Primary Operable Breast Cancer Research Articles

The calpain system is associated with survival of breast cancer patients with large but operable inflammatory and non-inflammatory tumours treated with neoadjuvant chemotherapy.

The calpains are a family of intracellular cysteine proteases that function in a variety of important cellular functions, including cell signalling, motility, apoptosis and survival. In early invasive breast cancer expression of calpain-1, calpain-2 and their inhibitor, calpastatin, have been associated with clinical outcome and clinicopathological factors.The expression of calpain-1, calpain-2 and calpastatin was determined using immunohistochemistry on core biopsy samples, in a cohort of large but operable inflammatory and non-inflammatory primary breast cancer patients treated with neoadjuvant chemotherapy. Information on treatment and prognostic variables together with long-term clinical follow-up was available for these patients. Diagnostic pre-chemotherapy core biopsy samples and surgically excised specimens were available for analysis.Expression of calpastatin, calpain-1 or calpain-2 in the core biopsies was not associated with breast cancer specific survival in the total patient cohort; however, in patients with non-inflammatory breast cancer, high calpastatin expression was significantly associated with adverse breast cancer-specific survival (P=0.035), as was low calpain-2 expression (P=0.031). Low calpastatin expression was significantly associated with adverse breast cancer-specific survival of the inflammatory breast cancer patients (P=0.020), as was low calpain-1 expression (P=0.003).In conclusion, high calpain-2 and low calpastatin expression is associated with improved breast cancer-specific survival in non-inflammatory large but operable primary breast cancer treated with neoadjuvant chemotherapy. In inflammatory cases, high calpain-1 and high calpastatin expression is associated with improved breast cancer-specific survival. Determining the expression of these proteins may be of clinical relevance. Further validation, in multi-centre cohorts of breast cancer patients treated with neoadjuvant chemotherapy, is warranted.

The adherence and tolerance of adjuvant endocrine therapy in geriatric breast cancer patients

BackgroundAdherence to and tolerance of oral adjuvant endocrine therapy (ET) are important to improve survival for hormone receptor (HR)-positive breast cancer patients. To date, there has been limited literature discussing this issue in elderly patients. Herein we have presented a retrospective study to analyze the tolerance to and completion rate of ET in a single medical center in Taiwan. Patients and methodsFrom 1996 to 2009, a total of 269 female patients over 70 years of age with primary HR-positive operable breast cancer were registered and analyzed for this study. ResultsIn our study, the completion rate was 49.4% for all 269 patients and was 56.7% for those willing to initiate ET. Of the 72 patients that discontinued ET early but not due to recurrence, 9.7% had well-documented ET-related adverse events, 33.3% refused to undergo ET but remained in follow-up, 44.4% did not undergo ET because of loss of follow-up before a complete ET period, and 12.5% of the patients discontinued ET arising from other medical conditions. The switch therapy, tamoxifen followed by aromatase inhibitor, showed a greater completion rate, compared with upfront tamoxifen or aromatase inhibitor. ConclusionsThe completion rate for patients who underwent oral ET in our study was similar to previous studies. The switch method of adjuvant oral endocrine therapy demonstrated a better tolerance and adherence in elderly breast cancer patients, compared with tamoxifen or aromatase inhibitor alone.

Comparison of the effectiveness and toxicity of neoadjuvant chemotherapy regimens, capecitabine/epirubicin/cyclophosphamide vs 5-fluorouracil/epirubicin/cyclophosphamide, followed by adjuvant, capecitabine/docetaxel vs docetaxel, in patients with operable breast cancer.

The aim of this study was to compare the effectiveness and toxicity of neoadjuvant chemotherapy regimens, xeloda/epirubicin/cyclophosphamide (XEC) vs 5-fluorouracil/epirubicin/cyclophosphamide (FEC), followed by adjuvant chemotherapy regimens, capecitabine/taxotere (XT) vs taxotere (T), in axillary lymph node (LN)-positive early-stage breast cancer. In this randomized, Phase III trial, 137 patients with operable primary breast cancer (T2-0, N0-1) who were tested axillary LN positive through aspiration biopsy of axillary LNs were randomized (1:1) to four 3-weekly cycles of XEC or FEC. Patients underwent surgery within 4–6 weeks after the fourth cycle, followed by four adjuvant cycles of 3-weekly XT or T. The primary end point was tumor pathological complete response. Toxicity profiles were secondary objectives. In total, 131 patients had clinical and radiological evaluation of response and underwent surgery. Treatment with XEC led to an increased rate of pathological complete response in primary tumor (18% vs 6%, respectively, P=0.027) and objective remission rate (87% vs 73%, P=0.048) compared to FEC. Clinical complete response occurred in 20% and 7% for XEC and FEC, respectively. Compared to FEC, XEC was associated with more hand-foot syndrome (57% vs 11%, P<0.001) and 3/4 grade nausea/vomiting/diarrhea (30% vs 14%, P=0.034) but less phlebitis (3% vs 14%, P=0.035). XT and T adjuvant chemotherapy regimens were well tolerated: treatment-related 3/4 grade adverse events occurred in 28% and 17% of patients receiving XT and T, respectively.

Differing pattern of biological characteristics of early operable primary breast cancer according to age.

e23272Background: Emerging evidence suggests that breast cancer in the older population tends to have less aggressive biological characteristics. This study aimed to explore a possible differing pa...

