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Raman Spectroscopy for Rapid Evaluation of Surgical Margins during Breast Cancer Lumpectomy.

ABSTRACT: Failure to precisely distinguish malignant from healthy tissue has severe implications for breast cancer surgical outcomes. Clinical prognoses depend on precisely distinguishing healthy from malignant tissue during surgery. Laser Raman spectroscopy (LRS) has been previously shown to differentiate benign from malignant tissue in real time. However, the cost, assembly effort, and technical expertise needed for construction and implementation of the technique have prohibited widespread adoption. Recently, Raman spectrometers have been developed for non-medical uses and have become commercially available and affordable. Here we demonstrate that this current generation of Raman spectrometers can readily identify cancer in breast surgical specimens. We evaluated two commercially available, portable, near-infrared Raman systems operating at excitation wavelengths of either 785?nm or 1064?nm, collecting a total of 164 Raman spectra from cancerous, benign, and transitional regions of resected breast tissue from six patients undergoing mastectomy. The spectra were classified using standard multivariate statistical techniques. We identified a minimal set of spectral bands sufficient to reliably distinguish between healthy and malignant tissue using either the 1064?nm or 785?nm system. Our results indicate that current generation Raman spectrometers can be used as a rapid diagnostic technique distinguishing benign from malignant tissue during surgery.

SUBMITTER: Zuniga WC

PROVIDER: S-EPMC6787043 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Raman Spectroscopy for Rapid Evaluation of Surgical Margins during Breast Cancer Lumpectomy.

Zúñiga Willie C WC Jones Veronica V Anderson Sarah M SM Echevarria Alex A Miller Nathaniel L NL Stashko Connor C Schmolze Daniel D Cha Philip D PD Kothari Ragini R Fong Yuman Y Storrie-Lombardi Michael C MC

Scientific reports 20191010 1

Failure to precisely distinguish malignant from healthy tissue has severe implications for breast cancer surgical outcomes. Clinical prognoses depend on precisely distinguishing healthy from malignant tissue during surgery. Laser Raman spectroscopy (LRS) has been previously shown to differentiate benign from malignant tissue in real time. However, the cost, assembly effort, and technical expertise needed for construction and implementation of the technique have prohibited widespread adoption. Re ...[more]

PMID: 31601985

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Project description:BackgroundThe effect of breast cancer subtype on margin status after lumpectomy remains unclear. This study aims to determine whether approximated breast cancer subtype is associated with positive margins after lumpectomy, which could be used to determine if there is an increased risk of developing local recurrence (LR) following breast-conserving surgery.MethodsWe studied 1,032 consecutive patients with invasive cancer who received lumpectomies and cavity margin (CM) assessments from January 2003 to November 2012. The following data were collected: patient age, cT stage, pT stage, grade, status of CM, lymph node status, menopausal status, ER, PR, HER-2, and Ki67, as well as the presence of extensive intraductal component (EIC) and lymphovascular invasion (LVI). A ?2 test was used to compare categorical baseline characteristics. Univariate and multivariate logistic regression analyses were performed to evaluate associations between pathologic features of CM status. Kaplan-Meier actuarial cumulative rates of LR (ipsilateral in-breast) were calculated.ResultsA total of 7,884 pieces of marginal tissue were collected from 1,032 patients, and 209 patients had positive CMs. Of the patients tested, 52.3% had luminal A subtype, 14.9% were luminal B, 12.8% were luminal-HER-2, 8.1% were HER-2 enriched, and 11.8% were triple negative. Univariate analysis showed that EIC (P < 0.001), LVI (P?=?0.026), pN stage (N1 vs. N0: P?=?0.018; N3 vs. N0: P < 0.001), and luminal B (P?=?0.001) and HER-2 (P < 0.001) subtypes were associated with positive CMs. Multivariable analysis indicated that only EIC (P < 0.001), pN stage (P?=?0.003), and HER-2 subtype (P < 0.001) were significantly correlated with positive CMs. On multivariable analysis, HER-2 subtype was an independent prognostic factor in LR (P?=?0.031).ConclusionsThe HER-2 subtype was the predictive factor most associated with positive CMs and an independent prognostic factor for LR. This result suggests that the increased risk of LR in HER-2 breast cancer is due to an increased microscopic invasive tumor burden, which is indicated by margin status after lumpectomy.

