|Year : 2021 | Volume
| Issue : 4 | Page : 611-620
Correlation of pathological complete response with outcomes in locally advanced breast cancer treated with neoadjuvant chemotherapy: An ambispective study
Priyanshu Choudhary1, Ajay Gogia1, S V. S Deo2, Dayanand Sharma3, Sandeep R Mathur4, Atul Batra1, Hari Krishna Raju Sagiraju5
1 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
4 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
5 Department of Preventive Oncology, National Cancer Institute, All India Institute of Medical Sciences, Badsa, Haryana, India
|Date of Submission||17-Aug-2021|
|Date of Decision||17-Oct-2021|
|Date of Acceptance||28-Nov-2021|
|Date of Web Publication||29-Dec-2021|
RM No: 20X, 2nd Floor, Dr. BRA-IRCH, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 049
Source of Support: None, Conflict of Interest: None
Background: Neoadjuvant chemotherapy response rates in locally advanced breast cancer (LABC) vary significantly among Indian patients, and the factors affecting pathological complete response (pCR) rate are not clear in this population.
Objectives: This study was aimed at identifying the various clinicopathological features associated with achieving pCR and its effect on disease-free survival (DFS) and overall survival (OS) among Indian women diagnosed with LABC.
Materials and Methods: Women diagnosed with LABC between 2013 and 2019 and who received neoadjuvant chemotherapy followed by surgery and radiotherapy were ambispectively analyzed for clinicopathological responses and survival outcomes. Factors associated with pCR and the role of pCR as a prognostic factor for survival outcomes were examined.
Results: After neoadjuvant chemotherapy, pCR was achieved in 99 (23.3%) patients, with the highest rates noted in patients with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive tumors. Compared to hormone receptor-positive tumors with HER2-negative status, all other tumor groups had significantly higher odds of achieving pCR after neoadjuvant chemotherapy (TNBC: adjusted odds ratio [aOR], 4.58 [95% CI, 2.20–9.53]; hormone receptor- and HER2+: aOR, 3.93 [95% CI, 1.66–9.27]; hormone receptor + and HER2+: aOR, 2.78 [95% CI, 1.20–6.44]). Hormone receptor status and attainment of a pCR after neoadjuvant chemotherapy were associated with better DFS and OS outcomes particularly in patients with HER2-positive and TNBC tumors.
Conclusions: Patients who attain a pCR following neoadjuvant chemotherapy have improved survival outcomes; pCR rates vary by hormone and HER2 receptor status. Therapeutic approaches such as anti-HER2 and platinum-based regimens may be considered for achieving better pCR rates. The use of biomarkers for the identification of individuals with breast cancer who will not benefit from neoadjuvant chemotherapy should be considered along with early cancer detection strategies.
Keywords: Locally advanced breast cancer, neoadjuvant chemotherapy, pCR, TNBC, HER2, BRCA
|How to cite this article:|
Choudhary P, Gogia A, Deo S V, Sharma D, Mathur SR, Batra A, Raju Sagiraju HK. Correlation of pathological complete response with outcomes in locally advanced breast cancer treated with neoadjuvant chemotherapy: An ambispective study. Cancer Res Stat Treat 2021;4:611-20
|How to cite this URL:|
Choudhary P, Gogia A, Deo S V, Sharma D, Mathur SR, Batra A, Raju Sagiraju HK. Correlation of pathological complete response with outcomes in locally advanced breast cancer treated with neoadjuvant chemotherapy: An ambispective study. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Jul 5];4:611-20. Available from: https://www.crstonline.com/text.asp?2021/4/4/611/334180
| Introduction|| |
Breast cancer is the most common cancer among Indian women, with a projected incidence of 1 in 29 women developing breast cancer during their lifetime., Owing to the lack of breast cancer awareness, cultural barriers, and emotional reasons, a significant proportion of women present to the clinic with locally advanced breast cancer (LABC), which poses a significant therapeutic challenge. Although LABC constitutes only 10%–20% of all breast cancers in Western countries, in India, its proportion varies from 30% to as high as 60%.
Neoadjuvant chemotherapy is the preferred initial line of therapy for patients with LABC to increase the rate of performing breast-conserving surgery and obtain pathological complete response (pCR), which is an important marker of favorable prognosis. Although few meta-analyses have concluded that neoadjuvant chemotherapy offered no overall survival (OS) benefit when compared to adjuvant chemotherapy, achieving pCR after neoadjuvant chemotherapy is associated with increased disease-free survival (DFS) and OS among patients with breast cancers, especially among those with human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers (TNBC).,,,
Very few Indian studies have reported outcome responses of neoadjuvant chemotherapy in patients with LABC. The reported pCR rates vary between 8% and 36%.,,,, Factors predictive of pCR and the role of pCR as a prognostic factor for survival are yet to be identified in this population. The aim of our study was to identify the clinicopathological factors associated with achieving pCR and its impact on DFS and OS among Indian women diagnosed with LABC.
| Materials and Methods|| |
General study details
We ambispectively analyzed the medical records of 575 women diagnosed with LABC and treated in the Department of Medical Oncology of the All India Institute of Medical Sciences, New Delhi, India, between 2013 and 2019. The study was approved on Mar 22, 2018, by the Institute Ethics Committee for Post Graduate Research (IECPG-116/21.03.2018) [Supplementary Appendix 1]. Waiver for obtaining informed consent (written, and verbal consent) was obtained from the Ethics Committee. The study was conducted according to the ethical guidelines established by the Declaration of Helsinki and other guidelines like Good Clinical Practice Guidelines and those established by the Indian Council of Medical Research. The study was not registered with any publicly available clinical trials registry like the Clinical Trials Registry of India and no funding was obtained for the conduct of this study.
LABC was defined as any large breast tumor (>5 cm) with either skin/chest wall involvement or fixed axillary lymph nodes or spread to ipsilateral internal mammary or supraclavicular nodes. All women with LABC and those with early-stage node-positive disease for whom breast-conserving surgery was planned, and who received at least one cycle of neoadjuvant chemotherapy before surgery were considered eligible for inclusion in the study. Patients with oligometastatic disease treated with curative intent were also included. Those with incomplete records or missing information regarding hormone receptor status or HER2 status and who did not undergo surgery due to any reason were excluded.
The primary outcome measures were clinical and pathological tumor response after neoadjuvant chemotherapy. The secondary outcome measures were DFS and OS. Age at diagnosis, menopausal status, comorbidities, tumor characteristics, and the neoadjuvant chemotherapy regimen were the study covariates.
PCR was defined as the absence of residual invasive or in situ cancer in the breast or axilla (ypT0ypN0). Clinical complete response was defined as no clinicoradiological abnormality identified after six to eight cycles of neoadjuvant chemotherapy. Partial response was defined as a reduction of at least 50% in the product of the bi-perpendicular diameters of the breast mass. Stable disease (SD) was defined as a reduction of <50% or an increase of <25% in the product of the bi-perpendicular diameters of the breast mass. Progressive disease (PD) was defined as an increase in this parameter by >25% or clinical or radiological evidence of new disease elsewhere. DFS was defined as the period from the date of surgical intervention to the occurrence of relapse or death due to disease or any other cause. Any locoregional (either breast or node on the same side) or systemic site of metastasis was considered as relapse. OS was defined as the period between the date of diagnosis to death from any cause. TNBC was defined by a lack of expression of the estrogen, progesterone, and HER2 receptors.
Study data were extracted retrospectively from the medical records and the computer database for patients registered before March 2018 and prospectively for those registered after March 2018. Participants were followed up until June 30, 2020, disease relapse, or death. For patients whose last follow-up visit was more than 6 months ago, the final survival outcome data were obtained at the time of the next follow-up appointment either through mail or over the phone, as per the institution protocol. Immunohistochemical (IHC) testing to determine the estrogen receptor/progesterone receptor (ER/PR) and HER2/neu receptor status was performed using standard procedures on 4 μm sections of paraffin-embedded tissue specimens stained with the monoclonal antibodies against ER (1:400; Thermo, USA), PR (1:400; Spring, USA), and HER2/neu (1:100; Thermo, USA). Nuclear staining of more than 1% of tumor cells was considered positive for ER/PR. Tumors were considered HER2-positive if they had an IHC score of 3 + or if more than 6 copies of the HER2/neu gene were detected by fluorescence in situ hybridization (FISH) or the HER2/neu to CEP17 ratio was more than 2 as per the DAKO Hercep test (Thermo, USA). TNBC was defined as any breast cancer having ≤1% expression of ER and PR by IHC and HER2/neu expression of either 0 or 1+ by IHC or 2+ by IHC and FISH negative.
