Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer.

INTRODUCTION: Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy. METHODS: Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher's exact test while Kaplan-Meier method was used to calculate survival. RESULTS: A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression. CONCLUSIONS: ALDH1 expression is a useful predictor of chemoresistance. The up-regulation of ALDH1 after NAC predicts poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells. TRIAL REGISTRATION: ACTRN12605000588695.

The role of chemotherapeutic drugs in the evaluation of breast tumour response to chemotherapy using serial FDG-PET.

INTRODUCTION: The aims of this study were to investigate whether drug sequence (docetaxel followed by anthracyclines or the drugs in reverse order) affects changes in the maximal standard uptake volume (SUVmax) on [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) during neoadjuvant chemotherapy in women with locally advanced breast cancer. METHODS: Women were randomly assigned to receive either drug sequence, and FDG-PET scans were taken at baseline, after four cycles and after eight cycles of chemotherapy. Tumour response to chemotherapy was evaluated based on histology from a surgical specimen collected upon completion of chemotherapy. RESULTS: Sixty women were enrolled into the study. Thirty-one received docetaxel followed by anthracyclines (Arm A) and 29 received drugs in the reverse order (Arm B). Most women (83%) had ductal carcinoma and 10 women (17%) had lobular or lobular/ductal carcinoma. All but one tumour were downstaged during therapy. Overall, there was no significant difference in response between the two drug regimens. However, women in Arm B who achieved complete pathological response had mean FDG-PET SUVmax reduction of 87.7% after four cycles, in contrast to those who had no or minor pathological response. These women recorded mean SUVmax reductions of only 27% (P < 0.01). Women in Arm A showed no significant difference in SUVmax response according to pathological response. Sensitivity, specificity, accuracy and positive and negative predictive values were highest in women in Arm B. CONCLUSIONS: Our results show that SUVmax uptake by breast tumours during chemotherapy can be dependent on the drugs used. Care must be taken when interpreting FDG-PET in settings where patients receive varied drug protocols.

PET changes management and improves prognostic stratification in patients with recurrent colorectal cancer: results of a multicenter prospective study.

UNLABELLED: The aims of our study were to examine the impact of PET in changing management in patients with proven or suspected colorectal cancer recurrence and to assess the impact of management change on disease-free survival. METHODS: Symptomatic patients with a residual structural lesion suggestive of recurrent tumor (group A) or patients with pulmonary or hepatic metastases considered to be potentially resectable (group B) underwent PET scans. Pre-PET management plans were documented by referring clinicians unaware of the PET results, and follow-up to 12 mo was performed to determine actual management and clinical outcomes. RESULTS: A total of 191 patients (118 men and 73 women; mean age, 66 y) were studied. PET detected additional sites of disease in 48.4% of patients in group A and in 43.9% of patients in group B. A change in planned management was documented in 65.6% of group A and in 49.0% of group B patients. These management plans were implemented in 96% of patients. Follow-up data in group A showed progressive disease in 60.5% of patients with additional lesions detected by PET, compared with conventional imaging, and in 36.2% of patients with no additional lesions detected by PET (P=0.04). In group B, progressive disease was identified in 65.9% of patients with additional lesions detected by PET and in 39.2% of patients with no additional lesions detected by PET (P=0.01). PET also provided valuable prognostic information on patients stratified into curative- or palliative-intent groups. CONCLUSION: These data demonstrate the significant impact of PET on management and outcomes in patients with suspected recurrent colorectal cancer.

Attitudes toward the diagnosis and disclosure of dementia among family caregivers and primary care physicians.

PURPOSE: This study examined attitudes of caregivers and physicians toward assessing and diagnosing dementia, with an emphasis on how a diagnosis is disclosed. DESIGN AND METHODS: Seventeen focus group interviews were conducted with caregivers or physicians from three sites; 52 caregivers participated in nine interviews (three each at the three sites), and 39 physicians participated in eight interviews (three each at two sites; two at one site). Structured interview protocols were used to assess diagnostic disclosure, first reactions, and suggestions for improving the diagnostic process. RESULTS: Caregivers recounted a highly negative emotional response to the disclosure, whereas many physicians reported that families handled the information well. Caregivers expressed a range of preferences for how the diagnosis should have been disclosed, from a direct approach to having the physician ease them into the results. IMPLICATIONS: Whenever possible, physicians should consult with the patient and family at the outset of the diagnostic process to better understand their preferences for diagnostic disclosure. Addressing diagnostic disclosure as part of physician education programs on dementia is recommended.