Does Breast Magnetic Resonance Imaging Combined With Conventional Imaging Modalities Decrease the Rates of Surgical Margin Involvement and Reoperation?: A Case-Control Comparative Analysis.

The objective of this study was to assess whether preoperative breast magnetic resonance imaging (MRI) combined with conventional breast imaging techniques decreases the rates of margin involvement and reexcision.Data on patients who underwent surgery for primary operable breast cancer were obtained from the Changhua Christian Hospital (CCH) breast cancer database. The rate of surgical margin involvement and the rate of reoperation were compared between patients who underwent conventional breast imaging modalities (Group A: mammography and sonography) and those who received breast MRI in addition to conventional imaging (Group B: mammography, sonography, and MRI).A total of 1468 patients were enrolled in this study. Among the 733 patients in Group A, 377 (51.4%) received breast-conserving surgery (BCS) and 356 (48.6%) received mastectomy. Among the 735 patients in Group B, 348 (47.3%) received BCS and 387 (52.7%) received mastectomy. There were no significant differences in operative method between patients who received conventional imaging alone and those that received MRI and conventional imaging (P = 0.13). The rate of detection of pathological multifocal/multicentric breast cancer was markedly higher in patients who received preoperative MRI than in those who underwent conventional imaging alone (14.3% vs 8.6%, P < 0.01). The overall rate of surgical margin involvement was significantly lower in patients who received MRI (5.0%) than in those who received conventional imaging alone (9.0%) (P < 0.01). However, a significant reduction in rate of surgical margin positivity was only observed in patients who received BCS (Group A, 14.6%; Group B, 6.6%, P < 0.01). The overall BCS reoperation rates were 11.7% in the conventional imaging group and 3.2% in the combined MRI group (P < 0.01). There were no significant differences in rate of residual cancer in specimens obtained during reoperation between the 2 preoperative imaging groups (Group A, 50%; Group B, 81.8%, P = 0.09). In multivariate analysis, multifocal/multicentric breast cancer (odds ratio = 2.38, P = 0.02) and without MRI use (odds ratio = 2.35, P < 0.01) were the major predisposing factors to margin involvement in patients received BCS.Preoperative breast MRI combined with conventional breast imaging results in a lower rate of surgical margin involvement and reoperations in patients who receive BCS.

Quality-of-life changes over time in breast cancer patients undergoing breast-conserving surgery: a prospective study in Greece.

The aim of the present study was to evaluate quality of life (QL) over time in patients undergoing breast-conserving surgery, due to primary operable breast cancer, in Greece. This was a prospective, questionnaire-based study in women with primary operable breast cancer. A Greek version of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was used. Patients filled out all six subscales of FACT-B, initially 24h prior to and then 3-7days and 9-12months after breast-conserving surgery. All participants received standard adjuvant therapy. Patients with metastatic disease, psychiatric comorbidities and those treated with neoadjuvant therapy were excluded. Data were statistically analyzed using parametric and nonparametric tests as indicated. In total, 155 women, with a mean age of 59.2years (range 30-80years), filled out the study questionnaire. Patients' social/family well-being improved 3-7days and 9-12months after the operation as compared with the preoperative period (p<0.05). Patient-doctor relationship and functional well-being deteriorated (p<0.05), while physical well-being improved (p<0.05) 9-12months after surgery than prior to or 3-7days postoperatively. Finally, emotional well-being and "additional concerns" and overall QL were all better 3-7days postoperatively than prior to or 9-12months after the operation (p<0.05). Among demographic factors, patient age and place of residence did not appear to have any effect on QL, in contrast to marital status, with married women having better QL in the social/family subscale (p<0.05). With respect to histopathological factors, patients with ER- and/or PR-positive tumors had better QL in the physical well-being but worse in the functional subscale, 9-12months after surgery. No significant correlation was found between QL and other histopathological factors. In the long term, patients' QL deteriorates with respect to functional and emotional well-being, "additional concerns" and patient-doctor relationship. Hence, specific interventions should aim to improve these aspects of QL in breast cancer patients undergoing breast-conserving surgery.

Effect of neoadjuvant chemotherapy on breast cancer phenotype, ER/PR and HER2 expression – Implications for the practising oncologist

PurposeTo assess the effect of neoadjuvant chemotherapy (NACT) on breast cancer characteristics, hormone receptors and human epidermal growth factor receptor 2 (HER2) expression and whether testing should be repeated on residual tumours. Material and methodsPatients with primary operable breast cancer who received NACT at a single United Kingdom tertiary referral centre were included. Tumour type, grade (including details of mitotic grade, tubule formation and pleomorphism), oestrogen receptor (ER), progesterone receptor (PR) and HER2 status were compared between pre-treatment and post-treatment residual samples using tissue microarrays. A control group of paired core and excision tumours from patients who did not receive NACT was also assessed. ResultsTwo hundred forty-six cases and 113 controls were included. Pathological complete response (path CR) was achieved in 21.5% of patients. In those patients failing to achieve a path CR, a change in the histological type was noted in 29 out of 178 cases (16.3%, p<0.001) with increase in the lobular and metaplastic types. Downgrading occurred in 28.8%, due to significant reduction in mitotic rate and prominent tubule formation. A change in ER/PR/HER2 status occurred in 12%, 14.5% and 7.1% of cases, respectively, predominantly as a switch from negative to positive status for ER and from positive to negative status for HER2. Further alterations in expression levels were also noted. Minimal changes in the low ER/PR expressors and the HER2 2+ tumours were found in the control group. ConclusionSignificant changes in tumour morphology, grade, hormone receptors and HER2 status occur following NACT. We recommend testing on residual invasive carcinoma. A switch from negative to positive status warrants offering endocrine/trastuzumab-based therapy to this group of patients.

