Individualized selection of the most effective adjuvant (or neoadjuvant) chemotherapy for breast cancer based on the molecular characteristics of the tumor could improve the risk:benefit ratio of current therapies. It could also streamline the development of new regimens for those who are unlikely to benefit from existing drugs. It is expected that combinations of markers will be more informative to predict response than any single gene and may yield regimen-specific predictors. Novel molecular analytical tools, particularly transcriptional profiling, provide a method to test this hypothesis. Several small exploratory studies have shown encouraging results. This article reviews recent progress in this field including experience from the breast cancer pharmacogenomic marker discovery program at the Nellie B. Connally Breast Center of the University of Texas M. D. Anderson Cancer Center. This manuscript is based on a presentation that was given during the Presidential Symposium of the annual meeting of the Japanese Breast Cancer Society in 2004.

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Translational research (TR) involves both the development of novel diagnostics and novel therapeutics. These two major developmental areas are often associated with each other and these associations often bring new paradigms in the management of cancer patients. For example, the development of trastuzumab-based treatments has been conducted in harmony with the development of new methodologies to assess the expression of the Her-2 gene or protein, and from this, a therapeutic modality was established for breast cancer patients as a novel and individualized treatment system. TR covers a broad spectrum, from diagnosis to treatment, and it seems to act as a catalyst for developing novel paradigms. Therefore, it is crucial to conduct TR in clinical trials, in particular, prospective clinical trials. In this regard, TR can accelerate the development of new methodologies and increase trial efficiency. In this review, we describe the importance of TR, particularly that related to novel therapeutics.

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Background: The relationship between a positive resection margin and the risk of ipsilateral breast tumor recurrence (IBTR) is controversial. To evaluate the radiation dose and other factors influencing the ipsilateral breast tumor control (IBTC) in patients with positive or close resection margins after breast conserving surgery (BCS), the Japanese Radiation Oncology Study Group (JROSG) S-99-3 study group conducted a multi-institute survey of these patients.
Methods: The patients with less than 5 mm tumor-free margins after BCS were eligible for this study. A total of 971 patients from 18 institutes were enrolled in the analysis. The final pathological margin status was classified into 3 groups. Radiation doses to the tumor bed were less than 60 Gy in 252 patients, 60 Gy in 456 patients and more than 60 Gy in 233 patients.
Results: IBTR was observed in 55 patients (5.8%). The IBTC rates at 5 and 10 years by the Kaplan Meier method were 95.6% and 87.3%, respectively. There was no significant difference in 10-year IBTC rates according to marginal status; 85.9% in positive margin patients, 91.0% in equal or less than 2 mm margin patients and 87.0% in 2.1-5 mm margin patients. Radiation dose to the tumor bed was a marginally significantly associated with the 10-year IBTC rate (≥60 Gy 90.8% vs <60 Gy 84.2%, p = 0.057). In patients with positive margins, IBTC with radiation dose equal to or more than 60 Gy was significantly better (p = 0.039). The other factors influencing the IBTC were age (≥35 years vs <35 years: p < 0.0001), menopausal status (p < 0.0001) and tumor size (p = 0.023).
Conclusions: In patients with positive margins, IBTC with radiation dose equal to or more than 60 Gy was significantly better than the others. We recommend that the tumor bed be irradiated with at least 60 Gy in the patients with positive margins. Further follow-up is necessary to draw final conclusions.

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Purpose: A single-arm phase II multicenter trial of the combination of cyclophosphamide (C), epirubicin (E), and 5-fluorouracil (F) followed by docetaxel as neoadjuvant chemotherapy is being conducted by the Japan Breast Cancer Research Group. This report describes an interim analysis of the clinical response and safety of 79 patients who finished preoperative chemotherapy and surgery.
Patients and Methods: Patients with operable breast cancer received C at 500 mg/m², E at 100 mg/m², and F at 500 mg/m² every 21 days for 4 cycles followed by docetaxel at 75 mg/m² every 21 days for 4 cycles.
Results: Of the 79 patients evaluable for analysis the median age was 46 years (28-59). and 61 patients (77.2%) had T2 tumors. A total of 312 of 316 (98.7%) cycles of CEF and 296 of 312 (94.9%) cycles of docetaxel were administered. Average total cumulative dose was 92% and 95% for CEF and docetaxel, respectively. The rate and grade of edema, neuropathy, arthralgia and myalgia were higher with docetaxel than with CEF. The overall clinical response rate was 70.9%. Breast conserving surgery was performed in 31 of 42 patients (73.8%) with a base-line tumor size of more than 3 cm.
Conclusions: Interim data suggest that CEF followed by docetaxel is an active and tolerable neoadjuvant chemotherapy regimen. A final analysis is planned for 2005.

