John T. Carpenter

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

PURPOSEnNeoadjuvant 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.nnnPATIENTS AND METHODSnEligible 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.nnnRESULTSnIn 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.nnnCONCLUSIONnIn 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.

Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657)

Neoadjuvant chemotherapy for breast cancer allows individual tumor response to be assessed depending on molecular subtype, and to judge the impact of response to therapy on recurrence-free survival (RFS). The multicenter I-SPY 1 TRIAL evaluated patients with ≥3xa0cm tumors by using early imaging and molecular signatures, with outcomes of pathologic complete response (pCR) and RFS. The current analysis was performed using data from patients who had molecular profiles and did not receive trastuzumab. The various molecular classifiers tested were highly correlated. Categorization of breast cancer by molecular signatures enhanced the ability of pCR to predict improvement in RFS compared to the population as a whole. In multivariate analysis, the molecular signatures that added to the ability of HR and HER2 receptors, clinical stage, and pCR in predicting RFS included 70-gene signature, wound healing signature, p53 mutation signature, and PAM50 risk of recurrence. The low risk signatures were associated with significantly better prognosis, and also identified additional patients with a good prognosis within the no pCR group, primarily in the hormone receptor positive, HER-2 negative subgroup. The I-SPY 1 population is enriched for tumors with a poor prognosis but is still heterogeneous in terms of rates of pCR and RFS. The ability of pCR to predict RFS is better by subset than it is for the whole group. Molecular markers improve prediction of RFS by identifying additional patients with excellent prognosis within the no pCR group.

A randomized prospective trial of radical (halsted) mastectomy versus modified radical mastectomy in 311 breast cancer patients

This study reports the results of a prospectively randomized trial for treatment of carcinoma of the breast comparing standard (Halsted) radical mastectomy to a modified radical mastectomy. Three hundred eleven patients with primary operable carcinoma of the breast were entered in a surgical and ad-junctive chemotherapy trial in Alabama between 1975 and 1978. A total of 91 surgeons participated (all Diplomats of the American Board of Surgery and Members of the American College of Surgeons). All operative reports, pathology and therapy were reviewed by referees. Histologically node positive patients were randomized after operation to receive melphalan or C.M.F. (cytoxan, methotrexate, and 5-FU) for 1 year. After a median follow-up of 5.S years, there was no significant difference in disease-free survival or in overall survival between the two groups. There was a trend toward improved 5-year survival rates in the radical mastectomy group compared to the modified radical mastectomy group (84% vs. 76%, p = 0.14). There was also an increased incidence of local wound recurrence in those patients receiving modified radical mastectomy, but the differences were not statistically significant (p = 0.09). Longer follow-up will be necessary to evaluate these results more fully.

Favorable factors in the adjuvant therapy of breast cancer.

One hundred seventy‐one patients received one year of melphalan or intermittent cyclophosphamide, methotrexate, and fluorouracil after mastectomy for breast cancer with involved axillary nodes. Analysis with a median follow‐up of three years indicates a favorable outcome only for patients with 1‐3 positive nodes who were treated with melphalan and who experienced a leukocyte count less than 3,000/mm3 (3.0 × 109/1). Tumor size, average percentage of dose received, menopausal status, and type of chemotherapy were not significant factors in recurrence of disease, after adjustment for the number of positive nodes and leukocyte count nadir during treatment based on a multifactorial analysis. These data suggest that administration of a dose of melphalan which does not produce a leukocyte count of less than 3,000/mm3 is ineffective in preventing early recurrence of disease. Since oral melphalan is known to be erratically absorbed, lack of hematologic toxicity may well be due to variable absorption of the drug on a fixed‐dose regimen. Failure to prevent recurrence of disease in this and other trials using oral melphalan may be due to chemotherapy‐related as well as disease‐related factors.

Significant impairment in immune recovery after cancer treatment.

