Carolyn Mies

Pathologic Complete Response Predicts Recurrence-Free Survival More Effectively by Cancer Subset: Results From the I-SPY 1 TRIAL—CALGB 150007/150012, ACRIN 6657

PURPOSE Neoadjuvant chemotherapy for breast cancer provides critical information about tumor response; how best to leverage this for predicting recurrence-free survival (RFS) is not established. The I-SPY 1 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) was a multicenter breast cancer study integrating clinical, imaging, and genomic data to evaluate pathologic response, RFS, and their relationship and predictability based on tumor biomarkers. PATIENTS AND METHODS Eligible patients had tumors ≥ 3 cm and received neoadjuvant chemotherapy. We determined associations between pathologic complete response (pCR; defined as the absence of invasive cancer in breast and nodes) and RFS, overall and within receptor subsets. RESULTS In 221 evaluable patients (median tumor size, 6.0 cm; median age, 49 years; 91% classified as poor risk on the basis of the 70-gene prognosis profile), 41% were hormone receptor (HR) negative, and 31% were human epidermal growth factor receptor 2 (HER2) positive. For 190 patients treated without neoadjuvant trastuzumab, pCR was highest for HR-negative/HER2-positive patients (45%) and lowest for HR-positive/HER2-negative patients (9%). Achieving pCR predicted favorable RFS. For 172 patients treated without trastuzumab, the hazard ratio for RFS of pCR versus no pCR was 0.29 (95% CI, 0.07 to 0.82). pCR was more predictive of RFS by multivariate analysis when subtype was taken into account, and point estimates of hazard ratios within the HR-positive/HER2-negative (hazard ratio, 0.00; 95% CI, 0.00 to 0.93), HR-negative/HER2-negative (hazard ratio, 0.25; 95% CI, 0.04 to 0.97), and HER2-positive (hazard ratio, 0.14; 95% CI, 0.01 to 1.0) subtypes are lower. Ki67 further improved the prediction of pCR within subsets. CONCLUSION In this biologically high-risk group, pCR differs by receptor subset. pCR is more highly predictive of RFS within every established receptor subset than overall, demonstrating that the extent of outcome advantage conferred by pCR is specific to tumor biology.

Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival.

In an effort to determine the patterns of failure and survival of rectosigmoid and rectal cancer, a retrospective review of 168 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. The 5‐year actuarial survival for the entire group was 67%. Survival rates decreased with increasing penetration of the bowel wall by tumor and the presence of lymph node metastasis, but only the latter reached statistical significance. Those patients who underwent an abdominoperineal resection also experienced a significant decrease in survival compared to a low anterior resection. Patterns of failure, expressed as the actuarial incidence of first failure at 5 years, were examined by stage. With the exception of stages B3 and C3, there was a trend towards increased abdominal, distant, and total failure with increasing bowel wall penetration by tumor. A similar trend was seen in local failure in those patients with positive nodes. Knowledge of these data may help identify those patients who may benefit most from adjuvant therapy.

Selection criteria for local excision with or without adjuvant radiation therapy for rectal cancer

As an alternative to radical surgery, local excision with or without adjuvant pelvic radiation therapy has been used in selected patients with rectal cancer. To determine which clinical and pathologic features can predict the presence of positive lymph nodes (LN+), a retrospective review of 168 patients who underwent potentially curative surgery for rectosigmoid and rectal cancer was performed. By univariate analysis, tumor penetration, grade, and histology were significant predictive features. This was confirmed by logistic regression analysis. The incidence of LN+ increased with increasing tumor penetration (T1, 0%; T2, 28%; T3, 36%; T4, 53%; P = 0.04), grade of adenocarcinoma (well‐differentiated, 0%; moderately differentiated, 30%; poorly differentiated, 50%; P = 0.07, [borderline significance]), and the presence of any colloid histology (pure adenocarcinoma, 30%; total colloid, 52%; P = 0.04). Using 2 × 2 contingency tables, the presence of blood vessel invasion (BVI), lymphatic vessel invasion (LVI), vascular invasion (VI), total colloid histology, and high grade further increased the incidence of LN+ with increasing tumor penetration. Regardless of tumor size, grade, histology, BVI, LVI, or VI, none of the nine patients with Stage T1 tumors or the seven with well‐differentiated adenocarcinomas had LN+. For this group, local excision alone is recommended. The incidence of LN+ was ≥19% in all other categories. For this group of patients, if there is no evidence of gross tumor in the pelvis, then a local excision plus adjuvant pelvic radiation may be an alternative to radical surgery.