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Background: Ipsilateral breast tumor recurrences (IBTR) after breast-conserving treatment include two different entities: true recurrence (TR) thought to occur when residual cancer cells grow gradually to detectable size and new primary (NP) thought to be de novo cancer independently arising in the preserved breast. The patients with ipsilateral breast tumor recurrence (IBTR) are potentially at high risk for subsequent distant metastasis, but many studies do not distinguish between these types of recurrence. The aim of this study is to clarify the biological difference between TR and NP, and to show the clinical significance of classifying IBTR into these two types of recurrence.
Patients and Method: A total of 172 patients with IBTR after breast-conserving therapy from the cohort of a long-term large scale study (Research of cancer treatment from the Ministry of Health, Labor and Welfare of Japan (no. 13-9)) were analyzed. We classified IBTRs as TR or NP based on tumor location and pathological findings. The characteristics of the primary tumors of TR and NP were compared. Survival rates and risk factors of each type of IBTR were examined by the Kaplan-Meier method. The results of salvage surgery were also analyzed.
Results: Of the 172 patients, 135 patients were classified as TR and 26 as NP. Eleven cases could not be categorized. The primary tumor of TR was characterized by a high rate of lymph node metastasis (37.8%) and short disease-free interval (mean DFI; 46.6 months) while that of NP showed a rather low lymph node positivity (8.7%) and longer DFI (62.1 months). The risk factors for TR were young age, positive surgical margin, omission of irradiation and positive lymph node metastasis. Those for NP were young age, omission of irradiation and contralateral breast cancer after the primary operation. The 5-year survival rates after IBTR were 71.0% in TR and 94.7% in NP (p = 0.022). Salvage operation was performed in 136 IBTRs. Eighty-one patients underwent salvage mastectomy and 55 patients underwent repeat lumpectomy. Five-year survival rates after salvage operation were 75.7% for mastectomy and 84.2% for lumpectomy (N.S.). Twenty percent of patients who underwent repeat lumpectomy developed secondary local relapse within 5 years after salvage treatment. The risk factors for secondary local relapse were analyzed. Limited to cases of IBTR which received radiation therapy after the primary operation, NP was the only factor influencing secondary local relapse by univariate analysis.
Conclusions: TR and NP show clinically quite different features; time to occurrence, characteristics of the original tumor, prognosis and risk factor profile for IBTR were all different. Classifying IBTR as TR or NP can provide clinically significant data for the management of IBTR.

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Purpose: To classify and assess ipsilateral breast tumor recurrences (IBTR) after breast-conserving therapy.
Methods: Between 1986 and 2001, 2,137 patients who had breast cancer underwent breast-conserving surgery with or without radiotherapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Of these patients, 83 (3.9%) had an IBTR. We classified the IBTR as a new primary cancer (NP) if the primary tumor had completely negative margins at first operation by detailed pathological examination and if the IBTR had an intraductal component. All other IBTRs were judged true local recurrence (TR).
Results: Of the 83 patients, 42 patients were classified as TR (29 had no radiotherapy) and 41 as NP (40 had no radiotherapy). Mean time to disease recurrence was 37 months for TR (52% were within 2 years) versus 55 months for NP (19% were within 2 years) (p = 0.031). Six patients (14%) with TR did not receive re-operation, and 67% received salvage mastectomy and 19% re-lumpectomy. All cases of NP were operable, 78% underwent salvage mastectomy and 22% underwent re-lumpectomy. Distant metastases were observed in 33% of patients with TR and 5% of patients with NP, and cause-specific death occurred in 6 cases with TR and in one with NP. The patients with NP had improved 5-year rates of overall survival (NP 91% vs. TR 76%, P = 0.0627) and distant disease-free survival (NP 93% vs. TR 61%, P = 0.0028). Patients with NP more often developed contralateral breast cancer (NP 37% vs. TR 12%, P = 0.018)
Conclusions: Patients with NP had better survival rates than those with TR. Distinguishing new primary breast carcinomas from local disease recurrences may have importance in therapeutic decisions and chemoprevention strategies.