Background: Although immunosuppression from cancer adjuvant therapy has been documented, how these suppressed immune responses recover to baseline values after completion of cancer adjuvant therapy has not been studied systematically. Objectives: The objective of this study was to examine the probability of immune recovery after cancer adjuvant therapy and the potential impact of cancer adjuvant therapy type and cancer stage on immune recovery in patients with newly diagnosed breast cancer. Methods: In a repeated-measures design, immune responses were measured four times in 80 patients with early-stage breast cancer: before and at 2, 6, and 12 months from the beginning of cancer adjuvant therapy. Natural killer cell activity, lymphokine-activated killer cell activity, lymphocyte proliferation, CD subsets (CD4, CD8, and CD56), and cytokines (interferon-&ggr;, interleukin [IL]-2, IL-4, IL-6, and IL-1&agr;) were selected for their relevance to breast cancer. Immune recovery was defined by the level of immune response reaching to and above baseline levels. Data were analyzed using a multivariate generalized linear mixed-model approach. Results: Delayed immune recovery to pretreatment baseline levels continued to the 12-month time point in all parameters. The percentages of immune recovery ranged from 6% to 76% of the patients, varying among immune parameters. Overall, immune recovery was poorer for interferon-&ggr;, IL-2, IL-4, lymphocyte proliferation, and natural killer cell activity than was for CD subsets and IL-6. The type of cancer adjuvant therapy, not cancer stage, showed selective influence on immune recovery. Chemotherapy or chemotherapy and radiotherapy combination significantly delayed IL-2 recovery, whereas radiotherapy significantly delayed IL-4 recovery. Discussion: Immune recovery after breast cancer adjuvant therapy is delayed significantly for an extended time period in numerous immune parameters. The type of cancer adjuvant therapy has selective influence on immune recovery. Future investigations are warranted to elucidate the time course of immune recovery, clinical significance of poor immune recovery, and factors influencing immune recovery to develop potential interventions.

Dose Effects of Relaxation Practice on Immune Responses in Women Newly Diagnosed With Breast Cancer: An Exploratory Study

PURPOSE/OBJECTIVESnTo determine the dose effects of relaxation practice on immune responses and describe the types of relaxation techniques preferred and the extent of relaxation practice over 10 months.nnnDESIGNnDescriptive, prospective, repeated measures.nnnSETTINGnAn interdisciplinary breast clinic at a university-affiliated comprehensive cancer center in the United States.nnnSAMPLEn49 women with newly diagnosed breast cancer and undergoing adjuvant therapy who participated in a stress management intervention.nnnMETHODSnRelaxation practice was assessed twice a month for 10 months with immune measurements (e.g., natural killer cell activity; lymphocyte proliferation; interferon [IFN]-γ; interleukin [IL]-2, -4, -6, and -10) at the beginning and end of 10-month practice.nnnMAIN RESEARCH VARIABLESnRelaxation practice (representing the concepts of stress and adherence), relaxation technique, and immune response.nnnFINDINGSnAfter adjusting for covariates, the extent of relaxation practice significantly contributed to the variance of natural killer cell activity, lymphocyte proliferation, IL-4, and IL-10 responses in a positive direction; the higher the relaxation practice, the higher the immune responses. In comparison, IFN-γ, IL-2, and IL-6 responses were not affected. The deep-breathing method was most preferred by participants, followed by progressive relaxation and imagination or visualization. The mean weekly frequency of relaxation practice was 5.29 (SD = 3.35), and the mean duration of relaxation practice was 19.16 (SD = 10.81) minutes per session.nnnCONCLUSIONSnPersistent relaxation practice may have positive effects on multiple immune responses in a dose-dependent manner.nnnIMPLICATIONS FOR NURSINGnAllowing the choice of preferred techniques and emphasizing the importance of long-term adherence, a relaxation program may need to be routinely offered to women under high stress.