The Long-term Prognostic Performance of Ki-67 in Primary Operable Breast Cancer and Evaluation of Its Optimal Cutoff Value.

Markers of proliferation are considered to have prognostic importance in breast cancer (BC). The Ki-67 index has been reported as a prognostic factor, but standardized cutoff values and counting methods are not yet established. We assayed the Ki-67 labeling index (LI) of 589 consecutive operable BC patients who underwent surgical resection. Ki-67 immunostaining was performed, and the LI was manually counted using an image processing program. We also compared the manual cell count (MCC) of Ki-67 to the whole-section eyeballed estimate count (EEC). Univariate survival analysis showed statistically significant differences in long-term BC-specific survival in the following factors: tumor size, histologic grade, nuclear grade, lymph node metastasis stage, estrogen receptor, progesterone receptor, human epidermal growth factor-2 (HER2) status, and intrinsic type (P<0.05). The MCC and EEC Ki-67 evaluations were statistically well correlated (Pearson correlation=0.683, P<0.001). Their agreement rate was highest at a 20% cutoff (κ-coefficient=0.464). With cutoff values of 14% and 20%, high Ki-67 LI was associated with poor BC-specific survival (P=0.028 and 0.012, respectively), and a 20% cutoff had a higher hazard ratio. High Ki-67 LI with a 20% cutoff was also associated with poor survival in the hormone receptor-positive and lymph node-positive subgroups (P=0.015 and 0.016, respectively). In conclusion, Ki-67 LI had prognostic significance, especially in hormone receptor-positive and lymph node-positive BC patients. EEC was relatively reliable counting method with a higher cutoff value. We suggest that the 20% cutoff value be the preferable value in clinical practice.

Abstract P4-02-03: The diagnostic accuracy of breast MRI in the prediction of malignant invasion of nipple areolar complex (NAC) of breast

Abstract Purpose: Nipple sparing mastectomy is increasingly used as a surgical treatment for breast cancer. To correctly predict the possibility of nipple invasion pre-operatively is critical important to prevent occult nipple invasion or early nipple recurrence. The objective of our study is to assess the diagnostic accuracy of breast MRI for the evaluation of malignant invasion of the nipple-areolar complex (NAC). Material and Methods: From January 2011 to December 2013, patients with primary operable breast cancer diagnosed and treated at Changhua Christian Hospital (CCH), Taiwan were searched. The inclusion criteria were primary operable breast cancer patients, who received pre-operative breast MRI, and received breast cancer operation at CCH. The exclusion criteria were patients whose primary tumor was removed before definite cancer operation, those who received neoadjuvant chemotherapy, or patient's detailed data not available. Breast MRI examinations were retrospectively reviewed for nipple invasion or retraction, periareolar skin thickening, nipple areolar complex enhancement, relationship to the subareolar mass, malignant mass pattern, thickness of nipple-areolar complex enhancement, tumor-nipple distance and tumor size, and were correlated with pathologic findings. The accuracy of breast MRI to predict nipple invasion was compared with pre-operative image and post-operative pathologic reports. Results: A total 704 primary operable breast cancers with pre-operative MRI and post operative pathologic reports were enrolled in our current study. In the total 704 patients, MRI showed signs of suspect NAC invasion in 160 (22.7%) patients. Total 41 (25.6%) patients were pathologic proven malignant invasion of NAC. In the final pathologic analysis, 57 pathologic confirmed NAC invasions were found in the 704 patients. The overall nipple invasion rate was 8.1% in this current study. The sensitivity of Breast MRI to predict NAC involvement was 71.9%. The Specificity of breast MRI to NAC invasion is 81.6%. The positive predictive value of breast MRI is 25.6%. The negative predictive value of breast MRI is 97.1%. The accuracy of breast MRI to predict NAC involvement is 80.8%. In univariate logistic regression analysis, tumor size, lymph node metastasis, central location of tumor, unilateral nipple enhancement, relationship to tumor, and HER-2 overexpression were prognostic factors for NAC invasion. In multivariate analysis, unilateral nipple enhancement (hazard ratio=4.944, CI: 1.938-12.616, P=0.001) was the most significant independently risk factor associated with the increased risk of NAC involvement. Multivariate analysis of factors related to nipple invasion Multivariate analysisParametersOdds ratio95% CIpMRI tumor size0.8500.716-1.0090.063Distance to nipples (cm)1.1990.931-1.5440.160Location of tumor (Central)1.6830.724-3.9120.226Nipple enhancement (Unilateral)4.9441.938-12.6160.001Relationship (Yes)1.6160.625-4.1770.322MRI Lymph node metastasis (Yes)1.6740.870-3.2240.123 Conclusion: MRI is an useful diagnostic image method for the evaluation of malignant invasion of the nipple-areolar complex. Through preoperative breast MRI evaluation of NAC status, more personalized oncoplastic breast surgery could be performed. Citation Format: Lai H-W, Chen S-T, Chen D-R, Wu H-K, Kuo S-J. The diagnostic accuracy of breast MRI in the prediction of malignant invasion of nipple areolar complex (NAC) of breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-02-03.

