Following our previous finding of an increase in the RhoC expression level and the number of tumor emboli in IBC patients in Egypt compared to the U.S.,11
this study served to determine if these molecular characteristics differed between IBC and non-IBC cases in Egypt. In this study, we identified 3 interesting observations: (1) tumors of IBC patients had significantly higher RhoC expression than tumors of non-IBC patients, even after adjusting for age, residence, parity, and number of tumor emboli; (2) tumor emboli were more frequent in IBC tumors than non-IBC tumors as expected; and (3) IBC patients tended to have fewer children and were less likely to present with a palpable mass at diagnosis than non-IBC patients. The association between parity and IBC diagnosis was not likely to be related to differences in age or menopausal status of the study population.
Our observation of higher overexpression of RhoC in IBC tumors than in non-IBC tumors in Egyptian patients is in agreement with previous researches.7,13
The combined results from our previous and current studies suggest that IBC tumors from Egyptian patients exhibit higher levels of RhoC overexpression than IBC tumors from U.S. patients or non-IBC tumors from either Egyptian or U.S. patients. Currently, no set of histopathologic criteria are suitable for the diagnosis of IBC and it is routinely diagnosed only by suggestive clinical criteria (erythema, edema, and peau d’orange).3
The ability to detect the level of RhoC expression in patient tissue biopsies may prove to be important tools that improve the diagnosis of IBC. Only the collection of data and specimen with defined guidelines and strict verifiable criteria as explained above would help clarify the diagnosis of IBC.
In addition to molecular factors, we observed a significant decrease in lifetime parity among IBC patients, and this observation was not likely to be explained by age or menopausal status in the present study. Only one previous study that compared data obtained from patients in France and Tunisia examined the relationship between parity and IBC status, but the results were not significant in either group.15
Other reproductive factors, such as prolonged breastfeeding and younger age at menarche were associated with an increased risk of IBC,15,16
but the information from these earlier studies was not available for use in the current study.
Although all of the non-IBC patients had a palpable mass at the time of diagnosis, the percentage of IBC patients having a palpable mass was also high. We found that about 73% of the Egyptian IBC patients in this study had a palpable mass at the time of diagnosis, which was generally higher than the proportion in clinical experience in the U.S. (50%).2
The relatively higher proportion of palpable masses at diagnosis in Egyptian IBC patients may be due to the more aggressive course of IBC found in Egypt.10
Most of the descriptive data included in the present study showed no statistically significant difference between the 2 groups. Both the IBC and non-IBC patients had no significant differences in previous family history of any type of breast cancer, similar to other studies in the U.S., France, and Tunisia.15,16
In addition, we did not find a significant association between BMI and IBC status. The current findings on the association between BMI and specific types of breast cancer (IBC vs. non-IBC) are inconclusive. After considering age and menopausal status upon diagnosis, Chang et al. found that overweight or obese (BMI > 26.65 kg/m2
) women in the U.S. had an increased risk of IBC (OR = 2.45; 95% CI = 1.05–5.73) compared to non-IBC.16
Obesity (BMI: 30.0+ kg/m2
) in postmenopausal women was also associated with poorer survival in IBC patients.17
However, another study in France found a significant crude OR of IBC in obese women only (BMI: 30+ kg/m2
: OR = 4.2, 95% CI = 1.3–13.0), but the association was eliminated after taking the duration of breastfeeding into consideration.15
Unlike breast cancer patients in the U.S. and other countries, Egyptian patients exhibit an unusually high proportion of IBC among all breast cancers, a tendency to early onset, a more aggressive clinical presentation, and a characteristic molecular profile.10,11
These features underscore the possibility that particular IBC risk factors are prevalent in Egypt. These may include environmental contaminants or infectious agents such as human mammary tumor virus, which has been associated with IBC tumors in northern Africa.18
Our previous research on non-IBC patients in Egypt suggests that women without a history of lactation had a significantly higher level of serum dichlorodiphenyldichloroethylene (DDE) than women who breastfed (P
Younger age of onset and older age at first childbirth were also associated with higher levels of serum DDE in premenopausal women.19
Egyptian women living in urban areas (OR =3.1, 95% CI = 1.1–9.3), with infertility (OR = 9.8, 95% CI = 1.1–89.7), and a higher level of oxidative DNA damage, presented with 7,8-dihydro-8-oxo-2′-deoxyguanine (8-oxo-dG) in circulated DNA (OR = 5.8, 95% CI = 1.9–17.5), showed a significantly higher risk of breast cancer than other Egyptian women.20
Interestingly, although the differences were not statistically significant, we found more rural residents in the IBC group than in the non-IBC group in the current study, suggesting a potentially high likelihood of farming-related exposures among IBC patients in Egypt. Further investigations should be conducted to explore the potential environmental exposures and lifestyle factors that may causally correlate with IBC in different countries.
There are many strengths in this study, one of which is the reproducibility of the data. Both the IBC and non-IBC slides were examined multiple times and by multiple researchers to determine RhoC scores and the number of tumor emboli. In the majority of the samples, all evaluations yielded the same results for each specimen. Another strength of this study was that RhoC scoring was done with the researcher blinded to the IBC status of the slide. This helped to remove any potential observation bias and ensured reproducibility. Additionally, this study included a relatively large number of patients with IBC, which is a rare condition. Study participants were selected from a large pool of non-IBC patients who were then matched with IBC patients on histopathologic type, to eliminate any variables that could have possibly mediated or confounded the comparisons between the 2 groups. This is also the first study to investigate epidemiologic and molecular characteristics of IBC and non-IBC in Egyptian patients, who appear to exhibit a unique form of IBC that differs from IBC as seen in patients from the U.S. or other countries.
The study also has limitations. The lack of reproductive data for the IBC and non-IBC patients is a limitation. These data might include the duration of lactation, the number of pregnancies, the time between the disease onset and the most recent pregnancy or lactation, and whether the patient was pregnant or lactating at diagnosis. Data on these reproductive factors were gleaned from the medical records and clinical reports, wherever possible, but this information was often not recorded. We aimed at collecting samples with epidermis for all non-IBC patients by including mastectomies of non-IBC tumors. However, a few of the specimens did not contain full thickness of skin, including Epidermis. Although the sample size of this study was small, we used appropriate statistical tests for such sample size such as the Fisher’s exact test, Mann–Whitney U-test, and non-parametrical ANOVA to robustly evaluate the associations. Although the sample is relatively small, it turns out that the differences are sufficiently robust to reach significant levels; a small sample would not give rise to false positive findings, especially when we are doing just a few comparisons.
The results of this study will give rise to a number of promising future studies. Possibilities include comparisons of molecular components of IBC in different racial and ethnic groups. Additional genetic, lifestyle, and environmental factors should be carefully examined to understand the relationship of RhoC expression and the number of tumor emboli with the diverse risk factors for IBC. Given that the diagnostic criteria for IBC have not been standardized worldwide, international research will shed more light on IBC etiology, and aid in developing a more accurate definition of IBC to be used in diagnosis of the disease.