Kapil Dhingra

Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy

PURPOSE To assess patient and tumor characteristics associated with a complete pathologic response (pCR) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer (LABC). PATIENTS AND METHODS Three hundred seventy-two LABC patients received treatment in two prospective neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy. Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy. Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics. Median follow-up was 58 months (range, 8 to 99 months). RESULTS The initial nodal status, age, and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR (P>.05). Patients with a pCR had initial tumors that were more likely to be estrogen receptor (ER)-negative (P<.01), and anaplastic (P = .01) but of smaller size (P<.01) than those of patients with less than a pCR. Upon multivariate analysis, the effects of ER status and nuclear grade were independent of initial tumor size. Sixteen percent of the patients in this study (n = 60) had a pathologic complete primary tumor response. Twelve percent of patients (n = 43) had no microscopic evidence of invasive cancer in their breast and axillary specimens. A pathologic complete primary tumor response was predictive of a complete axillary lymph node response (P<.01 ). The 5-year overall and disease-free survival rates were significantly higher in the group who had a pCR (89% and 87%, respectively) than in the group who had less than a pCR (64% and 58%, respectively; P<.01). CONCLUSION Neoadjuvant chemotherapy has the capacity to completely clear the breast and axillary lymph nodes of invasive tumor before surgery. Patients with LABC who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate. However, a pCR does not entirely eliminate recurrence. Further efforts should focus on elucidating the molecular mechanisms associated with this response.

Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer

BACKGROUND This study was performed to validate the prognostic significance of residual axillary lymph node metastases in patients with locally advanced breast cancer (LABC) treated with neoadjuvant chemotherapy and to analyze other clinicopathologic factors that might be independent predictors of disease-free survival (DFS) in an attempt to identify patients in whom axillary dissection might be omitted. METHODS One hundred sixty-five assessable patients with LABC were treated in a prospective trial of neoadjuvant chemotherapy utilizing four cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide. Responding patients were treated with segmental mastectomy and axillary dissection or modified radical mastectomy. Patients subsequently received additional chemotherapy followed by irradiation of the breast or chest wall and draining lymphatics. The median follow-up was 35 months. RESULTS Clinical tumor response to neoadjuvant chemotherapy (P = 0.046) and the number of residual metastatic axillary lymph nodes found at axillary dissection (P = 0.05) were the only independent predictors of DFS. Patients with a complete clinical response had a predictably excellent DFS and those with no change or progressive disease had a poor DFS. In patients with a partial response, the number of residual metastatic lymph nodes further stratified patients with respect to DFS (P = 0.006). CONCLUSIONS Clinical response and residual metastatic axillary lymph nodes following neoadjuvant chemotherapy are important predictors of DFS. Patients with a clinically positive axilla following neoadjuvant chemotherapy should undergo axillary dissection to ensure local control. However, the benefit of axillary dissection in patients with a clinically negative axilla may be minimal if the axilla will be irradiated, and histologic staging does not affect subsequent systemic treatment. A prospective randomized trial of axillary dissection versus axillary radiotherapy in patients with a clinically negative axilla following neoadjuvant chemotherapy is presently under way to evaluate this hypothesis.

Chromosome in situ hybridization on formalin-fixed mammary tissue using non-isotopic, non-fluorescent probes: technical considerations and biological implications.

SummaryFluorescentin situ hybridization techniques have provided an important tool for interphase cytogenetic studies of human neoplasms. However, these techniques are difficult to use on formalin-fixed archival tissue sections. We describe here a non-fluorescent, non-isotopicin situ hybridization (ISH) approach that is easily applicable to paraffin-embedded breast tissue sections. The technical steps that must be monitored and individualized to optimize signal generation and detection are discussed. This ISH technique has several advantages over fluorescent detection methods. The signal obtained can be viewed using an ordinary light microscope and does not fade with time. More importantly, the signal is observed and analyzed in the context of tissue morphology. The technique permits detection of numerical chromosomal abnormalities not only in malignant but also in apparently normal and potentially premalignant mammary tissue. This may allow identification of focal genetic abnormalities as well as field-defects and enable analysis of their evolution during the multistep transformation to mammary neoplasm. This technique is also suitable for analysis of tumor heterogeneity and the correlation of numerical chromosomal aberrations with histologic, immunocytochemical, and clinical features of breast tumors.

Phase II study of alpha-interferon and 13-cis-retinoic acid in metastatic melanoma.

SummaryThe combination of alpha-interferon and 13-cis-retinoic acid has shown significant activity against a number of human tumors. We conducted a phase II trial to test whether the combination would have a major response rate of 30% or more in patients with refractory, metastatic melanoma. Eleven patients were treated on the study. Alpha-interferon was administered subcutaneously three times a week at a dose of 10 million U/m2 and 13-cis-retinoic acid was administered orally at a dose of 1 mg/kg/day. No patient achieved a partial or complete remission. The combination of alpha-interferon and 13-cis-retinoic acid is unlikely to have significantly higher therapeutic activity than alpha-interferon alone.

Phase II study of paclitaxel in patients with metastatic breast carcinoma refractory to standard chemotherapy

The authors conducted a single institution Phase II clinical trial to determine whether paclitaxel had antitumor activity in patients with metastatic breast carcinoma that was refractory to standard chemotherapy.

