97% for the HER-2-positive group, which has experienced no local or regional failures to date (p = 0.07). Overall survival at 5 years in the HER-2-negative group was 94% and in the HER-2-positive group was 89% (p = 0.33). Cause-specific survivals at 5 years of 96% for the HER-2-negative group and of 95% for the HER-2-positive group were not statistically different (p = 0.96). Distant disease-free survival was also similar, at 93% at 5 years in the HER-2-negative group compared to 97% for the HER-2-positive group (p = 0.16).

[Lani]

DISCUSSION Go to:
The oncogene HER-2, a member of a family of protein kinases that includes the EGFRs, is an important molecular marker in breast cancer that is overexpressed in 20–30% of all breast cancers. Amplification of the gene has been associated with a poorer prognosis (2,3) and with resistance to chemotherapy and hormonal therapy (18,19). EGFR family members' overexpression has been implicated in radioresistance pathways. Very limited data exist with respect to the clinical interaction of HER-2 overexpression and breast irradiation.

Several studies have shown that overexpression of HER-2 and other EGFR family members is associated with radioresistance in laboratory systems. In a study using MCF-7 breast cancer cells, epidermal growth factor (EGF) stimulated growth and increased radioresistance in vitro (20). A study in a murine model including four breast carcinomas found that tumor radioresponsiveness was highly correlated with EGFR expression and that high levels of EGFR expression required a higher radiation dose to achieve 50% tumor control (TCD50) (21). A causal relationship between EGFR expression and radioresponse was suggested by a study in which EGFR (HER-1) was transfected into ovarian carcinoma cells, which showed an EGFR level dependent increase in radioresistance by a factor of 1.60 for high levels of expression, and by lesser factors for lower levels of expression (22). This effect was reversed by treatment of the transfected cells with C225, a monoclonal antibody that blocks EGFR.

[Lani]

These data raise concerns about increased radioresistance in tumors that overexpress HER-1 and HER-2. Irradiation may activate the EGFR signaling pathway as part of a cellular protective response, and inhibitors may abrogate this response. For example, overexpression of HER-2 in MCF-7 breast cancer cell lines enhanced the activation of the transcription factor, NF-B, induced in response to radiation (9). Trastuzumab both inhibited NF-B and increased the cells' radiosensitivity. In a group of six breast cancer cell lines, high levels of HER-2 expression correlated with radioresistance (11). Treatment with trastuzumab enhanced radiosensitization, depending on the level of HER-2 expression, by reducing phosphorylation of downstream molecules Akt and MAPK. A study in breast cancer cell lines that endogenously overexpress HER-1 or HER-2 or which were transfected with HER-2 were treated with an EGFR/HER-2 inhibitor prior to irradiation (8). The drug inhibited EGFR tyrosine phosphorylation in all cell lines and increased radiosensitivity in some.

A study using a novel small molecule EGFR inhibitor, CI-1033, in irradiated human breast cancer cell lines demonstrated a 23-fold increase in growth inhibition compared to radiation alone (23). Similar results have been seen in cells overexpressing HER-2 and treated with monoclonal antibody (13), an anti-erbB-2 single-chain antibody (10), and in various cell models using EGFR inhibitors, such as ZD1839 (Iressa) (11). Clinical studies of EGFR manipulation in breast cancer are limited, although there are several trials using EGFR inhibitors in the treatment of head and neck, and lung cancers (24–27).

[Lani]

In the current study, there was no difference in local recurrence rates between patients whose tumors did or did not overexpress HER-2. To date there have been no local recurrence events in the HER-2-positive patients at a median follow-up of 5.5 years, and local recurrences have occurred in 2% of HER-2-negative patients. These data suggest that HER-2 overexpression is not associated with a strong clinical radioresistance phenomenon. The use of BCT in women with early stage HER-2-positive tumors should therefore be considered a reasonable treatment option. Limitations on these conclusions are conferred by relatively small patient numbers, particularly in the HER-2-positive group, the need for longer follow-up, and the variable HER-2 testing and scoring methods used over the study period.

This study also found no difference in survival outcomes, including overall survival, relapse-free survival, cause-specific survival, and distant disease-free survival. More than 70 studies have found an adverse correlation between HER-2 overexpression and prognosis or survival compared to HER-2-negative breast cancers (28). That other negative prognostic features were not strongly associated with HER-2 overexpression in the current study should not be interpreted as contradicting the established literature. Rather, the relatively small patient numbers in the HER-2-positive group and limited follow-up time may have contributed to the lack of differences between the two groups.