Data related to the baseline demographics and clinicopathological characteristics such as age at diagnosis, menopausal status, comorbidities, tumor size, nodal involvement, stage, hormone receptor status, HER2 receptor status, the type of neoadjuvant chemotherapy received, such as sequential anthracycline and taxane-based regimens in HER2-negative tumors, and docetaxel, carboplatin, and trastuzumab (TCH) regimens in HER2-positive tumors, follow-up visits, disease relapse, and death were obtained from the clinical case records and electronic databases. All the patients were discussed by a multidisciplinary team. At baseline, positron emission tomography-computed tomography scan and mammogram were performed before starting neoadjuvant chemotherapy; during neoadjuvant chemotherapy, clinical assessment was performed, and after the completion of neoadjuvant chemotherapy, repeat imaging was performed to evaluate the radiologic response. Data related to the clinical and pathological response to treatment were extracted from the clinical records and pathological laboratory reports. Date and type of surgery, follow-up visit dates, and date of relapse or death were also recorded.
Data analysis was performed using the Stata version 13 analytical software, StataCorp. College Station, Texas, USA. Comparisons of the frequencies between groups of categorical variables were performed using the Chi-squared and Fisher's exact tests. Univariate and multivariate logistic regression analyses were performed to determine factors predictive of pCR. Kaplan–Meier method was used for survival analysis. The association of study variables with DFS and OS was assessed using the Cox proportional hazard regression model. Differences were considered statistically significant for a P < 0.05. Sample size calculation was not performed as this was an observational study and we included all eligible individuals registered at our department for the management of LABC.
| Results|| |
A total of 575 patients with LABC were registered at our institution between 2013 and 2019. Those who underwent upfront breast surgery (n = 148) and who died before the completion of neoadjuvant chemotherapy (n = 2) were excluded from the analysis. The remaining 425 patients who completed neoadjuvant chemotherapy followed by breast surgery and radiotherapy were included in this study. Patient recruitment in the study is shown in [Figure 1] and the baseline characteristics are shown in [Table 1].
|Figure 1: Patient recruitment flow chart. Abbreviations: LABC: Locally advanced breast cancer, NACT: Neoadjuvant chemotherapy, HR: Hormone receptor, HER2: Human epidermal growth factor receptor 2, TNBC: Triple negative breast cancer|
Click here to view
Majority of the patients received anthracycline and taxane-based chemotherapy, while the TCH regimen was given to 76 (17.9%) patients. HER2-targeted therapy was given only to 103 (59%) of the HER2-positive patients due to financial constraints. Following neoadjuvant chemotherapy, all patients underwent surgery and radiotherapy according to the institution protocol. Ultrasound-guided clip placement was performed before the start of neoadjuvant chemotherapy.
Response to neoadjuvant chemotherapy
Assessment of change in the tumor burden after neoadjuvant chemotherapy was made through various approaches. [Table 2] shows the neoadjuvant chemotherapy outcomes using various clinical and pathological response measures.
|Table 2: Neoadjuvant chemotherapy outcomes using various response measures|
Click here to view
Tumors of T4 clinical stage had the lowest rates of complete remission (CR, 4.4%), partial remission (PR, 18.3%), and pCR (19.4%) compared to T3 (CR, 9.8%; PR, 25.4%; pCR, 27.1%) and T2 (CR, 7.1%; PR, 42.9%; pCR, 39.3%) stages. Compared to Stage II tumors, Stage III tumors had significantly lower rates of CR (10.3% vs. 5.8%), PR (44.8% vs. 20.5%), and pCR (44.8% vs. 21.7%). Rates of clinical response did not vary based on the hormone receptor status and type of neoadjuvant chemotherapy received. However, the pathological assessment showed a significant variation in pCR rates across the hormone receptor groups. Hormone receptor-negative tumors with HER2 positivity and TNBC had higher pCR rates (31.2% and 31.5%, respectively) compared to hormone receptor-positive tumors. Hormone receptor-positive tumors with negative Her2/neu status had the lowest pCR rate at 8.9%; P < 0.001.
Clinical stage and hormone receptor status were significantly associated with achieving pCR, even after adjusting for age and type of neoadjuvant chemotherapy received. [Table 3] shows the results of univariate and multivariable logistic regression analyses, with pCR as outcome. Stage III tumors had 65% lower odds of attaining a pCR compared to stage II tumors (adjusted odds ratio [aOR], 0.35; 95% CI, 0.16–0.80). Compared to hormone receptor-positive tumors with negative HER2 status, all other tumor groups had significantly higher odds of achieving pCR after neoadjuvant chemotherapy, with TNBC having the highest odds of achieving a pCR compared to other groups (TNBC: aOR, 4.58; 95% CI, 2.20–9.53); hormone receptor-negative and HER2-positive: aOR, 3.93; 95% CI, 1.66–9.27; hormone receptor-positive and HER2-positive: aOR, 2.78; 95% CI, 1.20–6.44; hormone receptor-positive and HER2-negative: reference group).
|Table 3: Clinicopathological factors associated with pathological complete response|
Click here to view
Disease relapse following neoadjuvant chemotherapy
The median follow-up was 16.2 months. Disease relapse rates were significantly lower among those who achieved CR (14.9%) and PR (23.1%) compared to those with SD (34%) and PD (50%) [Supplementary Figure 1]. The relapse rate among those with pCR was significantly lower than that of those without pCR (13.1% vs. 27.3%). The estimated median DFS for the overall cohort was 52.7 months (95% CI, 35.5–64.1). Among patients with pCR after neoadjuvant chemotherapy, the estimated median DFS in the TNBC group was 52.8 months while the median DFS was not reached in the other hormone receptor groups. However, among those with no pCR after neoadjuvant chemotherapy, the estimated median DFS was the shortest for the TNBC group (22.2 months), followed by the hormone receptor-negative and HER2-positive group (24.1 months), hormone receptor-positive and HER2-positive group (34.8 months), and hormone receptor-positive and HER2-negative group (56.7 months). [Figure 2] shows the cumulative incidence of disease relapse among different hormone receptor groups according to their pCR status. The cumulative incidence of disease relapse varied significantly (log-rank P < 0.05) according to the pCR status among the TNBC and hormone receptor-negative and HER2-positive groups.
|Figure 2: Cumulative incidence of disease relapse among different hormone receptor groups according to the pathological complete response status. (a) Among hormone receptor+ (HR) and human epidermal growth factor receptor 2+ (HER2) (b) Among HR + and HER2− (c) Among HR − and HER2+ (d) Among triple negative breast cancer|
Click here to view
Results of the Cox proportional hazard model for disease relapse are shown in [Supplementary Table 1]. Age ≥45 years at the time of diagnosis was associated with lower odds of having a disease relapse, compared to age <45 years at the time of presentation (adjusted Hazard Ratio [aHR], 0.65; 95% CI, 0.42–1.00). Pathological presence of lymphovascular invasion (aHR, 1.71; 95% CI, 1.02–2.86) and extranodal extension (aHR, 3.98; 95% CI, 2.26–7.02) were associated with an increased hazard of relapse. Hormone receptor-negative tumors without pCR were associated with a significantly higher hazard for relapse compared to hormone receptor-positive and HER2-positive tumors. [Supplementary Table 2] shows the hazard ratios for each hormone receptor group according to the pCR status. The hazard of disease relapse was 78% less in the hormone receptor-negative and HER2-positive group with pCR compared to those without pCR in the same group; the hazard of disease relapse was 74% less in the TNBC group with pCR compared to the TNBC group without pCR. In other hormone receptor groups (hormone receptor-positive and HER2-positive and hormone receptor-positive and HER2-negative groups) attaining a pCR did not have any effect on the hazard of having a relapse.
