The relationship between the expression of parathyroid hormone-related protein (PTHrP) by breast cancer and skeletal metastases, was investigated using a monoclonal antibody against human PTHrP (4B3). The immunohistochemical localization of PTHrP was studied in sections of formalin-fixed, paraffin-embedded tissues from 28 breast cancers obtained surgically between 1980 and 1985. Of the 28 patients, 12 developed skeletal metastases, 8 developed lung metastases, and the other 8 were alive and disease-free at the time of this study. Sixteen of the 28 (57%) tumors showed positive immunoreactivity to 4B3, the PTHrP positive ratio being 83% in the patients who developed skeletal metastases, 38% in those who developed lung metastases, and 38% in those without recurrence, respectively. Thus, a significantly higher proportion of the patients who developed skeletal metastases were positive for PTHrP than the other two groups (P < 0.05). Furthermore, the level of positive staining was strongly related to positivity for estrogen and progesterone receptors (P < 0.01). These results are consistent with the hypothesis that PTHrP might be necessary for metastases to erode bone and grow in skeletal sites, and its expression could be related to certain hormones.

The expression of parathyroid hormone-related protein (PTHrP) at primary and metastatic sites was studied retrospectively in specimens obtained at opreation and autopsy from 11 patients. The anti-human PTHrP monoclonal antibody, 4B3, was used in the immunohistochemical studies. The 11 cases showed metastases to the liver and the lung, and 9 showed bone metastases at autopsy. At primary sites, PTHrP was positive in the 9 cases with bone metastases, while the other 2 cases were negative for PTHrP. Regardless of the intensities of immunohistochemical staining of PTHrP at primary sites, cancer cells at metastatic sites in the liver and the lung were almost all negative for PTHrP. On the other hand, all PTHrP-positive cases at primary sites at operation showed skeletal metastases at autopsy, and the intensity of the immunohistochemical staining of PTHrP was strongly positive at all the sites of skeletal metastasis. These results suggest that while PTHrP is an important factor that causes cancer cells to erode and grow in skeletal bone, the expression of PHTrP is, concurrently, affected by an osseous microenvironment.

Most chemotherapy regimens cause neutropenic nadirs between days 10 and 14, and administration of granulocyte colony-stimulating factor (G-CSF) support relies on this timing. In docetaxel (DOC)-based chemotherapy, the frequency of febrile neutropenia (FN) and the G-CSF dose administered varied greatly between studies. Our study goal was to forecast the necessary dose of G-CSF by comparing day 8 neutropenia with putative changes within the neutrophil pool. We conducted a retrospective observational analysis of 242 early breast cancer patients who had received adjuvant DOC-based chemotherapy (DOC group) compared with 43 patients who had received FEC chemotherapy (FEC group). Patients who were given a standard dose and had a blood test on day 8 in the 1 st cycle were eligible. In the DOC group, patients routinely received prophylactic administration of G-CSF (150 μg/body) on day 3 and received additional G-CSF based on a blood test on day 8. Results of the day 8 blood test showed that severe neutropenia (<500/mm 3 , average 494/mm 3 ) was observed in 152 out of 242 (62.8%) patients in the DOC group, while in the FEC group (n = 43), neutropenia was ambiguous (average 1,741/mm 3 ). In the FEC group, 9 out of 43 patients (20.9%) and in the DOC group, 27 out of 242 patients (11.1%) experienced FN. In the DOC group, day 8 neutropenia was predictive for FN in a logistic regression model (OR 0.79 [95% CI: 0.655–0.952], p = 0.013). Among 214 patients under 70 years old, the planned chemotherapy cycle was completed in 190 (88.8%) patients who also received the maximum dose of G-CSF (150 μg/body) four times, while 23 patients could not complete the planned chemotherapy cycle, but only five because of FN-related complications. Patients treated with DOC should be treated for primary prophylaxis with G-CSF support at an earlier time starting with a relatively small dose.

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