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Background: An attempt was made to visualize minute intraductal lesions using helical CT in patients with abnormal nipple discharge.
Methods: Galactography was performed, immediately followed by CT (ductal CT examination). Based on the image data obtained, ductal images were constructed on a workstation using a Pegasus viewer (ductal CT imaging). Since no criteria for diagnosis by this method are available, ductal CT images were diagnosed by reference to the known ductal fiberscopic findings.
Results: Ductal CT examination was performed in 10 cases, in 9 of whom ductal CT images were successfully constructed. Pathological examination was performed in 8 cases. It was possible to observe the structure of the luminal surface on the constructed ductoscopic images from all directions, but the color tone or the presence or absence of hemorrhage could not be observed.
Conclusions: In the examination for abnormal nipple discharge, ductal CT examination was useful for intraductal observation. Currently, it is a method that allows for observation of the most minute intraductal lesions. However, some issues still remain unresolved. The results of this study suggest that further studies with more cases hold the promise of making ductal CT imaging a useful examination method.

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Background: In order to achieve a good cosmetic result without increasing the risk of ipsilateral breast cancer recurrence after breast conserving surgery, it is very important to minimize the resection volume of the breast without compromising the negativity of the surgical margin. For this purpose, it is necessary to obtain precise information on tumor extension. We therefore developed a three-dimensional (3-D) ultrasound navigation system for breast cancer surgery, which can be performed in the operating room just before surgery.
Methods: We obtained 3-D breast tumor images by the 3-D ultrasound navigation system in 40 patients with primary breast cancer (stage 0-II) who underwent mastectomy or breast conserving surgery. The tumor size was measured in a coronal view of the 3-D tumor image and compared with the tumor size obtained from a pathological map of the tumor extension.
Results: We obtained 3-D tumor images in 38 patients (success rate = 95%). The tumor size in the images showed a very strong correlation with the pathological tumor size (r = 0.898). The difference in tumor size between the 3-D images and pathology was less than 1 cm in 29 tumors (76.3%) and less than 2 cm in 36 (94.7%). On the other hand, the difference in tumor size between palpation and pathology was less than 1 cm in 19 out of 38 tumors (50.0%) and less than 2 cm in 29 tumors (76.3%). The absolute difference between the 3-D images and pathology was significantly less than that between palpation and pathology (p = 0.0197).
Conclusions: Our 3-D ultrasound navigation system is useful in visualizing breast tumor extension and is more accurate than palpation. The system is expected to be helpful in deciding on the appropriate surgical margin in breast cancer surgery, resulting in a better cosmetic outcome without increasing the risk of surgical margin positivity.

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Background: The prolongation of the post-operative life of cancer patients brings new medical demands. The purpose of this paper is to estimate the total number of women patients with breast cancer who will have disability resulting from surgical treatment from 2000 to 2020 in Japan.
Methods: The estimation was carried out using four indices: the number of cases of women diagnosed with breast cancer, the proportion of surgical operations, the frequency of disability from surgical treatment, and the crude survival rate of the patient group.
The crude survival rates of surgically-treated breast cancer patients were estimated by the Weibull model. The frequencies of iatrogenic disabilities were calculated from several reports of complaints of pain in the chest wall or axilla and lymphedema of the arm, and 95% confidence intervals were calculated by the Monte Carlo simulation.
Results and Discussion: The number of women patients with disability from breast cancer treatment from 2000 to 2020 was estimated to be 42,016 (95% CI: 41,236, 42,796) people in 2000 and 72,514 (95% CI: 71,196, 73,832) people in 2020 for pain in the chest wall or axilla, and 22,486 (95% CI: 22,148, 22,823) people in 2000 and 38,692 (95% CI: 38,094, 39,290) people in 2020 for lymphedema of the arm. Treatment supports required for the disability are medication and social support. Cancer patients with disability after treatment need long-term support in their daily life.

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Background: Although breast-conserving surgery followed by definitive irradiation is an established treatment for patients with early breast cancer, the role of breast-conserving therapy (BCT) for patients with bilateral breast cancer has not been well studied and the radiation therapy technique is still under investigation. We examined the feasibility of breast-conserving therapy for bilateral breast cancer and present here our radiation therapy technique with CT simulator.
Methods: Between July 1990 and December 1998, we treated 17 patients with bilateral breast cancer who underwent bilateral breast-conserving surgery followed by definitive irradiation. Seven patients had synchronous bilateral breast cancer and ten had metachronous bilateral breast cancer. Radiation therapy consisted of 50 Gy to the bilateral whole breast in all patients but one. A CT simulator was used to plan a tangential radiation field to the breast in all patients. Boost irradiation of 10 Gy was administered to 8 tumors with close or positive margins.
Results: With a median follow-up periods of 95 months from each operation, no patients showed loco-regional recurrence on either side, and none suffered distant metastasis. Furthermore no serious late adverse effects were observed.
Conclusion: This study demonstrated that BCT is feasible for bilateral breast cancer and the CT simulator is useful for determining the radiation field, especialy when lesions are metachronous.