Abstract P4-02-02: Did adding breast MRI decrease the surgical margin involved rate than conventional breast image? - A case controlled comparison analysis

Abstract Purpose: Resection of primary tumor with clear margin is the goal of surgical management for primary operable breast cancer. Surgical margin involvement was associated with increased local recurrence, and usually mandated further surgery. The objective of current study is to assess whether combining breast MRI would decrease the rate of margin involvement compared with conventional breast image. Material and Methods: A retrospective, case controlled comparison study was conducted. Patients with primary operable breast cancer who received surgical management were searched from Changhua Christian Hospital (CCH) breast cancer database. The rate of surgical margin involvement was compared between two groups of patients with conventional breast image (Group A: mammogram and sonogram) or combined with breast MRI (Group B: mammogram, sonogram and MRI). Surgical margin involvement was defined as cancer cells present at surgical margin, or &amp;lt; 1mm. To further evaluate the effect of breast MRI on surgeon's margin involved rates, the index surgeons, defined as with more than 100 breast cancer operations in both Group A and Group B, were selected and analyzed. Results: Group A, conventional breast image group, consisted of 741 breast cancer patients. Among them, 381(51.4%) received partial mastectomy, and 360 (48.6%) received total mastectomy. Overall, 66 (8.9%) margin involved events were found in Group A. The margin involved rate in Group A patients received partial mastectomy or total mastectomy was 14.4% (55/381), and 3.1% (11/360), separately. The Group –B (combined with MRI) consisted of 736 breast cancer patients. Among them, 347 (47.1%) received partial mastectomy, and 389(52.9%) received total mastectomy. The margin involved rate in Group B was overall 4.8%(35/736). The margin involved rate in Group B patients who received partial mastectomy or total mastectomy was 6.1%(21/347), and 3.6% (14/ 389), respectively. The surgical margin involved rate was decreased after combination of MRI to conventional breast image as showed in table 1. Margin involved rate with conventional breast image or combined with MRI Conventional Breast ImageCombined Breast MRI Patient741736P valuePartial mastectomy51.4%47.1%0.107Total mastectomy48.6%52.9% Rate of margin involvement P valueOverall8.9%4.8%0.002Partial mastectomy14.4%6.1%0.001Total mastectomy3.1%3.6%0.834 Two index surgeons were selected for comparison of surgical margin involved rate before and after breast MRI. The "Surgeon A" 's margin involved rate in conventional breast image -&amp;gt; combined MRI were: overall: 7.6% -&amp;gt; 4.9%(0.202), partial mastectomy: 14.0% -&amp;gt; 8.1%(P=0.151), and total mastectomy: 1.3% -&amp;gt; 2.2%(P=0.8066). "Surgeon B" ‘s margin involved rate (from no MRI -&amp;gt; MRI ) was: overall: 9.0% -&amp;gt; 5.0%(P=0.121), partial mastectomy: 12.1% -&amp;gt; 3.9%(P=0.034), and total mastectomy: 6.2% -&amp;gt; 6.59%(P=0.722). Conclusion: Adding breast MRI to conventional breast image decreased the surgical margin involved rate, with the cost of mild increase the mastectomy rate. This decreasing surgical margin involved rate was not mainly due to increase mastectomy rate, but due to the selection of patients who were not suitable for partial mastectomy to receive total mastectomy. Citation Format: Lai H-W, Chen S-T, Chen D-R, Wu H-K, Ku S-J. Did adding breast MRI decrease the surgical margin involved rate than conventional breast image? - A case controlled comparison analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-02-02.

Abstract P6-09-11: Independent prognostic value of age depends on breast cancer subtype