Abstract P2-18-06: Low dose capecitabine is effective and relatively nontoxic in breast cancer treatment

Capecitabine has been widely used in treatment of both early and advanced breast cancer in the United States since 1998. The dose limiting toxicity is diarrhea, which is dose limiting and can be severe. Lower doses are widely used without any apparent compromise in efficacy and are consistently less toxic (see Naughton, Clinical Breast Cancer 2010). Here a continuous dose regimen of capecitabine 1000 mg. daily was used in 24 patients with breast cancer, both early and advanced, from March 2012-September 2013. Four received the drug as adjuvant treatment, 8 as preoperative therapy, and 12 for advanced disease. Duration of treatment ranged from 0.5 to 15 months. Toxicity was modest: 1 had moderate nausea, none experienced vomiting, 2 mild anemia (one with marrow replacement by tumor), 2 mild palmar irritation, and 1 grade 1 thrombopenia. No diarrhea was seen. One patient died of hepatic necrosis and portal vein thrombosis; the relationship to treatment was uncertain. 12/20 with measurable disease experienced a response to treatment (1 complete and 11 partial responses by RECIST criteria), 1 had stable metastatic disease for 9 months, and 7 had progression of disease. The median duration of response was 5 months (range 2-15 months). Use of capecitabine in this dose and schedule for treatment of breast cancer appears comparably effective to higher conventional doses and dramatically less toxic. Citation Format: John Carpenter. Low dose capecitabine is effective and relatively nontoxic in breast cancer treatment [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-18-06.

The Accuracy of MRI in Predicting Pathologic Complete Response in Invasive Breast Cancer Patients Receiving Neoadjuvant Systemic Treatment.

Background: Magnetic resonance imaging (MRI) has increased sensitivity to detect abnormalities in breast tissue as compared with mammography or ultrasound. Published reports of MRIs ability to predict pathologic response to neoadjuvant chemotherapy have shown conflicting results that vary depending on baseline molecular characteristics and chemotherapeutic regimens, with some studies suggesting higher predictive accuracy in Her2 positive patients receiving trastuzumab. This study examines both the ability of MRI to predict pathologic response and how tumor molecular profiles and treatment regimens influence MRI sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Sensitivity, specificity, PPV, and NPV for the combination of post-treatment mammogram, ultrasound, and MRI studies in predicting pathologic complete response (pCR) was also explored.Methods: Eighty-one patients with invasive breast cancer treated with neoadjuvant systemic therapy between 2002 to 2009 and imaged pre and post-treatment with breast MRI were reviewed. Patient, tumor, and treatment characteristics including tumor grade, histologic type, receptor status (ER, PR, and Her2), breast cancer subtype [luminal A, luminal B, Her2 positive, triple negative (TN)], correlative pre- and post-treatment mammographic and ultrasound imaging, drug regimen, and pathologic findings were recorded. Complete pathologic response was defined as no residual invasive or pre-invasive disease in the breast.Results: Patients had the following subtypes of breast cancer: 21/81 (26%) luminal A, 13/81 (16%) luminal B, 23/81 (28%) Her2 positive, and 24/81(30%) TN. Of the Her2 positive, only 12/23 (52%) treated after May 2005 received adjuvant trastuzumab. Twenty patients (25%) had a complete radiographic response (rCR) on post-treatment MRI and 23/81(28%) had a pCR. The sensitivity, specificity, PPV, and NPV of MRI for predicting pathologic response was 57%, 88%, 65%, and 84%, respectively. Analysis of breast cancer subtype did not demonstrate a predilection in any particular subtype for correlation of radiographic and pathologic response, although MRI sensitivity (100%) and NPV (100%) were highest in luminal A disease, and specificity and PPV were highest for patients with ER negative (96% and 90%) and triple negative (100% and 100%) disease, respectively. Mammographic and ultrasound post-treatment findings of residual disease did not significantly correlate with pathologic findings in the setting of a rCR on MRI. Multivariate analysis of factors potentially influencing MRIs sensitivity and specificity failed to show that tumor characteristics (ER status, PR status, HER2 status) or neoadjuvant treatment (ACT vs other or trastuzumab) had any effect on these parameters.Conclusions: MRI has the highest specificity and PPV in the setting of ER negative and TN breast cancer. Although treatment results and breast cancer subtype did not influence the sensitivity, specificity, PPV, or NPV of MRI in predicting pathologic response, only half of the Her2 positive subset received trastuzumab. Results from an ongoing large multi-institutional study will further clarify these results. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4022.