A total of 47 deaths were reported during the follow-up period, of which only 4 occurred among those with a pCR after neoadjuvant chemotherapy. The median OS was not reached for the total cohort. However, among those without pCR, in the hormone receptor-negative and HER2-positive group and the TNBC group, the median OS was 48.8 (95% CI, 40.0–53.4) and 47.8 (95% CI, 38.9-not reached) months, respectively. Median OS was not achieved in patients with hormone receptor-positive tumors. Among those with pCR, median OS was not achieved, except in the TNBC group (59.2 months; 95% CI, 58.1-not reached). [Figure 3] shows the OS probabilities according to the hormone receptor group and pCR status. Cox proportional hazard model for OS [Supplementary Table 3] showed that age >50 years and pCR were significantly associated with lower hazard of death, while hormone receptor negativity and pathological presence of extranodal extension were associated with a significantly higher hazard of death.
|Figure 3: Overall survival estimates by hormone receptor groups among those with and without pCR after NACT. (a) KM estimates for OS among those with pCR after NACT (b) KM estimates for OS among those without pCR after NACT. NACT: Neoadjuvant chemotherapy, HR: Hormone receptor, HER2: Human epidermal growth factor receptor 2, TNBC: Triple negative breast cancer, pCR: Pathological complete response, OS: Overall survival, KM: KaplanMeir|
Click here to view
| Discussion|| |
We examined the clinicopathological characteristics associated with pCR after neoadjuvant chemotherapy and the role of pCR as a prognostic factor for survival among women with LABC. Rates of pCR varied significantly depending on the tumor stage and IHC markers, with pCR rates being the lowest among patients with Stage III tumors and hormone receptor-positive tumors and highest among hormone receptor-negative tumors with HER2 positivity and TNBC. Age <45 years at the time of presentation, hormone receptor negativity, presence of extranodal extension, lymphovascular invasion, and residual disease after neoadjuvant chemotherapy were all associated with an increased hazard of disease relapse. The role of pCR as a prognostic factor of survival outcomes was mostly limited to hormone receptor-negative and HER2-positive tumors and TNBC.
In general, breast cancer has been reported to occur more than a decade earlier in Indian patients as compared to their Western counterparts. Hence, most of the patients with breast cancer in India are in their fifth decade of life and a significant proportion are premenopausal at the time of presentation; the median age of patients in our study was 46 years. Contrarily, in the Western population, the majority of the patients are postmenopausal and in their seventh decade of life. While early breast cancer is the predominant type in Western countries, LABC comprises the majority of the cases in the Indian population. Our study on 425 women with LABC who received neoadjuvant chemotherapy is the largest among the reported LABC studies from India. We used a uniform and standard treatment protocol, i.e., neoadjuvant chemotherapy followed by surgery and radiotherapy for all patients.
The overall pCR rate in our study was 23.3%, which although lower compared to that reported in Western studies, was better than those reported in earlier studies of LABC from India (8%–19%); it is similar to the pCR rate of 23.2% reported in a study by Agrawal et al. in 2016.,, The relatively high pCR rate in our study could be due to the more uniform and standard institutional chemotherapy protocol, utilizing sequential anthracyclines and taxanes in HER2/neu-negative disease. Moreover, the use of HER2-targeted therapy was also higher in our study compared to other studies. One study with a small number of Indian patients with LABC reported a pCR rate as high as 36%; however, in this study, 48% of the patients had Stage II tumors, while 93% of the patients in our study had Stage III tumors. In our study, we found that Stage III tumors had significantly lower rates of pCR compared to Stage II tumors when adjusted for other study variables.
Hormone receptor-negative tumors and HER2-positive tumors benefitted more from neoadjuvant chemotherapy in terms of the pathological response. The rate of pCR was lowest in hormone receptor-positive/HER2-negative tumors in our study (8.8%), which is comparable to the results of the CTNeoBC meta-analysis in which low-grade hormone receptor-positive tumors had a pCR rate of 8%. The rate of pCR in hormone receptor-positive/HER2-positive tumors in our study (24.7%) was lower compared to that reported in the CTNeoBC meta-analysis (32%), however, in the subset of patients in this group who received HER2-directed therapy (n = 47), the pCR rate was 32%. The addition of anti-HER2 therapy to neoadjuvant chemotherapy also increased pCR rates from 20% to 38.3% among patients with hormone receptor-negative/HER2-positive tumors in our study. Various large trials of neoadjuvant chemotherapy plus HER2-directed therapy have shown higher pCR rates with the addition of trastuzumab or pertuzumab to neoadjuvant chemotherapy. The pCR rates in trials that utilized trastuzumab ranged from 38% to 55%., The pCR rate reported among individuals with HER2-positive tumors in our study was lower than that reported in these studies, 24.7% in hormone receptor-positive/HER2-positive and 31.2% in hormone receptor-negative/HER2-positive tumors. In addition, Indian women present with larger tumors compared to their Western counterparts and at an earlier age. Dual HER2-directed therapy was received by only a small number of patients, and hence, no definitive conclusion can be drawn regarding this from our study.
In the TNBC subset of our study, the pCR rate of 31.5% was similar to those reported (33%–47%) in various large Western studies utilizing anthracyclines and taxanes and in the CTNeoBC meta-analysis.,,,, Very few HER2-positive patients in our study received carboplatin as part of the neoadjuvant chemotherapy regimen, and the pCR rate in our study was similar to the control arms of various trials that utilized carboplatin. None of the patients in our study received nab-paclitaxel. The proportion of patients with TNBC in our study (29.9%) was similar to that in other Indian studies (24%–37%).,,
Although our median follow-up was short (16.2 months), the estimated DFS and OS rates were equal to or better than those reported by various other Indian studies.,, This too could be attributed to the uniform institutional protocol and a higher proportion of patients receiving HER2-targeted therapy. The results of our study also confirm that achieving pCR following neoadjuvant chemotherapy is an important prognostic factor for breast cancer survival, especially among HER2-positive tumors or TNBC, which are known to be aggressive. Individuals with HER2-positive tumors who attained a pCR had a better DFS in our study. Similar results were also reported by two large meta-analyses conducted by Cortazar et al. and Spring et al., Similarly, patients with TNBC who achieved pCR had significantly better DFS than those who did not. This is in line with the results of the above-mentioned meta-analyses. The results of the multivariate Cox proportional hazards regression in our study also confirmed the previously published reports which suggested that hormone receptor negativity was an independent risk factor for lower PFS and OS and suggested the prognostic association of pCR with long-term outcomes in these tumors.
Our study re-emphasizes that the ability of pCR to predict survival outcomes is better for subsets than it is for the whole group. Our results support the importance of achieving pCR, particularly in hormone receptor-negative tumors, and suggest that pCR post-neoadjuvant chemotherapy is a significant surrogate marker for survival., The benefit of achieving pCR in hormone receptor-negative individuals is particularly strong, as the survival function curves in our study showed that an estimated 50% of individuals with hormone receptor-negative and HER2-positive tumors and TNBC without pCR developed disease recurrence within 2 years from surgery; this proportion was less than 25% among those with pCR [Supplementary Figure 1]. The hazard ratios for DFS in hormone receptor-negative and HER2-positive tumors (0.22) and TNBC (0.26) with pCR [Supplementary Table 2] were similar to those reported (0.19–0.22) in recent meta-analyses.,, Lymphovascular invasion and extranodular extension were also significant predictors of DFS in our study population, as reported in other studies.,
Identifying patients who are likely to have residual disease after neoadjuvant chemotherapy is also beneficial; accordingly, the chemotherapy can be altered using more aggressive regimens or novel treatments such as platinum-based neoadjuvant chemotherapy (e.g., carboplatin, capecitabine) to increase the chances of achieving pCR.,, A recent meta-analysis showed that platinum-based neoadjuvant chemotherapy compared to platinum-free neoadjuvant chemotherapy significantly increased pCR rate from 37.0% to 52.1%. Our study also demonstrated an unmet need for HER2-directed therapy in the Indian population. The proportion of HER2-positive tumors (41%) in our study was higher than that in other studies from India and significantly higher than that reported in the Western literature. This can be explained in part by the referral bias of HER2-positive tumors to our institute. Only about 60% of these patients were able to receive HER2-directed therapy due to financial constraints. A recent study among Indian women with LABC has shown that neoadjuvant concurrent chemoradiation is associated with a higher pCR rate than that reported with neoadjuvant chemotherapy alone. The role of other biomarkers such as molecular signatures, RNA classifiers, PAM50 subtyping, Ki67 expression, etc., should be further evaluated in identifying more patients with excellent prognosis among those who do not attain pCR after neoadjuvant chemotherapy.,
Our study has a few limitations. It was an ambispective analysis and may have suffered from selection bias. Furthermore, there was a referral bias, as our institution is a tertiary cancer care center. Information related to the grading of tumors was not available for the majority of patients in our study, and hence, was not considered for analysis. As the median follow-up period was only 16 months, the results of OS outcomes are immature.