Abstract Background: Young women present more often with aggressive breast cancer phenotypes and have worse prognosis. It remains controversial whether age is an independent prognostic factor in early stage breast cancer. Arbitrarily chosen age cut-off values have been proposed in different studies. Furthermore, few studies have examined the impact of breast cancer subtypes on the prognostic value of age. This abstract represents an update of a prior analysis (San Antonio Breast Cancer Symposium, December 4-8 2012, P06-07-29). Methods: We included all primary operable female breast cancer patients from our prospectively managed database in UZ Leuven, Belgium. We assessed the effect of age on locoregional free interval (LRRFI), distant metastasis interval (DMFI) and breast cancer specific survival (BCSS). In univariate analysis, using Cox regression models, we determined the best categorization of age at diagnosis into two or three age groups by considering all possible combinations of cut-off values. Best categorization was obtained with three age groups. We further determined, using multivariate analysis (correcting for phenotype, tumor size, nodal status, adjuvant chemo -, hormone – and radiotherapy, type of surgery and procedure of axillary staging), whether age at diagnosis remains an independent predictor of outcome (LRRFI, DMFI and BCSS). We further explored whether age at diagnosis is an independent predictor of event risk (LRRFI, DMFI and BCSS) in different breast cancer subtypes. Luminal A-like (grade I or II, ER and/or PR positive, HER 2 positive), Luminal B-like (idem but grade III), Luminal HER 2 like (ER and/or PR positive, HER 2 positive), HER 2 like (ER/PR negative, HER 2 positive), triple negative (ER/PR negative, HER 2 negative). Results: We included 4180 patients with a mean/median age of 58/57 year and with a median follow up of 8.9 year. Multivariate analysis confirmed age as an independent prognostic variable for LRRFI, DMFI and BCSS. Results multivariable analysis with age in 3 groups (HR (95% CI) P-VALUE) LRRFIDMFIBCSSYoungest versus middle1.61 (1.18-2.18) 0.00251.54 (1.23-1.93) 0.00021.72 (1.26-2.36) 0.0007Youngest versus oldest3.45 (1.85-6.45) 0.00011.25 (0.89-1.77) 0.19821.31 (0.85-2.02) 0.2220Middle versus oldest2.15 (1.22-3.79) 0.00820.81 (0.61-1.09) 0,17060.76 (0.55-1.06) 0.1014 We found optimal cut-off values for LRRFI at 44y and 72y, for DMFI at 47y and 71y and for BCSS at 41y and 70y. In an exploratory analysis, with age as continuous variable, by subtype we found a significant independent association between age and LRRFI (P=0.0169), DMFI (P=0.0344) in luminal A-like, LRRFI (P=0.0022) in luminal B-like and DMFI (P=0.0010) and BCSS (P=0.0053) in triple negative breast cancer. No significant associations were found in luminal HER2 and HER2 like breast cancers. Conclusion: This study has shown that young age is an independent prognostic factor for LRRFI, DMFI and BCSS after correction for the most important clinical prognostic factors. The prognostic effect is most important in luminal A and triple negative subtypes. Additional analyses for subtypes with age as a categorical variable will be performed and optimal cut off values will be defined. Citation Format: Poppe A, Brouckaert O, Laenen A, Soubry A, Remmerie C, Floris G, Leunen K, Berteloot P, Amant F, Vergote I, Nevelsteen I, Smeets A, Christiaens M-R, Weltens C, Peeters S, Van Limbergen E, Wildiers H, Neven P. Independent prognostic value of age depends on breast cancer subtype. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-09-11.

Abstract P3-07-13: Homologous recombination deficiency (HRD) as a predictive biomarker of response to preoperative systemic therapy (PST) in TBCRC008 comprising a platinum in HER2-negative primary operable breast cancer

Abstract Background: Biomarkers to predict response to platinum-based therapy in early breast cancer are needed. HRD is a promising predictor of response to DNA damaging agents, such as platinums. We hypothesized that HRD (high HRD score ≥ 42 and/or tumor BRCA [tBRCA] mutation) would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer treated with PST comprising a platinum, regardless of estrogen receptor (ER) status. Methods: TBCRC008 was a multicenter placebo-controlled trial that investigated pCR (no invasive cancer in breast/axilla) following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without vorinostat in patients with ER-positive or triple-negative breast cancer (TNBC) (Connolly RM. JNM 2015). The pCR rate was similar in both arms (vorinostat 25.8%, placebo 29%). We performed an exploratory biomarker study correlating baseline tumor biopsy HRD status with pCR. The analysis population included all patients with available HRD and pCR data. We compared the proportion of patients with pCR by HRD status using Fisher's exact test. A subset analysis compared pCR proportions by high (≥42) vs. low (&amp;lt;42) HRD score in those patients who did not have tBRCA mutation. A logistic regression model included HRD status, ER status, treatment arm, tumor grade and use of additional anthracycline-based non-study chemotherapy prior to definitive surgery. Results: HRD status and pCR data were available for 48/62 patients (30 ER-positive, 18 TNBC). Of these, 46% of tumors were HR deficient (n=22/48, 33% ER-positive [10/30], 67% TNBC [12/18]). We observed a significantly higher pCR rate in patients with HR deficiency vs not (50% vs 7.7%, p=0.002) in the overall population. A similar trend was observed in ER-positive (30% vs 5%, p=0.095) and TNBC (66.7% vs 16.7%, p=0.13) patients. There was no significant difference when analyzed by treatment arm (vorinostat vs placebo). In a subgroup analysis (n=40) of patients without tBRCA (25 ER-positive, 15 TNBC), a significantly higher pCR rate was observed in those with high vs low HRD score (64.3% vs 7.7%, p &amp;lt;0.001). After adjusting for ER status, randomized treatment, use of AC treatment, and tumor grade, patients whose tumors exhibited HR deficiency had a greater than 6 fold increase in pCR compared to those without HR deficiency (adjusted odds ratio = 6.76, 95% CI = 0.85-53.99, p=.072). Conclusion: This is the first study to evaluate the predictive role of HRD status in patients with ER-positive, HER2-negative breast cancer treated with platinum-based therapy. Our results also support prior observations that HRD status is a promising predictive biomarker of response to platinum agents in TNBC. Further evaluation of this question is warranted in both TNBC and ER-positive breast cancer. Citation Format: Connolly R, Elkin E, Timms K, Goetz M, Boughey J, Zhang Z, Walsh B, Carpenter J, Storniolo A, Watkins S, Gabrielson E, Hartman A-R, Stearns V. Homologous recombination deficiency (HRD) as a predictive biomarker of response to preoperative systemic therapy (PST) in TBCRC008 comprising a platinum in HER2-negative primary operable breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-13.