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Background: Healing is a phenomenon by which the intraductal component of breast cancer disappears and is replaced by fibrous tissue. Focally localized healing often prevents confirmation of the continuity of intraductal carcinoma.
Objective: To clarify the clinicopathological characteristics of breast cancer with healing.
Patients and Methods: At our hospital, 308 patients (311 breasts) underwent breast conservation therapy without neoadjuvant chemotherapy for breast cancer in 2000. These surgical specimens were histopathologically investigated with 5 mm serial sections. We assessed the proportion and the characteristics of breast cancer with healing.
Results: (1) The proportion of breast cancer with healing was 7% (21/311). (2) In the 21 patients, the mean age was 59.2 years, and the mean diameter was 2.8 cm. (3) The histological type of the breast cancer varied: noninvasive ductal carcinoma in 2 cases, papillotubular carcinoma in 5, solid-tubular carcinoma in 8, scirrhous carcinoma in 5, invasive lobular carcinoma in 1, and Paget's disease in 1. However in all cases, the histologic type of the intraductal carcinoma foci was the comedo/solid type and the nuclear grade of cancer cells was high. (4) In cases with healing, areas of healing were seen in an average of 5 (1-26) blocks, compared with intraductal carcinoma foci in 13 blocks (2-40). Healing was located on the nipple side of the main lesion in 8 cases, the peripheral side in 9, and both sides in 4. In 3 cases, healing was seen at the surgical margin of the partial mastectomy specimen.
Conclusion: The proportion of breast cancer cases with healing was 7% and these cases were intraductal carcinoma of the comedo/solid type, consisting of highly malignant cancer cells.

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Invasive cribriform carcinoma (ICC) is a rare, unique type of invasive breast carcinoma that exhibits a cribriform pattern in the majority of the invasive component and is associated with an excellent prognosis. Only one male patient with ICC has been previously reported. Mammography studies often suggest that ICC contains microcalcifications, but the histological finding of extensive microcalcification has only been reported in one patient with ICC. Here we report a male patient diagnosed with ICC and exhibiting histologically confirmed extensive microcalcification is reported. The patient was a 64-year-old Japanese man in whom a breast tumor was detected during an annual check up. Mammography demonstrated a circumscribed high-density mass with microcalcifications. Breast-conserving surgery with axillary node dissection was performed. The tumor was located in the subareolar region of his left breast. The excised tumor had a maximum diameter of 1.0 cm, and no signs of invasion to extramammary tissue were observed. Histologically, the tumor cells were arranged in a cribriform pattern with invasive and non-invasive components. High-grade carcinoma or tubular carcinoma components were not observed. Extensive calcification was seen within the cribriform spaces. Immunohistological staining revealed that the cribriform spaces did not contain basement membrane material, and the tumor cells had not differentiated into basaloid cells or lactationl mammary epithelium. The patient is presently free from local recurrence or metastasis 7 months after undergoing surgery.

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Carcinosarcoma is a rare malignant tumor of the breast. A 59-year-old woman was admitted to our hospital with a complaint of a right breast mass for one month. The mass grew rapidly, and modified radical mastectomy was performed. Based on the histological findings of carcinomatous and sarcomatous components entangled without a transition area, and the results of immunohistochemical staining, carcinosarcoma of the breast was diagnosed. Within 9 months of the surgery, a recurrent lesion appeared in her chest wall. As shown by local resection, this recurrent tumor had only a carcinomatous component.
Such tumors are very rare, and there have been no detailed reports of recurrence patterns of carcinosarcoma. Here we report our pathological findings in detail.

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A 52-year-old Japanese woman presented with a mass in the left breast. A tumor 2.9 cm in diameter was found in the D area on ultrasonography. An ipsilateral swollen axillary lymph node was detected. Invasion of the tumor to the pectoralis major muscle was seen. Based on a diagnosis of malignant lymphoma by fine needle aspiration cytology, radical mastectomy with ipsilateral axillary lymph node dissection was performed. Malignant diffuse large B-cell type lymphoma was diagnosed histologically according to the World Health Organization classification, and the clinical stage was IIE by the Ann Arbor staging system. Four courses of adjuvant chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were subsequently performed. The patient is free of recurrence 7 years after surgery. Up to 2002, 380 cases of primary breast non-Hodgkin's lymphoma had been documented in the Japanese literature. When the tumor size was bigger than 4.5 cm, the outcome was poor. Regarding treatment methods, we showed that only enucleation of the tumor is necessary and axillary dissection is not necessary. In our case, we thought that the prognosis was good despite the large tumor and axillary lymph node metastasis, and that we could omit axillary dissection.

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