Future studies are required to identify novel chemotherapy regimens that increase the pCR rate and to identify biomarkers that predict the risk for residual cancer burden after neoadjuvant chemotherapy among Indian women with LABC. In addition, the promotion of breast cancer awareness and screening practices for early detection should be made a priority in the Indian population, as LABC is mostly an outcome of neglect due to the lack of awareness and appropriate referral in the Indian scenario.
| Conclusions|| |
The clinical stage of the tumor and hormone receptor status are important predictors of pCR among Indian women with LABC. Achieving a pCR after neoadjuvant chemotherapy may be considered a good prognostic factor in hormone receptor-negative tumors with HER2 positivity and in TNBC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| Supplementary Figure|| |
| Supplementary Tables|| |
| Supplementary Appendix|| |
Supplementary Appendix 1: Study protocol
| Supplementary Appendix|| |
Supplementary Appendix 1
List of abbreviations
CR Complete response
DFS Disease free survival
HR Hormone receptor
LABC Locally advanced breast cancer
LVI Lymphovascular invasion
NACT Neoadjuvant chemotherapy
ORR Overall response rate
OS Overall survival
PCR Pathological complete response
PD Progressive disease
PNI Perineural invasion
PR Partial response
TNBC Triple-negative breast cancer
SD Stable disease
| Introduction and Review of Literature|| |
Breast cancer is the most common cancer among females worldwide and a major cause of cancer-related mortality in females. An estimated 2 million new breast carcinoma cases were recorded worldwide in 2018. In 2018 Breast cancer had an age-standardized rate (ASR) of around 46/100,000 females and caused more than 6 lakhs deaths worldwide.
| Indian Scenario|| |
Unlike in the west, breast cancer in Indian women usually presents at an earlier age and in the advanced stage. This may be due to lack of inadequate breast cancer screening, lack of awareness, poor socioeconomic status, and unavailability of appropriate medical facilities.
According to 2018 GLOBOCAN data, India had around 1.1 million cases of cancer annually with an ASR rate of 89.4/100,000 population. Breast cancer is the most common female cancer with an ASR of 24.7/100,000 population in 2018. In 2018 there were around 1.6 lakh new cases of breast cancer cases in India and around 87,000 deaths due to breast cancer. In 2018, breast cancer constituted around 27% cases of new cases of cancer in females.
In India, the age of presentation of breast cancer is more than a decade earlier than in the west. Various Indian studies have shown median age ranging from 45 to 50 years. In comparison, in the USA, during 2012–2016, the median age at the time of breast cancer diagnosis was 62 years.
In a study of hospital-based registries, the median age at presentation was 44.2 years in Dibrugarh, 46.8 years in Delhi, 47 years in Jaipur, to 49.6 years in Bangalore and Chennai.
This late presentation can be due to the lack of a national screening program, poor social status of women, or a different disease biology.
Rationale for neoadjuvant therapy
Neoadjuvant systemic chemotherapy (chemotherapy given before definite surgical treatment) which was earlier reserved for patients with locally advanced breast cancer (LABC) has become increasingly common. Earlier neoadjuvant chemotherapy was used in large inoperable tumors with the goal to render them operable or in large operable tumors in patients desiring breast conservation whose tumor would otherwise require mastectomy. NACT also improves cosmesis in existing candidates for breast conservation and reducing postoperative complications such as lymphedema.
Neoadjuvant chemotherapy also provides for assessing the response to treatment, i.e., achievement of pathological complete response (PCR). With various trials showing that residual tumor after neoadjuvant therapy is a poor prognostic factor, newer therapies are increasingly being used in these patients to improve survival outcomes. Hence, the use of neoadjuvant chemotherapy which provides a real-time evaluation of tumor response has become increasingly common.
Neoadjuvant chemotherapy has shown similar survival outcomes when compared to adjuvant therapy in various randomized trials.
In a Phase 3 RCT, EORTC 10902 compared four cycles of FEC administered preoperatively versus 4FEC after surgery. At a median follow-up of 56 months, the trial results showed no significant difference between neoadjuvant and adjuvant treatment in terms of overall survival.
National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial compared four cycles of doxorubicin/cyclophosphamide (AC) given preoperatively versus the same treatment postoperatively. This trial showed no statistically significant overall differences in overall survival or DFS between the two treatment groups after a follow-up of 9 years. Patients in the preoperative chemotherapy arm received more lumpectomies than postoperative patients, especially among patients with tumors >5 cm at baseline. A 2008 update of the NSABP-18 study by Rastogi et al., showed trends in favor of preoperative chemotherapy for DFS and OS in women <50 years old.
A 2005 meta-analysis that evaluated nine randomized studies with a total of 3946 patients compared neoadjuvant to adjuvant systemic treatment in breast cancer, found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms with respect to death, disease progression, or distant disease recurrence.
A Cochrane Database Systematic Review done in 2007 that included 14 studies and 5500 patients compared the effectiveness of preoperative chemotherapy in women with operable breast cancer versus postoperative chemotherapy. The results showed equivalent overall survival rates of neoadjuvant chemotherapy when compared to adjuvant chemotherapy.
An Early Breast Cancer Trialists' Collaborative Group meta-analysis that included 10 trials and 4756 patients showed no significant differences between neoadjuvant chemotherapy versus adjuvant chemotherapy in the risk of distant recurrence or breast cancer mortality. Patients receiving NACT underwent more frequent breast-conserving surgery compared to patients receiving adjuvant chemotherapy.
Neoadjuvant therapy for hormone-positive breast cancer
Various studies have shown that HR-positive cancers, especially luminal A cancers are less likely to achieve a pCR compared to more aggressive histologies.
Various studies have shown that the prognostic value of pCR is greatest in patients with triple-negative or human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A major limitation of using pCR to predict survival outcomes in patients with ER-positive disease is that pCR is achieved in only around 10% of patients with ER-positive disease.
In the CTneoBC meta-analysis, among patients with HR-positive, HER2-negative disease, the pCR was positively associated with event-free survival (EFS: hazard ratio [HR] 0.49, 95% CI 0.33–0.71) and overall survival (OS: HR 0.43, 95% CI 0.23–0.71). The presence of pCR was associated with long-term outcomes in the HER2-positive subgroup, both among patients with HR-positive and HR-negative disease (EFS: HR 0.39, 95% CI 0.31–0.50; OS: 0.34, 0.24–0.47).
In another metanalysis published in 2020, among HR + patients, those with pCR had a 5-year EFS of 97% (95% PI: 87%–100%), while those without a pCR had a 5-year EFS of 88% (95% PI: 75%–95%). Similarly, HR + patients, those who experienced pCR achieved a 5-year OS of 98% (95% PI: 86%–100%), while those without a pCR achieved a 5-year OS of 82%(95% PI: 3%–97%).
- In the CTNeoBC metanalysis among patients with HR-positive, HER2-negative disease high-grade tumors had a higher pCR rate compared with low-to-intermediate grade tumors (16% vs. 8%). HR-positive, HER2-positive disease showed a higher pCR rate of 31% when trastuzumab was given with chemotherapy.
Neoadjuvant endocrine therapy (NET) is an option in patients with strongly ER/PR positive tumors and any contraindications for chemotherapy. NET may be useful in older females where rapid progression is not anticipated as pCR to this therapy is less likely. NET can be an option, especially during the current situation with COVID19 as various elective surgeries have been delayed.
| Neoadjuvant Therapy for Patients with Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer|| |
Several randomized trials of neoadjuvant therapy in HER2-positive breast cancer that have used anthracycline and taxane-based NACT regimens show a pCR rate of around 40-50 percent. Some of the studies are as follow:
- American College of Surgeons Oncology Group (ACOSOG) Z1041
In this trial, 282 patients with operable HER2-positive cancers were treated with four cycles of FEC followed by paclitaxel with trastuzumab versus paclitaxel with trastuzumab followed by FEC with concurrent trastuzumab. The overall pCR rate at 55% was similar in both arm. In node-positive patients, the pCR was 48%.
- The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 study reported a pCR rate of 49% in HER2-positive breast cancer patients who received four cycles of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel-trastuzumab. Node-positive patients reported a pCR of 48%
- The GeparQuinto study reported a PCR rate of 45% using three weekly, four cycles of epirubicin and cyclophosphamide with trastuzumab followed by four cycles of docetaxel with trastuzumab. Node-positive patients constituted approximately 70% of the patients.
In all these studies, the pCR rate was higher among patients with hormone receptor (HR)-negative disease versus HR-positive disease.
The Gepar-Septo study which compared weekly paclitaxel with weekly nab paclitaxel for 12 cycles followed by four cycles of EC every 3 weeks, as neoadjuvant therapy for clinical stage II to III breast cancer showed a trend toward improved pCR (62% vs. 54%), but at a cost of increased toxicity (neutropenia and neuropathy), in both HR-positive and HR-negative cohorts.
The TRAIN-2 trial randomized stage II to III HER2-positive breast cancer patients to three cycles FEC followed by six cycles of paclitaxel and carboplatin versus nine cycles of paclitaxel and carboplatin along with trastuzumab and pertuzumab every 3 weeks with all chemotherapy cycles.