Association between HER2 status and response to neoadjuvant anthracycline followed by paclitaxel plus carboplatin chemotherapy without trastuzumab in breast cancer.

We recently showed HER2-positive breast cancers are less likely to respond to neoadjuvant anthracycline chemotherapy. Here, we investigated whether HER2-positive breast cancers responded to sequential neoadjuvant anthracycline followed by paclitaxel plus carboplatin regimen in the absence of trastuzumab. Women (n=372) with operable primary breast cancer initially received two cycles of neoadjuvant anthracyclines, the clinical tumor response was assessed, then patients were received four cycles of paclitaxel plus carboplatin regimen. All the patients did not received trastuzumab treatment in the neoadjuvant setting. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core-biopsy breast cancer tissue obtained before the neoadjuvant chemotherapy. Eighteen percent (67/372) of patients achieved a pathologic complete response (pCR) in their breast. HER2-positive tumors had a significant higher pCR rate than HER2-negative tumors (33.0% versus 13.5%, P<0.001) in this cohort of 372 patients, and positive HER2 status remained an independent favorable predictor of pCR in a multivariate analysis [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.18 to 4.36, P=0.015]. Furthermore, patients who responded to initial anthracycline regimens were more likely to respond to paclitaxel plus carboplatin than patients who did not (pCR, 27.2% versus 14.6%, P=0.005). Patients with HER2-positive tumors exhibited a significant higher pCR rate than did patients with HER2-negative tumors in both anthracycline response group (40.5% versus 20.0%, P=0.025) and anthracycline non-response group (28.3% versus 11.3%, P=0.002). Under the circumstance of no trastuzumab treatment, women with HER2-positive cancers derive a large benefit from paclitaxel-carboplatin-based neoadjuvant chemotherapy.

The decision-making process for senior cancer patients: treatment allocation of older women with operable breast cancer in the UK.

ObjectiveUp to 40% of women over 70 years with primary operable breast cancer in the UK are treated with primary endocrine therapy (PET) as an alternative to surgery. A variety of factors are important in determining treatment for older breast cancer patients. This study aimed to identify the patient and tumor factors associated with treatment allocation in this population.MethodsProspectively collected data on treatment received (surgery vs. PET) were analysed with multivariable logistic regression using the variables age, modified Charlson Comorbidity Index (CCI), activities of daily living (ADL) score, Mini-Mental State Examination (MMSE) score, HER2 status, tumour size, grade and nodal status.ResultsData were available for 1,122 cancers in 1,098 patients recruited between February 2013 and June 2015 from 51 UK hospitals. About 78% of the population were treated surgically, with the remainder being treated with PET. Increasing patient age at diagnosis, increasing CCI score, large tumor size (5 cm or more) and dependence in one or more ADL categories were all strongly associated with non-surgical treatment (P<0.05).ConclusionIncreasing comorbidity, large tumor size and reduced functional ability are associated with reduced likelihood of surgical treatment of breast cancer in older patients. However, age itself remains a significant factor for non-surgical treatment; reinforcing the need for evidence-based guidelines.

81P Clinicopathologic factors related to margin involvement, reoperation, and residual breast cancer in primary operable breast cancer

Aim/Background: Positive or involved margins result in higher rates of local recurrence in breast cancer patients and often need further operations. Identification of patients at increased risk for positive surgical margins may enhance clinical pre-operative decision-making.Methods: A retrospective study of 1468 primary operable breast patients were enrolled in our current margin analysis study, and factors associated with positive surgical margin, re-excision, and residual cancer detection in the re-excision specimen were analyzed.Results: Among them, 103 (7%) patients were found to have positive surgical margin involvement. The positive surgical margin involved rate was 10.7% (78/730) in breast-conserving surgery patients, and 3.4% (25/743) in total mastectomy group (P < 0.0001). In multivariate analysis, the positive surgical margin involvement was associated with lower body surface area (BSA), larger tumor size (HR = 1.458, CI = 1.162-1.831), pathologic multifocal (HR = 2.801, CI: 1.160-6.762), and without MRI use (HR = 2.381, CI = 1.318-4.301).No further re-excision was performed in the 25 margin-positive total mastectomy patients. Among the 78 breast-conserving surgery patients with positive surgical margin, 55(70.5%) received further re-excision. Patients without MRI pre-operative evaluation, or DCIS were factors related to re-operation.Among the 55 patients with positive surgical margin and who had undergone further surgical excision, 31 (56.4%) were found to have residual tumor in the re-excision specimen. Compared with the no residual tumor in the second operation group, no difference in tumor size, lymph node status, Ki-67, pathologic multifocal, or MRI use was found. The only difference was that DCIS histologic subtype was associated with higher residual tumor than other types of breast cancer.Conclusions: Lower BSA, larger tumor size, pathologic multifocal, and without MRI use were associated with increased risk for positive surgical margin involvement. Patients with DCIS who had positive surgical margin involvement were associated with increased risk for re-operation and residual cancer found at second operation.Disclosure: All authors have declared no conflicts of interest. Aim/Background: Positive or involved margins result in higher rates of local recurrence in breast cancer patients and often need further operations. Identification of patients at increased risk for positive surgical margins may enhance clinical pre-operative decision-making. Methods: A retrospective study of 1468 primary operable breast patients were enrolled in our current margin analysis study, and factors associated with positive surgical margin, re-excision, and residual cancer detection in the re-excision specimen were analyzed. Results: Among them, 103 (7%) patients were found to have positive surgical margin involvement. The positive surgical margin involved rate was 10.7% (78/730) in breast-conserving surgery patients, and 3.4% (25/743) in total mastectomy group (P < 0.0001). In multivariate analysis, the positive surgical margin involvement was associated with lower body surface area (BSA), larger tumor size (HR = 1.458, CI = 1.162-1.831), pathologic multifocal (HR = 2.801, CI: 1.160-6.762), and without MRI use (HR = 2.381, CI = 1.318-4.301). No further re-excision was performed in the 25 margin-positive total mastectomy patients. Among the 78 breast-conserving surgery patients with positive surgical margin, 55(70.5%) received further re-excision. Patients without MRI pre-operative evaluation, or DCIS were factors related to re-operation. Among the 55 patients with positive surgical margin and who had undergone further surgical excision, 31 (56.4%) were found to have residual tumor in the re-excision specimen. Compared with the no residual tumor in the second operation group, no difference in tumor size, lymph node status, Ki-67, pathologic multifocal, or MRI use was found. The only difference was that DCIS histologic subtype was associated with higher residual tumor than other types of breast cancer. Conclusions: Lower BSA, larger tumor size, pathologic multifocal, and without MRI use were associated with increased risk for positive surgical margin involvement. Patients with DCIS who had positive surgical margin involvement were associated with increased risk for re-operation and residual cancer found at second operation. Disclosure: All authors have declared no conflicts of interest.