[Lani]

Few other studies have examined the question of clinically apparent radioresistance in HER-2-positive patients by analyzing local recurrences after radiation. In a series from the MD Anderson Cancer Center, investigators compared 32 HER-2-positive and 76 HER-2-negative patients with more advanced disease who underwent neoadjuvant chemotherapy, mastectomy, and postoperative chest irradiation in four clinical trials of neoadjuvant chemotherapy (29). HER-2 status was retrospectively analyzed on archival tissue by IHC and FISH. The chest wall received a median dose of 50 Gy and a median boost dose of 10 Gy. The HER-2-positive patients in this group had a higher rate of ER-negative tumors and supraclavicular disease at diagnosis and a greater number of positive lymph nodes at the time of surgery. However, despite these negative features, there was no increase in the actuarial rate of local-regional recurrence at 5 or 10 years in HER-2-positive patients compared to the HER-2-negative group.

In a study from Yale University, investigators performed a case control analysis of the significance of HER-2 overexpression in 16 patients with an isolated local recurrence as the site of first failure and 20 matched controls without any local recurrence, all treated with BCT (30). HER-2 expression was retrospectively assayed using IHC on tissue from paraffin blocks. None of the patients had received chemotherapy or hormonal therapy. In the index cases, 56% had high HER-2 immunoreactivity, compared to 18% of the matched controls (p = 0.03). Therefore, in this small case-control series, there appeared to be a correlation between HER-2 overexpression and the risk of a local recurrence.

[Lani]

Few other studies have examined the question of clinically apparent radioresistance in HER-2-positive patients by analyzing local recurrences after radiation. In a series from the MD Anderson Cancer Center, investigators compared 32 HER-2-positive and 76 HER-2-negative patients with more advanced disease who underwent neoadjuvant chemotherapy, mastectomy, and postoperative chest irradiation in four clinical trials of neoadjuvant chemotherapy (29). HER-2 status was retrospectively analyzed on archival tissue by IHC and FISH. The chest wall received a median dose of 50 Gy and a median boost dose of 10 Gy. The HER-2-positive patients in this group had a higher rate of ER-negative tumors and supraclavicular disease at diagnosis and a greater number of positive lymph nodes at the time of surgery. However, despite these negative features, there was no increase in the actuarial rate of local-regional recurrence at 5 or 10 years in HER-2-positive patients compared to the HER-2-negative group.

In a study from Yale University, investigators performed a case control analysis of the significance of HER-2 overexpression in 16 patients with an isolated local recurrence as the site of first failure and 20 matched controls without any local recurrence, all treated with BCT (30). HER-2 expression was retrospectively assayed using IHC on tissue from paraffin blocks. None of the patients had received chemotherapy or hormonal therapy.

[Lani]

In the index cases, 56% had high HER-2 immunoreactivity, compared to 18% of the matched controls (p = 0.03). Therefore, in this small case-control series, there appeared to be a correlation between HER-2 overexpression and the risk of a local recurrence.

The current study is limited by the information available from HER-2 assessment at the time of diagnosis, which reflects a period of time prior to standardization of the scoring of HER-2 overexpression. HER-2 IHC performed at the University of Pennsylvania represented 83% of the patients tested. However, while the patients presented in this series generally had HER-2 expression assessed by IHC, the antibodies used differed during the study period and the majority of samples were scored as "positive" or "negative." Some patients interpreted as HER-2-positive might not actually overexpress the gene, especially if their IHC was in the "2+" range and amplification was not confirmed by FISH. Recent studies have shown that while 98% of HER-2 IHC 3+ cancers have gene amplification, only about 25% of HER-2 IHC 2+ cancers have amplification (31,32). Thus the evolving testing standard is to consider FISH in all HER-2 2+ cancers. This expression profile was not known during the study period, so FISH was not routinely performed.

HER-2 is an important molecular marker and prognostic indicator in breast cancer. Given the findings of two randomized trials for early stage breast cancer patients comparing adjuvant chemotherapy alone to chemotherapy plus trastuzumab (NSABP B-31 and North Central Cancer Group [NCCTG] N9831) (6,7), which showed an increase in disease-free survival in the arms including trastuzumab, routine assessment of HER-2 status has become even more important. Therefore, as data are accumulated from clinical trials and institutional experiences, it is important to examine the impact of HER-2 expression on other modalities, including radiation. In this study we found no apparent evidence for radioresistance in HER-2-positive tumors with respect to local recurrence after BCT at 5 years.

Based on the data from the present study, HER-2 overexpression does not appear to be a contraindication to BCT including definitive irradiation. Further studies in larger numbers of patients and with longer follow-up, ideally using more uniform assessment of HER-2 expression, need to be performed to confirm these findings

[Lani]

mimeographing machines and photocopy machines were illegal so people had to type out their dissertations for their university professors using carbon paper (reportedly hard to come by!) to get it out to all the parties who had to judge whether it warranted an advanced degree.

When it is made more difficult to get information out, adjustments are made

I actually think the computer age hastened the downfall of the Soviet Union as it would have been impossible to keep information down if the country was to be able to compete in an information-technology oriented world.

Why the new limit on 2500 characters?