The pCR rates were similar in both arms (67% vs. 68%). The anthracycline arm patients had a higher rate of febrile neutropenia and cardiotoxicity.
| Role of Human Epidermal Growth Factor Receptor 2 Targeted Therapy|| |
Various randomized studies and meta-analyses, as shown below, have demonstrated improvements in pCR rate, EFS, and OS with the use of Trastuzumab in neoadjuvant setting.
- The CTneoBC meta-analysis included around 2000 patients with HER2-positive disease treated with neoadjuvant chemotherapy ± trastuzumab. Patients trastuzumab had a higher pCR rate (40 vs. 23). Achievement of pCR was associated with better long-term outcome (EFS: hazard ratio [HR] 0.39, 95% CI 0.31–0.50; OS: 0.34, 0.24–0.47)
- In the NOAH trial, the pCR rate increased to 38% from 19% with the addition of Trastuzumab to anthracycline- and taxane-based neoadjuvant chemotherapy
The 5-year EFS was also better in the Trastuzumab arm 58% versus 43% in the chemotherapy arm (HR 0.64 P = 0.016). EFS was also strongly associated with pathological complete remission in patients receiving trastuzumab.
Pertuzumab is a monoclonal antibody that binds to a different epitope on HER2 than trastuzumab thereby blocking the formation of HER2:HER3 heterodimers, which is believed to be an important mechanism of resistance to trastuzumab is typically given in combination with trastuzumab to maintain suppression of signaling initiated by HER2 homodimers. Various trials of pertuzumab are as follow:
NeoSphere trial–randomly assigned patients to 4 cycles of NACT with trastuzumab, prtuzumab, or both or dual HER2 therapy without chemotherapy. The chemotherapy used was docetaxel. The results of this trial showed that patients assigned to docetaxel and trastuzumab and pertuzumab had a higher pCR rate (46%) compared with those receiving docetaxel with just trastuzumab (29%) or just pertuzumab (24%). In the group that received pertuzumab and trastuzumab without docetaxel, the pCR rate was around 17%.
- TRYPHAENA trial - The Phase II TRYPHAENA trial randomized patients to FEC followed by docetaxel, with trastuzumab and pertuzumab starting either concurrently with FEC or upon initiation of docetaxel or to docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). The pCR rates were similar in both the anthracycline arms (56% vs. 55%) and 64% for TCHP arm. Cardiotoxicity was similar in the two groups receiving anthracycline-based treatment and slightly lower in the TCHP arm. The pCR rate was higher in patients with hormone receptor-negative tumors compared with patients with hormone receptor-positive tumors.
| Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer|| |
Various Clinical trials have shown PCR ranging from 30% to 50% in TNBC patients using neoadjuvant anthracycline and taxanes. The CTNeoBC metanalysis showed a pCr rate of 34% in TNBC subgroup. Gepar Trio used TAC chemotherapy and reported 37% pCR rate. Similar results were shown by the Gepar septo trial utilizing Nab paclitaxel showed a PCR of 48%.
Various randomized trials have shown improved pathologic complete response (pCR) rates with the addition of carboplatin to paclitaxel-and anthracycline-containing NACT regimens
The addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide in increased the pCR rate from 31% to 58% in the BrighTNess Trial but at increased hematologic toxicity.
The Gepar Sixto investigators reported a better pCR rate (53% vs. 37%) with the addition of weekly carboplatin to the backbone of weekly paclitaxel and non-pegylated liposomal doxorubicin.
Neoadjuvant immunotherapy in triple-negative breast cancer
The KEYNOTE-522 trial results showed that in TNBC patients the addition of Pembrolizumab to NACT for triple-negative breast cancer (TNBC) improved pCR rates (from 51% to 65%. The pCR improvement was observed in both programmed cell death ligand 1 (PD-L1)-positive and PD-L1 negative TNBC patients.
| Indian Literature|| |
LABC seems to constitute a larger proportion of breast cancer than the west, as shown in various Indian published studies. Gupta et al. from All India Institute of Medical Sciences, New Delhi, published a study that evaluated 3000 women, of whom 91 were eligible. Anthracycline-based regimes were used in 54 patients and docetaxel in 37 patients. Most (90%) were T4 tumors and 70% were Stage IIIB. It reported pathological CR (pCR) rates of 19% and 13% in anthracycline and taxane arms, respectively. There was no significant difference in DFS (3 year 56.84% vs. 61.16%, P = 0.80) and OS (3 year 70% vs. 78.5%, P = 0.86) between the two groups despite higher pCR.
In another trial by Gupta et al. from the TMH which included women with large primaries/N23 disease, reported pCR was 11.5%. The clinical and pathological response to chemotherapy after 2–6 cycles of anthracycline-based regimens (5fluorouracil, adriamycin, and cyclophosphamide/5fluorouracilepirubicin-cyclophosphamide [FAC/FEC]) in LABC has been reported by Mukherjee et al. in a prospective study. Clinical CR was seen in 10% of cases, 30% of patients had PR and 60% had stable disease after NACT. Pathological CR with no evidence of viable tumor was observed in 20% of the patients. Raina et al. evaluated 128 patients with LABC, using FEC in NACT the reported pCR was 7.8%. Median DFS and OS were 33 and 101 months, respectively. The DFS and OS at 5 years were 41% and 58%, respectively.
In a study by Doval et al. of 3453 breast cancer patients, the proportion of Stage I, II, and III cases were 11.75%, 66.79%, and 21.64%, respectively. Hormone receptor-positive cases were 55%, TNBC 24%, and HER2 positive cases were 21%.
In a study of 550 patients of breast cancer by Gogia et al., the TNM stage distribution was Stage I 4%; Stage II-33%; Stage III-45% and Stage IV-18%. Locally advanced breast cancer constituted 40% of the cases. The proportion of estrogen receptor/progesterone receptor-positive cases was 59%, 29% of patients were HER2/neu positive and TNBC constituted 28% of patients. Neoadjuvant chemotherapy was given in 26.6% of patients, of these 19% achieved pathological complete remission. Sequential anthracycline and taxane were used as NACT/adjuvant chemotherapy in most cases. Of the eligible patients, 30% received anti-HER2/neu therapy.
In another study of 120 patients by Gogia et al. evaluating taxane and Anthracycline Based Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer the overall clinical response rate was 85% and pathological complete responses were obtained in 15%.
Around 55% of tumors were HR + and 25% were HER2 positive, TNBC was 25%. The 3-year relapse-free survival was 50% and 3 years OS was 70%.
| Evaluation of Response to Neoadjuvant Chemotherapy|| |
Various studies of NACT in breast cancer have utilized different methods for response evaluation like the NSABP 18 system, Miller Payne grading, Staloff method, Chevallier method, Residual cancer burden, etc.
Pathological complete response
Pathologic complete response (pCR) defined as the absence of residual invasive tumor in breast and axilla (ypT0/is ypN0) has been shown to be associated with improved survival outcomes in various studies, especially in TNBC, and (HER2)-positive breast cancer.
The CTNeoBC pooled analysis evaluated data from 12 trials and included 11,955 patients in the analysis. The analysis showed that achievement of pathological CR in both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was associated with improved EFS (HR-0·54) and OS (0.36, 0.30–0.44; 0·36, 0.31–0.42) compared to tumor eradication from the breast alone (ypT0/is; EFS: HR 0.60, 95% CI 0.55–0.66; OS 0.51, 0.45–0.58).
A meta-analysis of 52 studies that included 27,895 patients showed that patients who achieved pCR after NACT had significantly better EFS (HR 0.31, 95% PI: 0.24–0.39), particularly for triple negative (HR 0.18, 95% PI: 0.10–0.31) and HER2+ (HR 0.32, 95% PI: 0.21–0.47) disease. Achievement of pCR after NACT was also associated with improved survival (HR 0.22, 95% PI: 0.15–0.30).
Miller Payne grading system
Ogsten, Miller, Payne et al. in 2003 evaluated 176 patients with large (>4 cm) and locally advanced breast cancers treated with multimodality therapy including neoadjuvant chemotherapy. The response to chemotherapy was graded using a 5-point histological grading system. Pathological responses were compared to 5-year overall survival and disease-free survival using log-rank tests There was a significant correlation between pathological response using this grading system with OS and DFS. In a multivariate analysis of known prognostic factors, the Miller/Payne grading system was an independent predictor of overall patient survival.
Lymphovascular invasion (LVI) (defined as the presence of tumor cells within a lymphatics or blood vessels in the breast surrounding invasive carcinoma) has been shown in various studies to be associated with an increased risk of axillary lymph node and distant metastases.