Use of Preoperative Magnetic Resonance Imaging for Breast Cancer: A Canadian Population-Based Study.

Contrary to practice guidelines, breast magnetic resonance imaging (MRI) is commonly used in the preoperative evaluation of women with breast cancer. While existing literature has found little benefit to MRI in most patients, potential downstream consequences associated with breast MRI are not well described. To describe patterns of preoperative breast MRI utilization in a health care system with universal insurance and its association with downstream investigations and clinical outcomes. This was a population-based retrospective cohort study using administrative heath care databases in Ontario, Canada (2012 population, 13.5 million) over 14 geographic regions were evaluated within the data set. Participants comprised 53 015 patients with primary operable breast cancer treated from 2003 to 2012. Use of preoperative breast MRI by year, geographic region, and breast cancer stage. Postdiagnosis imaging, biopsy, and short-term surgical outcomes were also evaluated between those who did and did not receive MRI. Overall, 14.8% of patients (7824 of 53 015) had a preoperative MRI. During the 10-year study period, MRI use increased across all stages by 8-fold (from 3% to 24%; P < .001 for trend). Factors associated with MRI use were younger age, higher socioeconomic status, higher Charlson comorbidity score, surgery performed in a teaching hospital, and fewer years of surgeon experience. Multivariate analyses showed that preoperative breast MRI was associated with higher likelihood of the following: postdiagnosis breast imaging (odds ratio [OR], 2.09; 95% CI, 1.92-2.28), postdiagnosis breast biopsies (OR, 1.74; 95% CI, 1.57-1.93), postdiagnosis imaging to assess for distant metastatic disease (OR, 1.51; 95% CI, 1.42-1.61), mastectomy (OR, 1.73; 95% CI, 1.62-1.85), contralateral prophylactic mastectomy (OR, 1.48; 95% CI, 1.23-1.77), and a greater than 30-day wait to surgery (OR, 2.52; 95% CI, 2.36-2.70) (all ORs are adjusted). Preoperative breast MRI use has increased substantially in routine clinical practice and is associated with a significant increase in ancillary investigations, wait time to surgery, mastectomies, and contralateral prophylactic mastectomies.

Disseminated Tumor Cells in the Bone Marrow of Patients with Operable Primary Breast Cancer: Prognostic Impact in Immunophenotypic Subgroups and Clinical Implication for Bisphosphonate Treatment

Disseminated tumor cells (DTC) in the bone marrow (BM) of primary breast cancer (BC) patients are a promising surrogate marker of micrometastatic spread and an independent predictor of poor prognosis for disease-free survival (DFS) and overall survival (OS). The present study aims to analyze DTCs as an independent prognostic factor for DFS/OS in tumor biology and bisphosphonate treatment. A total of 504 patients with operable primary BC and a median observation time of 72.3 months [lower quartile (LQ) 58.1; upper quartile (UQ) 82.8] have been included. DTCs were detected via immunohistochemistry as MUC-1 positive cells in the BM of 59.13 % (298 of 504) of the patients. The immunophenotyping of cancer cells was achieved immunohistochemically as well. For luminal A/B carcinoma patients, we observed a significant benefit of BM DTC negativity with respect to DFS (luminal A, P = 0.0498; luminal B, P = 0.0224). In triple-negative patients, DTC-negative BM was associated with a longer OS (P = 0.0326). In a multivariate Cox survival analysis relating to DFS and OS, the DTC status was identified as an independent prognostic factor for DFS in luminal A/B BC (P = 0.0071). A multivariate Cox survival analysis among DTC-positive patients with luminal immunophenotype showed bisphosphonate application (P = 0.0326) to be an independent prognostic factor for DFS. The findings of our multivariate analyses reveal BM DTC positivity as an independent risk factor for DFS particularly in luminal A/B BC patients. This might be a novel criterion for the identification of candidates most likely to benefit from additional adjuvant therapy possibly including bisphosphonates.