Potentially curative surgery of colon cancer: patterns of failure and survival.

In an effort to determine the patterns of failure and survival of colon cancer, a retrospective review of 294 patients who underwent potentially curative surgery at the New England Deaconess Hospital (NEDH) was performed. For the entire group, the 5-year crude survival rate was 68% and the actuarial rate was 80%. Survival decreased with increasing bowel wall penetration by tumor and the presence of lymph node metastasis. Although survival varied with the tumor site, none of the differences was statistically significant. Other variables, including the grade of adenocarcinoma, size, and the type of surgery had a significant impact on survival. Patterns of failure, expressed as the actuarial incidence of first diagnosed failure at 5 years, were examined by stage and site. There was a trend toward increased failure with increasing bowel wall penetration by tumor and the presence of lymph node metastasis. Abdominal failure, either as the only site or as a component of failure, was the most common type of failure. When compared by site, patients with cecal carcinoma had a significantly lower incidence of local and distant failure than patients with disease in other selected sites. No differences in patterns of failure were seen in patients with carcinomas in the mobile sections of the colon compared with those who had disease arising in the nonmobile sections of the colon. These data may be useful in identifying those patients who might benefit most from adjuvant therapy.

High Energy Shock Waves Suppress Tumor Growth in Vitro and in Vivo

Exposure of the Dunning R3327AT-3 rat prostatic carcinoma and SK-Mel-28 human melanoma, in vitro, to high energy shock waves resulted in a reduction in cell viability as determined by trypan blue exclusion and a decrease in the number of colonies formed in a clonogenic assay. Flow cytometric determination of DNA content in R3327AT-3 cells treated in vitro indicated a selective diminution of cells in the G2 and M phases of the cell cycle. When R3327AT-3 cells exposed to high energy shock waves were subsequently injected into rats, or tumor bearing animals were treated by high energy shock waves targeted at the tumor, a delay in tumor growth was observed. These observations indicate that high energy shock waves are cytotoxic to tumor cells in vitro and in vivo. Additional research into the possible use of high energy shock waves in the non-invasive destruction of animal and human tumors is warranted.

Prognostic value of infranodal conduction time in patients with chronic bundle branch block.

His bundle recordings were obtained in 121 patients with chronic bundle branch block and the patients were followed for a mean period of 18 months. Seventy-nine patients had an infranodal conduction time (H-Q) < 70 msec while 42 had H-Q > 70 msec. There was no significant difference in mean age, smoking history, diabetes, syncope, dizziness, blood pressure, and serum cholesterol or triglyceride levels between the two groups. There was significantly greater incidence of progression to second degree or third degree atrioventricular block (9/42, 21%percnt;), and of severe congestive heart failure (16/42, 38%percnt;) in patients with H-Q > 70 compared with those with H-Q < 70 (1/79, 1.3%percnt;; and 13/79, 16%percnt;, respectively). The risk of sudden death was significantly greater only in the group with H-Q. 70 and severe congestive heart failure. There was no correlation between the presence of first degree atrioventricular block and/or any particular type of bundle branch block pattern with sudden death and/or progression to second degree or third degree atrioventricular block. Analysis of the surface electrocardiogram is only of limited value in predicting high risk patients with chronic bundle branch block. Electrophysiologic studies are of greatest value in patients with bundle branch block with transient neurologic symptoms in whom no cause for the symptoms is evident.