In a study by Lee et al. LVI was shown as an independent prognostic factor in lymph node-negative breast cancer treated with adjuvant chemotherapy. A study by Song et al. showed in operable breast cancer with positive axillary lymph nodes LVI was an independent prognostic factor. Uematsu et al. in a study showed that the degree of LVI is an important factor for the prediction of NACT efficacy in breast cancer. Another study by Liu et al. showed that patients with no LVI with HR + or HER2 overexpression had the most favorable relapse-free survival and overall survival, the patients with LVI and triple-negative subtype had the worst RFS and OS.
A study by Freedman et al. showed that LVI is not an independent predictor of locoregional control or survival in early-stage breast cancer.
McCready et al. evaluated perineural invasion (PNI) as a common factor together with lymphovascular invasion in two studies., These studies showed that local recurrence and distant metastasis occurred significantly more frequently in patients with lymphovascular-PNI, and this common parameter had an independent prognostic significance in these two studies. Nevertheless, it is not possible to detect how much of this prognostic value is due to PNI or lymphovascular invasion.
In another study by Duraker et al., PNI had no prognostic significance with recurrence or survival.(40)
A study by Huang et al. which evaluated predictors of locoregional recurrence in patients with locally advanced breast cancer PNI was not associated with locoregional relapse.(41)
Extranodal extension/extracapsular extension
A study by Huang et al. which evaluated predictors of locoregional recurrence in patients with locally advanced breast cancer presence of extracapsular invasion was associated with an increased risk of locoregional relapse.(41)
Various studies have suggested that tumor tissue invading the extranodal compartment represents a prognostic factor in determining disease-free survival and overall survival. ENE has been reported to be associated with an increased risk of relapse and inferior survival outcomes.(42),(43),(44),(45),(46),(47)
| aims and objectives|| |
To determine the clinicopathological characteristics of patients with locally advanced breast cancer.
To determine pathological CR rate and factors affecting pathological CR in patients with locally advanced breast cancer.
To determine Disease-free survival (DFS).
To determine treatment-related toxicity of therapy.
| Materials and Methods|| |
Ambispective cohort study.
Place of the study
All locally advanced breast cancer patients registered in the Department of Medical Oncology, Dr. BRA-IRCH, AIIMS, New Delhi.
January 2018–June 2020.
All female patients with locally advanced breast cancer of all age treated with institute protocol (as given below) from January 01, 2013, to May 31, 2019, were included in the study.
- All female patients with locally advanced breast cancer
- ER, PR, and Her-2 Neu status should be available for all patients
- Patients should have received at least 1 cycle of neoadjuvant chemotherapy before surgery.
- Incomplete baseline workup
- Patients not undergoing surgery for any reason.
| Study Design|| |
We will ambispectively analyze data of 425 female LABC patients treated at our institute between October 1, 2012, and December 31, 2019. We will retrieve the data regarding baseline clinical and pathological characteristics, treatment received, toxicity, clinical and pathological response from our computer database and prospectively maintain clinical case records from our medical records section using ICD code 50. All patients who received at least 1 cycle of NACT and underwent surgery will be included. Patients with incomplete records (missing information regarding ER/PR or HER-2/neu status) and those who did not undergo surgery due to any reason will be excluded. Patients with male breast cancer will be excluded.
Locally advanced breast cancer (LABC) is defined as: large breast tumors (>5 cm) associated with either skin/chest wall involvement or with fixed axillary lymph nodes or spread to ipsilateral internal mammary or supraclavicular nodes
Chemotherapy regimen used was sequential anthracycline and taxane based in HER-2/neu negative tumors and TCH/PTCH in HER-2/neu + tumors. All patients receiving NACT will be evaluated clinically every 2 cycles. Patients responding to NACT or with stable disease completed 6–8 cycles of scheduled chemotherapy. Patients progressing clinically will be evaluated for surgery, those who underwent surgery will be included in the final analysis. Those who could not be operated will be excluded from the analysis.
The pathological complete response (pCR) is defined as the absence of residual invasive or in situ cancer in breast or axilla ypT0/is ypN0. Miller Payne grading system is used for grading of pathological response to NACT. Toxicity was graded according to National Cancer Institue Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Disease-free survival (DFS) was defined as the period from the date of surgical intervention (MRM/BCS) to the occurrence of any of the following event-Relapse/Death. Overall Survival (OS) is defined as the period between the date of diagnosis to death from any cause. This study was ethically approved by the All India Institute of Medical Sciences (AIIMS) Institutional Ethics Committee (IECGP-116/21.03.2018).
| Treatment Protocol|| |
Institute protocol for LABC is neoadjuvant chemotherapy with sequential anthracycline and taxane (4(F) EC-4T fluorouracil 600 mg/m2 plus epirubicin 75 mg/m2 plus cyclophosphamide 600 mg/m2 followed by four cycles of docetaxel at 85 mg/m2) once in every 3 weeks in Her2 negative disease. HER2/Neu positive cases received TCH (Docetaxel at 75 mg/m2 + Trastuzumab 8 mg/kg loading f/b 6 mg/kg + Carboplatin AUC 6) in HER2 positive disease. Few patients also receive dual anti Her2 therapy with pertuzumab (840 mg loading f/b 420 mg) plus trastuzumab, docetaxel, and carboplatin in the doses mentioned above.
| Pathological Assesment|| |
Hormone and HER2/neu are tested by immunohistochemical (IHC). Allred scoring is used for ER/PR receptor status. The percentage of cells showing ER positivity and intensity will be recorded. A score of 3 or more is considered positive. IHC testing for ER, PR, and HER2/neu status will be performed using the standard procedures on 4-μm sections of paraffin-embedded tissue specimens stained with the monoclonal antibodies (1:400; Thermo Scientific, Wal-tham, MA; 1:400; abcam, Cambridge, MA; and 1:100, Thermo for ER, PR, and HER2/neu, respectively). Nuclear staining >1% of tumor cells will be considered as positive for ER and PR. Patients will be considered HER2 positive if they have IHC 3+-positive or fluorescence in situ hybridization is amplified (more than six copies of HER2/neu gene or HER2/neu: centromere enumerator probe 17 ratio of more than two). HER2/neu status will be tested as per the ASCO/College of American Pathologists guidelines. A score of 3 + is considered positive, and 2+ is considered equivocal. All 2 + results of HER2/neu were confirmed by the fluorescence in situ hybridization method as per standard guidelines. The response to neoadjuvant chemotherapy is reported using the Miller Payne grade. In addition, pathological staging (AJCC) is recorded for all the patients. Lymphovascular emboli and perineural invasion will also be recorded.
| Response Evaluation|| |
All patients undergoing NACT will be clinically evaluated after every 2 cycles. Those who were responding or had a clinical stable disease will be continued their chemotherapy. The patients who have a clinical progression will be evaluated for surgery. In case surgery was not possible they will be taken up for 2nd line chemotherapy or palliative treatment (RT/BSC). Only the patients who underwent surgery will be included in the final analysis.
| Outcome Variables|| |
Data regarding the patient's baseline clinical characteristics histology, receptor status (ER, PR, and HER2 receptors), clinical and pathological response assessment, and survival will be recorded from medical records.
Patients will be prospectively followed up till the date of data cut off for relapse or death.
Data entry will be done using Excel and analysis will be done using Stata13 (StataCorp, College Station, TX, USA). Nominal data will be presented as number and percentage, and continuous data will be presented as median and range The clinical and pathological characteristics will be described as frequencies along with 95% CI. Association of clinical and pathological features with pCR will be assessed using the Chi-square test. Association of DFS and OS was assessed using KaplanMeir survival analysis followed by cox regression for estimating the hazard ratio
Nominal data were presented as number and percentage, and continuous data were presented as median and range. The median duration of follow-up will be calculated by the reverse Kaplan–Meier method. Overall survival (OS) is defined as the duration from the start of treatment to the last visit or death. Disease-free survival (DFS) will be calculated from the date of surgery to the date of relapse or death. The KaplanMeier method will be used for survival analysis. Estimated survival data will be presented as median with 95% CI and proportions. Univariable analysis will be performed by Cox regression. Multivariable analysis will be performed for those parameters that will be significant in the univariable analysis by Cox regression. Results of univariable and multivariable analyses will be presented in P value and hazard ratio (95% CI). Differences will be considered statistically significant for P = 0.05. Patients will be contacted telephonically for present status, and survival data will be censored on June 30, 2020. Data will be analyzed in Stata 13 and SPSS software (College Station, TX, USA).
| References|| |
- Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
- SEER*Stat Databases: November 2018 Submission. Available from: https://seer.cancer.gov/data-software/documentation/seerstat/nov2018/. [Last accessed on 2020 Sep 08].
- NCRP Anual Reports. Available from: https://seer.cancer.gov/data-software/documentation/seerstat/nov2018/. [Last accessed on 2020 Sep 08].