Association of PIK3CA Mutation Status before and after Neoadjuvant Chemotherapy with Response to Chemotherapy in Women with Breast Cancer.

The association between PIK3CA mutations and response to neoadjuvant chemotherapy in women with primary breast cancer is not fully elucidated. PIK3CA mutations in breast cancer tissues that were taken prior to the initiation of neoadjuvant chemotherapy were identified in 729 operable primary breast cancer patients who received neoadjuvant chemotherapy. Among these, the PIK3CA mutations were also reassessed in tumor tissues procured following operation in 102 patients after completion of neoadjuvant chemotherapy. A total of 206 out of 729 (28.3%) patients had PIK3CA mutations, and 19.5% of patients (142/729) in this cohort achieved a pathologic complete response (pCR) after neoadjuvant chemotherapy. Patients with PIK3CA mutations exhibited a lower pCR rate than did those with wild-type (14.6% vs. 21.4%, P = 0.035). No significant differences in disease-free survival (DFS) or distant disease-free survival (DDFS) were observed between PIK3CA mutant and wild-type in the entire study population. Among the 102 patients with PIK3CA mutation statuses available before and after neoadjuvant chemotherapy, 24 patients (23.5%) had PIK3CA mutations before neoadjuvant chemotherapy. Of these 24 patients, 15 patients retained their initial PIK3CA mutations and 9 patients lost their initial mutations after neoadjuvant chemotherapy. Patients who retained the initial mutations after neoadjuvant chemotherapy (n = 15) had a worse DDFS than the remaining patients (n = 87) in this subgroup [unadjusted HR, 2.34; 95% confidence interval (CI), 0.98-5.62; P = 0.050]. Patients with PIK3CA mutations are less likely to respond to neoadjuvant chemotherapy. Patients who retain their initial PIK3CA mutations after neoadjuvant chemotherapy have an unfavorable survival.

Comprehensive prognostic analysis in breast cancer integrating clinical, tumoral, micro-environmental and immunohistochemical criteria.

Significant morphological, clinical and biological prognostic factors vary according to molecular subtypes of breast tumors, yet comprehensive analysis of such factors linked to survival in each group is lacking. Clinicopathological and micro-environmental criteria, estrogen (ER), progesterone (PR) receptors, HER2, Ki67, basal markers, CD24, CD44, ALDH1, BCL2, E-Cadherin and Trio were assessed in 1070 primary operable breast cancers from a single center according to five main molecular subtypes and associations with distant metastasis-free survival (DMFS) were examined. There were 682 (64 %) luminal A (LA), 166 (16 %) Luminal B HER2 negative (LBH−), 47 (4 %) Luminal B HER2 positive (LBH+), 108 (10 %) triple negative (TN) and 67 (6 %) HER2-enriched tumors (H2+). Median follow-up was 13.7 years. At 5 years, DMFS in LA (90 %) was better than in LBH− (80.9 %), hazard ratio (HR) = 2.22 [1.44–3.43] P < 0.001; LBH+ (74.5 %), HR = 3.14 [1.69–5.84] P < 0.001, TN (71.5 %) HR = 3.63 [2.34–5.63], P < 0.001; and H2+ (65.2 %), HR = 4.69 [2.90–7.59], P < 0.001. In multivariable analysis, factors associated with shorter DMFS varied according to molecular subtype, with tumor size being associated with shorter DMFS in the LBH−, LBH+ and TN groups and the Rho GEF Trio and BCL2 phenotypes in TN tumors only. These findings help to define new clinicophenotypic models and to identify new therapeutic strategies in the specific molecular subgroups.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1297-8) contains supplementary material, which is available to authorized users.

Meta-analysis to determine the clinical impact of axillary lymph node dissection in the treatment of invasive breast cancer.

There are divergent opinions regarding the optimum surgical management of the axilla in patients with invasive breast cancer. Guidelines mandate axillary lymph node dissection (ALND) in the setting of positive sentinel lymph nodes. However, recent studies have questioned the true benefits of this procedure. Therefore, a meta-analysis of relevant randomized trials was performed in order to clarify the oncological benefit of axillary lymph node dissection. A comprehensive search of published randomized trials that compared patients with primary operable breast cancer with/without ALND was performed using MEDLINE, and available data were cross-referenced. Reviews of each study were conducted, and data were extracted. Primary outcomes were overall survival and recurrent axillary disease. A total of 7347 patients with operable primary breast cancer were identified from 8 randomised controlled trials comparing axillary recurrence in patients with or without ALND. Six of these trials provided data on overall survival on 6895 patients. Overall survival favours patients having ALND (OR = 1.22 (95% CI 1.03-1.44, p = 0.02). Similarly, patients undergoing ALND had increased recurrence-free survival (OR = 2.25 (95% CI 1.28-3.94, p = 0.0047). ALND appears to positively impact on overall and recurrence-free survival from breast cancer. These data highlight the enduring benefits of ALND in an era where adjuvant therapies are being promoted to manage regionally advanced/metastatic disease.