Project description:ImportanceSurgery after initial lumpectomy to obtain more widely clear margins is common and may lead to mastectomy.ObjectiveTo describe surgeons' approach to surgical margins for invasive breast cancer, and changes in postlumpectomy surgery rates, and final surgical treatment following a 2014 consensus statement endorsing a margin of "no ink on tumor."Design, setting, and participantsThis was a population-based cohort survey study of 7303 eligible women ages 20 to 79 years with stage I and II breast cancer diagnosed in 2013 to 2015 and identified from the Georgia and Los Angeles County, California, Surveillance, Epidemiology, and End Results registries. A total of 5080 (70%) returned a survey. Those with bilateral disease, missing stage or treatment data, and with ductal carcinoma in situ were excluded, leaving 3729 patients in the analytic sample; 98% of these identified their attending surgeon. Between April 2015 and May 2016, 488 surgeons were surveyed regarding lumpectomy margins; 342 (70%) responded completely. Pathology reports of all patients having a second surgery and a 30% sample of those with 1 surgery were reviewed. Time trends were analyzed with multinomial regression models.Main outcomes and measuresRates of final surgical procedure (lumpectomy, unilateral mastectomy, bilateral mastectomy) and rates of additional surgery after initial lumpectomy over time, and surgeon attitudes toward an adequate lumpectomy margin.ResultsThe 67% rate of initial lumpectomy in the 3729 patient analytic sample was unchanged during the study. The rate of final lumpectomy increased by 13% from 2013 to 2015, accompanied by a decrease in unilateral and bilateral mastectomy (P = .002). Surgery after initial lumpectomy declined by 16% (P < .001). Pathology review documented no significant association between date of treatment and positive margins. Of 342 responding surgeons, 69% endorsed a margin of no ink on tumor to avoid reexcision in estrogen receptor-positive progesterone receptor-positive cancer and 63% for estrogen receptor-negative progesterone- receptor-negative cancer. Surgeons treating more than 50 breast cancers annually were significantly more likely to report this margin as adequate (85%; n = 105) compared with those treating 20 cases or fewer (55%; n = 131) (P < .001).Conclusions and relevanceAdditional surgery after initial lumpectomy decreased markedly from 2013 to 2015 concomitant with dissemination of clinical guidelines endorsing a minimal negative margin. These findings suggest that surgeon-led initiatives to address potential overtreatment can reduce the burden of surgical management in patients with cancer.

Project description:The accurate analytical characterization of metastatic phenotype at primary tumor diagnosis and its evolution with time are critical for controlling metastatic progression of cancer. Here, we report a label-free optical strategy using Raman spectroscopy and machine learning to identify distinct metastatic phenotypes observed in tumors formed by isogenic murine breast cancer cell lines of progressively increasing metastatic propensities. Methods: We employed the 4T1 isogenic panel of murine breast cancer cells to grow tumors of varying metastatic potential and acquired label-free spectra using a fiber probe-based portable Raman spectroscopy system. We used MCR-ALS and random forests classifiers to identify putative spectral markers and predict metastatic phenotype of tumors based on their optical spectra. We also used tumors derived from 4T1 cells silenced for the expression of TWIST, FOXC2 and CXCR3 genes to assess their metastatic phenotype based on their Raman spectra. Results: The MCR-ALS spectral decomposition showed consistent differences in the contribution of components that resembled collagen and lipids between the non-metastatic 67NR tumors and the metastatic tumors formed by FARN, 4T07, and 4T1 cells. Our Raman spectra-based random forest analysis provided evidence that machine learning models built on spectral data can allow the accurate identification of metastatic phenotype of independent test tumors. By silencing genes critical for metastasis in highly metastatic cell lines, we showed that the random forest classifiers provided predictions consistent with the observed phenotypic switch of the resultant tumors towards lower metastatic potential. Furthermore, the spectral assessment of lipid and collagen content of these tumors was consistent with the observed phenotypic switch. Conclusion: Overall, our findings indicate that Raman spectroscopy may offer a novel strategy to evaluate metastatic risk during primary tumor biopsies in clinical patients.

Project description:Intraoperative frozen-section analysis of the lumpect-omy margin during breast-conserving surgery (BCS) is an excellent method in obtaining a clear resection margin. This study aimed to investigate the usefulness of intraoperative circumferential frozen-section analysis (IOCFS) of lumpectomy margin during BCS for breast cancer, and to find factors that increase the conversion into mastectomy.From 2007 to 2011, 509 patients with breast cancer underwent IOCFS during BCS. The outer surfaces of the shaved lumpectomy margins were evaluated. A negative margin was defined as no ink on the tumor. All margins were evaluated using the permanent section analysis.Among the 509 patients, 437 (85.9%) underwent BCS and 72 (14.1%) finally underwent mastectomy. Of the 483 pathologically confirmed patients, 338 (70.0%) were true-negative, 24 (5.0%) false-negative, 120 (24.8%) true-positive, and 1 (0.2%) false-positive. Twenty-four patients (4.7%) among total 509 patients had undetermined margins as either atypical ductal hyperplasia or ductal carcinoma in situ in the first IOCFS. The IOCFS has an accuracy of 94.8% with 83% sensitivity, 99.7% specificity, 93.4% negative predictive value, and 99.2% positive predictive value. Sixty-three cases (12.4%) were converted to mastectomy, the first intraoperatively. Of the 446 (87.6%) patients who successfully underwent BCS, 64 patients received additional excisions and 32 were reoperated to achieve clear margin (reoperation rate, 6.3%). Twenty-three of the reoperated patients underwent re-excisions using the second intraoperative frozen section analysis, and achieved BCS. Nine cases were additionally converted to mastectomy. No significant differences in age, stage, and biological factors were found between the BCS and mastectomy cases. Factors such as invasive lobular carcinoma, multiple tumors, large tumor, and multiple excisions increased the conversion to mastectomy.The IOCFS analysis during BCS is useful in evaluating lumpectomy margins and preventing reoperation.

Dataset Information

Raman Spectroscopy for Rapid Evaluation of Surgical Margins during Breast Cancer Lumpectomy.

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Raman Spectroscopy for Rapid Evaluation of Surgical Margins during Breast Cancer Lumpectomy.

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