Technical approach for the study of the genetic evolution of breast cancer from paraffin-embedded tissue sections

SummaryWe have optimized a technique that allows the study of numerous chromosomal loci (n = 20–50) from single paraffin-embedded tissue sections by microsatellite length polymorphism analysis. DNA samples from normal and breast cancerous tissue can be obtained from the same section by means of microdissection. This technique was further improved by subjecting DNA to several cycles of amplification with a degenerate (universal) primer and then with specific microsatellite primers. This amplified DNA was also used to screen for mutations in the p53 gene by means of PCR-SSCP. In addition adjacent tissue sections were used to assess specific chromosome copy number by interphase cytogenetic analyses (chromosomein situ hybridization) and to analyze expression of specific genes such as p53 and ERBB2. As an example of the use of our approach we performed a detailed chromosome 17 allelotypic analysis in 22 breast tumors (5 ductal carcinomasin situ, 13 invasive ductal carcinomas, and 4 invasive lobular carcinomas). We detected mutations in the p53 gene by PCR-SSCP in 36% of the samples. Samples with significant levels of p53 protein accumulation detected by immunohistochemistry were also positive for mobility shifts in the SSCP analysis. We observed that chromosome 17 allelic losses and imbalance occurred at as early a stage as ductal carcinomain situ (DCIS). Although in some cases we observed allelic losses or imbalance affecting the 17p13 region, close to the p53 locus, several of the tumors showed dissociation between such loss or imbalance and p53 mutation. Lobular carcinomas were predominantly disomic for chromosome 17 in contrast with ductal tumors, which often showed polysomy for chromosome 17. This comprehensive approach correlating the tumor subtype, its allelotype, with specific chromosome copy number and specific gene mutations and expression in preinvasive or early invasive breast cancer lesions will potentially provide information of relevance for a better understanding of the multistep mechanisms of breast carcinogenesis.

A phase I trial of recombinant alpha-2a interferon (Roferon-A) with weekly cisplatinum

Eighteen patients with advanced solid tumors were treated in a phase I study of cisplatinum in combination with recombinant alpha-2a Interferon (Roferon-A, Hoffman-LaRoche, Inc, Nutley, NJ). Roferon-A was administered at a dose of 5 MU/m2 S.C. three times a week and the dose levels of cisplatinum were 15, 20, 25, 33, and 42 mg/m2/week given intravenously. All patients experienced grade I/II fatigue, nausea and vomiting. Grade III toxicity occurred in 4/6 patients at dose level 4. The dose limiting toxicities were myelosuppression [leukopenia (two patients), neutropenia (one patient), thrombocytopenia (one patient)], vomiting (one patient) and severe fatigue leading to a decrease in performance status (one patient). One patient with non-small cell lung carcinoma had a mixed response and another a minor response. The recommended dose level of this combination for phase II studies is cisplatinum 25 mg/m2/week and Roferon-A 5 MU/m2 three times a week.

Phase II study of deoxyspergualin in metastatic breast cancer

We conducted a phase II trial of the novel immunomodulatory/cytotoxic agent 15-deoxyspergualin in patients with metastatic breast cancer who had failed treatment with front-line chemotherapy. Thirty-eight courses of treatment were administered to fourteen patients enrolled in this trial, 25 at a dose of 1800 mg/m2/ d (dose level 0) and 13 at a dose of 2150 mg/m2/d (dose level +1) administered by continuous intravenous infusion for 5 days. Treatment was well tolerated with neuromuscular side-effects (myalgias, paresthesias) and granulocytopenia (nadir granulocyte count of 0.50–0.99 x 109/1) in two and three courses, respectively, as the only grade III toxicities. The neuromuscular toxicity of deoxyspergualin is probably related to the occurrence of hypomagnesemia. No partial or complete responses were observed in this study. One patient achieved a minor response but had progressive disease 65 weeks after enrollment. The response was observed coincident with an increase in T4/T8 ratio in the peripheral blood. The median time to progression for the entire cohort was eight weeks (range, 4–65 weeks). There was no clinical evidence of immunosuppression and no decrease in total peripheral blood lymphocyte counts or helper T-cells was observed. At the doses and schedule employed in this trial, deoxyspergualin does not appear to have significant activity against metastatic breast cancer resistant to front-line chemotherapy. The correlation between hypomagnesemia and neuromuscular toxicity of deoxyspergualin is an intriguing, previously unknown observation and requires further investigation.

Phase I study of vinorelbine and paclitaxel by 3-hour simultaneous infusion with and without granulocyte colony-stimulating factor support in metastatic breast carcinoma.

The purpose of the study was to determine the maximum tolerated dose (MTD) of vinorelbine and paclitaxel given concomitantly in patients with advanced breast carcinoma, the toxicity of this combination, and whether the addition of granulocyte colony‐stimulating factor (G‐CSF) would allow administration of higher doses of the combination.

Suppression of human anti-mouse antibody response to murine monoclonal antibody L6 by deoxyspergualin: A phase I study

The concept of using monoclonal antibodies (MAbs) to localize and treat human tumors has become a clinical reality over the last few years. Antibodies have been used to modulate the host immune system to activate tumoricidal effector mechanisms and are being used as targeting vehicles for delivery of exogenous cytotoxic molecules such as radioisotopes, chemicals and biologicals. Their ability to selectively target tumor cells also makes them attractive for radioimmunoimaging and for assessing tumor response to therapy1.