Resectable adenocarcinoma of the rectosigmoid and rectum. II. The influence of blood vessel invasion

Several series have examined the influence of blood vessel invasion (BVI) by tumor on survival of patients with colorectal cancer; however, little data are available regarding its influence on patterns of failure. In an effort to determine the influence of BVI on the patterns of failure and survival in rectosigmoid and rectal cancer, a retrospective review of 168 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. In patients who had tumors with extramural BVI, there was a significant decrease in five‐year actuarial survival compared with patients who had tumors with intramural BVI or were BVI‐negative (BVI‐). When the intramural and extramural types of BVI were combined, no significant impact was noted on the patterns of failure or survival in patients with BVI+ versus those with BVI‐ tumors. In contrast, the presence of lymphatic vessel invasion was found to significantly decrease survival. By using a proportional hazards analysis, it was found that BVI was not an independent prognostic variable. Therefore, the use of BVI alone is not recommended for selecting patients with rectosigmoid and rectal cancer who may benefit from adjuvant therapy.

Lymphatic vessel invasion is an independent prognostic factor for survival in colorectal cancer

To assess whether lymphatic vessel invasion (LVI) is an independent prognostic factor in colorectal cancer, we retrospectively reviewed the records of 462 patients who underwent potentially curative surgery for carcinoma of the colon and rectosigmoid/rectum (rs/rectum) at the New England Deaconess Hospital from 1965-1978. Sixty-one patients were identified as having tumors with lymphatic vessel invasion (LVI+), and they were compared with the remaining group of 401 patients who had tumors without lymphatic vessel invasion (LVI-). The incidence of lymphatic vessel invasion was significantly increased in tumors with blood vessel invasion (24% vs. 5%, p = 0.000001). Patients with LVI+ tumors also had a significantly increased incidence of positive nodes (59% vs. 25%, p = 0.0004), the average number of positive nodes (4.8 vs. 2.2, p = 0.0003), and a lower 5-year survival rate (colon: 57% vs. 84%, p = 0.0001; rs/rectum: 38% vs. 71%, p = 0.004). There was a significant (p less than or equal to 0.05) increase in local (16% vs. 7%), abdominal (33% vs. 9%), and distant (13% vs. 4%) failure as a component of component of failure in patients with LVI+ colon cancer and a significant increase in abdominal (33% vs. 11%) and distant (13% vs. 8%) failure as a component of failure in patients with LVI+ rectosigmoid/rectal cancer. Proportional hazards analysis demonstrated that lymphatic vessel invasion was an independent prognostic factor for survival.

Molecular biological analysis of paraffin-embedded tissues

Molecular biology techniques have been adapted to the analysis of paraffin-embedded tissues (PETs), expanding their clinical utility. In vitro amplification with the polymerase chain reaction (PCR) promises to be the most useful means of retrospective analysis because it can be performed successfully on nucleic acids that have been partially degraded during fixation, paraffin embedding, and the extraction process. Five clinical situations in which DNA analysis of PETs can be helpful are: (1) confirmatory molecular diagnosis of lymphoma in which fresh tissue has not been obtained at the time of surgery, (2) identification of infectious agents, (3) genetic characterization of a putative inherited disease in which the affected individual has died, (4) confirmation of donor cell malignancy in transplant recipients, and (5) specimen identification. The role of the pathologist in molecular diagnosis will grow because of the feasibility of using PETs, a venue unique to our profession.

Potentially curative surgery of colon cancer: the influence of blood vessel invasion.

A number of series have examined the influence of blood vessel invasion (BVI) by tumor on survival of patients with colorectal cancer; however, there are little data available regarding its influence on patterns of failure. In an effort to determine the influence of BVI on the patterns of failure and survival in colon cancer, a retrospective review of 294 patients who underwent potentially curative surgery at the New England Deaconess Hospital (NEDH) was performed. Patients whose tumors had BVI experienced a significant decrease in the 5-year actuarial survival rate. BVI had little impact on the patterns of failure in stage B2 disease, but a significant increase in total failure and local failure (as a component of failure) occurred in stage C2. However, when examined by proportional hazards analysis, BVI was found not to be an independent prognostic variable. For patients with stage C2 tumors, which are also BVI+, radiation therapy to the tumor bed might play a contributory role in overall management.