- NCRP Anual Reports. Available from: https://ncdirindia.org/NCRP/Annual_Reports.aspx. [Last accessed on 2020 Sep 08].
- Gogia A, Deo SV, Shukla NK, Mathur S, Sharma DN, Tiwari A. Clinicopathological profile of breast cancer: An institutional experience. Indian J Cancer 2018;55:210-3.
- Nair N, Shet T, Parmar V, Havaldar R, Gupta S, Budrukkar A, et al. Breast cancer in a tertiary cancer center in India – An audit, with outcome analysis. Indian J Cancer 2018;55:16-22.
- van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. Preoperative chemotherapy in primary operable breast cancer: Results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 2001;19:4224-37.
- Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: Nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 2001;30:96-102.
- Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: Updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol 2008;26:778-85.
- Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: A meta-analysis. J Natl Cancer Inst 2005;97:188-94.
- Mieog JS, van der Hage JA, van de Velde CJ. Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst Rev 2007;2007:CD005002.
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: Meta-analysis of individual patient data from ten randomised trials. Lancet Oncol 2018;19:27-39.
- Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 2014;384:164-72.
- Spring LM, Fell G, Arfe A, Sharma C, Greenup R, Reynolds KL, et al. Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: A comprehensive meta-analysis. Clin Cancer Res 2020;26:2838-48.
- Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, et al. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): A randomised, controlled, phase 3 trial. Lancet Oncol 2013;14:1317-25.
- Robidoux A, Tang G, Rastogi P, Geyer CE Jr., Azar CA, Atkins JN, et al. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): An open-label, randomised phase 3 trial. Lancet Oncol 2013;14:1183-92.
- Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): A randomised phase 3 trial. Lancet Oncol 2012;13:135-44.
- Loibl S, Jackisch C, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, et al. Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: A subanalysis of data from the randomized phase III GeparSepto trial. Ann Oncol 2017;28:497-504.
- van Ramshorst MS, van der Voort A, van Werkhoven ED, Mandjes IA, Kemper I, Dezentjé VO, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018;19:1630-40.
- Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): Follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 2014;15:640-7.
- Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13:25-32.
- Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): A multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016;17:791-800.
- Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24:2278-84.
- Loibl S, O'Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): A randomised, phase 3 trial. Lancet Oncol 2018;19:497-509.
- Hahnen E, Lederer B, Hauke J, Loibl S, Kröber S, Schneeweiss A, et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: Secondary analysis of the GeparSixto randomized clinical trial. JAMA Oncol 2017;3:1378-85.
- Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810-21.
- Gupta D, Raina V, Rath GK, Shukla NK, Mohanti BK, Sharma DN. Clinical and pathological response rates of docetaxel-based neoadjuvant chemotherapy in locally advanced breast cancer and comparison with anthracycline-based chemotherapies: Eight-year experience from single centre. Indian J Cancer 2011;48:410-4.
- Gupta S, Bharath R, Shet T, Desai SB, Patil VM, Bakshi A, et al. Single agent weekly paclitaxel as neoadjuvant chemotherapy in locally advanced breast cancer: A feasibility study. Clin Oncol (R Coll Radiol) 2012;24:604-9.
- Mukherjee P, Sharma S, Sheikh ZA, Vijaykumar DK. Correlation of clinico-pathologic and radiologic parameters of response to neoadjuvant chemotherapy in breast cancer. Indian J Cancer 2014;51:25-9.
- Raina V, Kunjahari M, Shukla NK, Deo SV, Sharma A, Mohanti BK, et al. Outcome of combined modality treatment including neoadjuvant chemotherapy of 128 cases of locally advanced breast cancer: Data from a tertiary cancer center in northern India. Indian J Cancer 2011;48:80-5.
- Doval DC, Radhakrishna S, Tripathi R, Kashinath RI, Talwar V, Batra U, et al. A multi-institutional real world data study from India of 3453 non-metastatic breast cancer patients undergoing upfront surgery. Sci Rep 2020;10:5886.
- Gogia A, Raina V, Deo SV, Shukla NK, Mohanti BK, Sharma DN. Taxane and anthracycline based neoadjuvant chemotherapy for locally advanced breast cancer: Institutional experience. Asian Pac J Cancer Prev 2014;15:1989-92.
- Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: Prognostic significance and survival. Breast 2003;12:320-7.
- Lee AH, Pinder SE, Macmillan RD, Mitchell M, Ellis IO, Elston CW, et al. Prognostic value of lymphovascular invasion in women with lymph node negative invasive breast carcinoma. Eur J Cancer 2006;42:357-62.
- Song YJ, Shin SH, Cho JS, Park MH, Yoon JH, Jegal YJ. The role of lymphovascular invasion as a prognostic factor in patients with lymph node-positive operable invasive breast cancer. J Breast Cancer 2011;14:198-203.
- Uematsu T, Kasami M, Watanabe J, Takahashi K, Yamasaki S, Tanaka K, et al. Is lymphovascular invasion degree one of the important factors to predict neoadjuvant chemotherapy efficacy in breast cancer? Breast Cancer (Tokyo, Japan) 2011;18:309-13.
- Liu YL, Saraf A, Lee SM, Zhong X, Hibshoosh H, Kalinsky K, et al. Lymphovascular invasion is an independent predictor of survival in breast cancer after neoadjuvant chemotherapy. Breast Cancer Res Treat 2016;157:555-64.
- Freedman GM, Li T, Polli LV, Anderson PR, Bleicher RJ, Sigurdson E, et al. Lymphatic space invasion is not an independent predictor of outcomes in early stage breast cancer treated by breast-conserving surgery and radiation. Breast J 2012;18:415-9.
- McCready DR, Chapman JA, Hanna WM, Kahn HJ, Murray D, Fish EB, et al. Factors affecting distant disease-free survival for primary invasive breast cancer: Use of a log-normal survival model. Ann Surg Oncol 2000;7:416-26.
- McCready DR, Chapman JA, Hanna WM, Kahn HJ, Yap K, Fish EB, et al. Factors associated with local breast cancer recurrence after lumpectomy alone: Postmenopausal patients. Ann Surg Oncol 2000;7:562-7.
- Duraker N, Caynak ZC, Türköz K. Perineural invasion has no prognostic value in patients with invasive breast carcinoma. Breast 2006;15:629-34.
- Huang EH, Tucker SL, Strom EA, McNeese MD, Kuerer HM, Hortobagyi GN, et al. Predictors of locoregional recurrence in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, mastectomy, and radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:351-7.
- Nottegar A, Veronese N, Senthil M, Roumen RM, Stubbs B, Choi AH, et al. Extra-nodal extension of sentinel lymph node metastasis is a marker of poor prognosis in breast cancer patients: A systematic review and an exploratory meta-analysis. Eur J Surg Oncol 2016;42:919-25.
- Aziz S, Wik E, Knutsvik G, Klingen TA, Chen Y, Davidsen B, et al. Extra-nodal extension is a significant prognostic factor in lymph node positive breast cancer. PLoS One 2017;12:e0171853.
- Dobi E, Bazan F, Dufresne A, demarchi M, Villanueva C, Chaigneau L, et al. Is extracapsular tumour spread a prognostic factor in patients with early breast cancer? Int J Clin Oncol 2012;18:607-13.
- Kanyılmaz G, Fındık S, Yavuz BB, Aktan M. The significance of extent of extracapsular extension in patients with T1-2 and N1 breast cancer. Eur J Breast Health 2018;14:218-24.
- Stitzenberg KB, Meyer AA, Stern SL, Cance WG, Calvo BF, Klauber-DeMore N, et al. Extracapsular extension of the sentinel lymph node metastasis: A predictor of nonsentinel node tumor burden. Ann Surg 2003;237:607-12.
- Katz A, Strom EA, Buchholz TA, Thames HD, Smith CD, Jhingran A, et al. Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol 2000;18:2817-27.
Annexure 1: PROFORMA
Locally advanced breast cancer PROFORMA
General examination details
- Respiratory System :
- Per Abdomen :
- CVS :
- CNS :
Biopsy Acc No
HPR Acc no
- Invasive Cancer Subtype:
- Perineural Invasion:
- Lymph vascular Invasion:
- ER Status:
- PR Status:
- Her 2 Status:
- Extra nodal extension
- Pathological CR/Miller Payne grade
- Bone Scan
- CECT Chest/Abdomen/Pelvis
- PET Scan
- First Line chemotherapy ± targeted therapy
- First line hormonal therapy
Oral Mucocitis/Diarrhoea/CINV/FN/Others with CTC Grade
Pathological response to NACT
Miller PAYNE grade-
| References|| |
Mathur P, Sathishkumar K, Chaturvedi M, Das P, Sudarshan KL, Santhappan S, et al.
Cancer statistics, 2020: Report from national cancer registry programme, India. JCO Glob Oncol 2020;6:1063-75.
Shetty R, Mathew RT, Vijayakumar M. Incidence and pattern of distribution of cancer in India: A secondary data analysis from six population-.based cancer registries. Cancer Res Stat Treat 2020;3:678-82. [Full text]
Ramani PA, Niharika VS, Lakhsmi BK, Jahnavi S, Reddy GV. Incidence of locally advanced breast cancer in women presenting to a tertiary care center. Int Surg J 2019;6:3626-31.
Gogia A, Deo SV, Shukla NK, Mathur S, Sharma DN, Tiwari A. Clinicopathological profile of breast cancer: An institutional experience. Indian J Cancer 2018;55:210-3.
] [Full text]
Chen Y, Shi XE, Tian JH, Yang XJ, Wang YF, Yang KH. Survival benefit of neoadjuvant chemotherapy for resectable breast cancer: A meta-analysis. Medicine (Baltimore) 2018;97:e10634.
Pathak M, Deo SS, Dwivedi SN, Sreenivas V, Thakur B, Julka PK, et al.
Role of neoadjuvant chemotherapy in breast cancer patients: Systematic review and meta-analysis. Indian J Med Paediatr Oncol 2019;40:48.
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al.
Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 2014;384:164-72.
Klein J, Tran W, Watkins E, Vesprini D, Wright FC, Look Hong NJ, et al.
Locally advanced breast cancer treated with neoadjuvant chemotherapy and adjuvant radiotherapy: A retrospective cohort analysis. BMC Cancer 2019;19:306.
Mukherjee P, Sharma S, Sheikh ZA, Vijaykumar DK. Correlation of clinico-pathologic and radiologic parameters of response to neoadjuvant chemotherapy in breast cancer. Indian J Cancer 2014;51:25-9.
] [Full text]
Gogia A, Raina V, Deo SV, Shukla NK, Mohanti BK, Sharma DN. Taxane and anthracycline based neoadjuvant chemotherapy for locally advanced breast cancer: Institutional experience. Asian Pac J Cancer Prev 2014;15:1989-92.
Agrawal S, Banswal L, Saha A, Arun I, Datta SS, Chatterjee S, et al.
Progesterone receptors, pathological complete response and early outcome for locally advanced breast cancer – A single centre study. (PPLB-01). Indian J Surg Oncol 2016;7:397-406.
Sivasanker M, Sistla SC, Manwar SA, Vivekanandam S. Clinical and pathologic response following taxane based neoadjuvant chemotherapy in locally advanced breast cancer patients in a tertiary care centre in India. Indian J Cancer 2016;53:220-5.
] [Full text]
Narendra H, Thomas J, Ray S, Fernandes DJ. An analysis of response to neo-adjuvant chemotherapy in patients with locally advanced breast cancer with emphasis on pathological complete response. Indian J Cancer 2014;51:587-92.
] [Full text]
Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th
edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471-4.
Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, et al.
Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): Follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 2014;15:640-7.
Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, et al.
5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): A multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016;17:791-800.
Echavarria I, Lopez-Tarruella S, Picornell A, García-Saenz JÁ, Jerez Y, Hoadley K, et al.
Pathological response in a triple-negative breast cancer cohort treated with neoadjuvant carboplatin and docetaxel according to Lehmann's refined classification. Clin Cancer Res 2018;24:1845-52.
Philipovskiy A, Corral J, Dwivedi KA, Heydarian R, Gaur S. Efficacy of neoadjuvant versus adjuvant chemotherapy in Hispanic/Latino (H/L) women with local or locally advanced triple-negative breast cancer (TNBC). In Vivo
Biswas T, Efird JT, Prasad S, Jindal C, Walker PR. The survival benefit of neoadjuvant chemotherapy and pCR among patients with advanced stage triple negative breast cancer. Oncotarget 2017;8:112712-9.
Bagegni NA, Tao Y, Ademuyiwa FO. Clinical outcomes with neoadjuvant versus adjuvant chemotherapy for triple negative breast cancer: A report from the National Cancer Database. PLoS One 2019;14:e0222358.
Doval DC, Radhakrishna S, Tripathi R, Kashinath RI, Talwar V, Batra U, et al.
A multi-institutional real world data study from India of 3453 non-metastatic breast cancer patients undergoing upfront surgery. Sci Rep 2020;10:5886.
Kumar RV, Panwar D, Amirtham U, Premalata CS, Gopal C, Narayana SM, et al.
Estrogen receptor, Progesterone receptor, and human epidermal growth factor receptor-2 status in breast cancer: A retrospective study of 5436 women from a regional cancer center in South India. South Asian J Cancer 2018;7:7-10.
] [Full text]
Bajpai J, Susan D, Patil V, Nair R, Ghosh J, Badwe RA, et al.
Taxane combination chemotherapy in breast cancer: Experience from a tertiary cancer centre in India. Indian J Med Paediatr Oncol 2017;38:18-21.
] [Full text]
Gupta D, Raina V, Rath GK, Shukla NK, Mohanti BK, Sharma DN. Clinical and pathological response rates of docetaxel-based neoadjuvant chemotherapy in locally advanced breast cancer and comparison with anthracycline-based chemotherapies: Eight-year experience from single centre. Indian J Cancer 2011;48:410-4.
] [Full text]
Spring LM, Fell G, Arfe A, Sharma C, Greenup R, Reynolds KL, et al.
Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: A comprehensive meta-analysis. Clin Cancer Res 2020;26:2838-48.
Biswas T, Jindal C, Fitzgerald TL, Efird JT. Pathologic Complete Response (pCR) and Survival of Women with Inflammatory Breast Cancer (IBC): An analysis based on biologic subtypes and demographic characteristics. Int J Environ Res Public Health 2019;16:E124.
Masood S. Neoadjuvant chemotherapy in breast cancers. Womens Health (London) 2016;12:480-91.
Fournier MV, Goodwin EC, Chen J, Obenauer JC, Tannenbaum SH, Brufsky AM. A predictor of pathological complete response to neoadjuvant chemotherapy stratifies triple negative breast cancer patients with high risk of recurrence. Sci Rep 2019;9:14863.
Xia LY, Hu QL, Zhang J, Xu WY, Li XS. Survival outcomes of neoadjuvant versus adjuvant chemotherapy in triple-negative breast cancer: A meta-analysis of 36,480 cases. World J Surg Oncol 2020;18:129.
I-SPY2 Trial Consortium; Yee D, DeMichele AM, Yau C, Isaacs C, Symmans WF, et al.
Association of event-free and distant recurrence-free survival with individual-level pathologic complete response in neoadjuvant treatment of stages 2 and 3 breast cancer: Three-year follow-up analysis for the I-SPY2 adaptively randomized clinical trial. JAMA Oncol 2020;6:1355-62.
Kanyılmaz G, Fındık S, Yavuz BB, Aktan M. The significance of extent of extracapsular extension in patients with T1-2 and N1 breast cancer. Eur J Breast Health 2018;14:218-24.
Chintalapani SR, Bala S, Konatam ML, Gundeti S, Kuruva SP, Hui M. Triple-negative breast cancer: Pattern of recurrence and survival outcomes. Indian J Med Paediatr Oncol 2019;40:67. [Full text]
Chan JJ, Tan TJ, Dent RA. Are there any clinically relevant subgroups of triple-negative breast cancer in 2018? J Oncol Pract 2018;14:281-9.
Costa RL, Gradishar WJ. Triple-negative breast cancer: Current practice and future directions. J Oncol Pract 2017;13:301-3.
Poggio F, Bruzzone M, Ceppi M, Pondé NF, La Valle G, Del Mastro L, et al.
Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: A systematic review and meta-analysis. Ann Oncol 2018;29:1497-508.
Akram Hussain SM. Molecular-based screening and therapeutics of breast and ovarian cancer in low- and middle-income countries. Cancer Res Stat Treat 2020;3:81-4. [Full text]
Radhakrishnan V. Drug pricing: A major barrier to access to cancer care in India. Cancer Res Stat Treat 2021;4:195-7. [Full text]
Iyer P, Radhakrishnan V, Balasubramanian A, Sridevi V, Krishnamurthy A, Dhanushkodi M, et al.
Study of pathological complete response rate with neoadjuvant concurrent chemoradiation with paclitaxel in locally advanced breast cancer. Indian J Cancer 2020;57:428.
] [Full text]
Arora S, Gogia A. Recent updates in systemic therapy of breast cancer: A brief narrative review. Cancer Res Stat Treat 2021;4:99-109. [Full text]
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]