Multiple Ipsilateral Breast Cancers Research Articles

Evaluation of the impact of breast-conserving surgery on cancer outcomes of multiple (multifocal or multicentric) ipsilateral breast cancer

Background Breast conservative therapy (BCT) includes conservative breast surgery (CBS) with adjuvant radiotherapy and is now considered a standard treatment for early-stage breast cancer to achieve survival with acceptable aesthetic outcomes. Management of multiple ipsilateral breast cancer (MIBC) is a challenge, since the choice of optimal surgical procedures is controversial. Recently, many breast surgeons have advocated CBS is technically feasible to safely excise MIBC in selected cases. Aim This study aimed to evaluate the outcome of MIBC patients who received CBS with special attention on local control and recurrence. Patient and method This retrospective study was carried out on 90 patients at Al Azhar University Hospital and Ain Shams University Hospitals between January 2021 and January 2023. Results The majority of patients 85 (94.4%) had two foci of disease while five (5.5%) patients had three foci. The distance between the lesions ranges between 0.5 and 6.5 cm. The most common type of CBS was wide local excision en bloc resection of all lesions with normal tissue in between was done in 85 (94.4%) patients and five (5.5%) patients had two separate incisions leaving normal tissue in between. Clear margins were reported in 79 (87.7%) patients. 15 (5.5%) patients had different pathological lesion types (heterogeneous). One patient had a recurrence and another had distant metastases. Conclusion With good patient selection, there is no difference between CBS and mastectomy in the management of MIBC. CBS is oncological safe provided that an adequate excision with clear margins followed by whole-breast radiation therapy and adjuvant systemic therapy.

Oncologic safety of breast conserving surgery after neoadjuvant chemotherapy in patients with multiple ipsilateral breast cancer: A retrospective multi-institutional cohort study

IntroductionThe recent ACOSOG Z11102 trial demonstrated low recurrence rates with breast conserving surgery (BCS) in women with multiple ipsilateral breast cancers (MIBC). Questions remain regarding the oncologic safety of BCS in women with MIBC receiving neoadjuvant chemotherapy (NAC). MethodsWe conducted a retrospective cohort study of adult patients who underwent BCS following NAC for stage I-III breast cancer from 2012 to 2021 at two academic centers. Descriptive statistics were used to summarize the data and the Kaplan-Meier method was used to provide estimates for recurrence and survival outcomes. MIBC was defined as ≥2 foci of malignancy. ResultsA total of 544 patients were included; 29.4% (n = 160) ER+/HER2-, 17.7% (n = 96) ER+/HER2+, 18.2% (n = 99) ER-/HER2+, and 34.7% (n = 189) with ER-/HER2-disease. Overall, 80.5% (n = 438) had unifocal breast cancer while 19.5% (n = 106) had MIBC. Of patients with MIBC, 90.6% (n = 96) had multifocal and 9.4% (n = 10) had multicentric disease. Pathologic complete response was achieved in 41.1% of patients with MIBC versus 41.5% of patients with unifocal disease (p = 0.94). At a median follow-up of 55 months (IQR 32-83); 4.8% of patients in the unifocal group and 4.7% of patients in the MIBC group had had a local recurrence (p = 0.97). There was no difference in 5-year local recurrence-free survival (p = 0.92), recurrence-free survival (p = 0.06), or overall survival (p = 0.07) between the groups. ConclusionIn this large cohort of women undergoing BCS post-NAC, there was no significant difference in in breast tumor recurrence or survival outcomes between patients with unifocal disease and those with MIBC.

208 (PB-115) Poster - Breast conserving therapy in patients with multiple ipsilateral breast cancer in the era of neoadjuvant therapy – a nationwide population based study

208 (PB-115) Poster - Breast conserving therapy in patients with multiple ipsilateral breast cancer in the era of neoadjuvant therapy – a nationwide population based study

Current understanding and distinct features of multifocal and multicentric breast cancers.

Multifocal (MF) and multicentric (MC) breast cancers are referred to as synchronous, multiple ipsilateral breast cancers; however, the definitions vary among the literature, which has made understanding and analyzing these diseases challenging. The incidence ranges from 1% to 60%, with a higher prevalence in pre-menopausal women. MF and MC breast cancers, compared with unifocal breast cancers, tend to be more aggressive and are associated with lower survival rates, higher recurrence, and lymph node metastasis. Typically, patients with MF/MC breast cancers are treated with radical surgery, while breast conservation therapy may also be considered. Investigations have focused on elucidating the distinct biological features of MF/MC breast cancers, including the clonality of the cancers, the genetic alterations, and the impact of these features on disease aggressiveness and patient prognosis. These findings will broaden the understanding of these breast cancer subtypes and aid in the development of more tailored treatment plans for patients.

The unifying concepts of the sick lobe hypothesis, field cancerisation and breast conservation treatment for multiple ipsilateral breast cancers: a narrative review.

In the past, it was conventionally thought that multiple ipsilateral breast cancer (MIBC) was a contraindication to breast conservation surgery, especially if multicentric foci in different quadrants of the breast were present. However, over time, there has been a growing body of evidence in the literature demonstrating no survival detriment or poorer local control with breast conservation for MIBC. There is, however, a paucity of information integrating anatomy, pathology with surgical treatment of MIBC. Understanding mammary anatomy, pathology of the sick lobe hypothesis and molecular impact of field cancerisation contributes significantly to the understanding of the role of surgical treatment of MIBC. The purpose of this narrative overview is to review the paradigm shifts over time in the use of breast conservation treatment (BCT) for MIBC, and how the concepts of the sick lobe hypothesis and field cancerisation interact with this therapeutic strategy. A secondary objective is to explore the feasibility of surgical de-escalation for BCT in the presence of MIBC. A PubMed search was performed for articles relating to BCT, multifocal, multicentric and MIBC. A separate literature search was performed for sick lobe hypothesis and field cancerisation and their interaction for surgical treatment for breast cancer. The available data was then analysed and synergised into a coherent summary of how the molecular and histologic aspects of MIBC interact with surgical therapy. There is a growing body of evidence supporting the use of BCT for MIBC. However, there is scant data connecting the basic science aspects of breast cancer in terms of pathology and genetics to adequacy of surgical extirpation of breast malignancies. This review bridges this gap by demonstrating how information on basic sciences available in contemporary literature can be extrapolated for use in artificial intelligence (AI) systems to assist in BCT for MIBC. This narrative review connects several aspects of the surgical treatment for MIBC: historical perspectives of therapy compared with contemporary philosophy based on clinical evidence, anatomy/pathology (sick lobe hypothesis) and molecular findings (field cancerisation) as potential indicators of adequate surgical resection, and how current technology can be used to forge future AI applications in breast cancer surgery. These form the foundation for future research to safely de-escalate surgery for women with MIBC.

Local Recurrence After Breast-Conserving Therapy in Patients With Multiple Ipsilateral Breast Cancer: Results From ACOSOG Z11102 (Alliance).

Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC. Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%. Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy-proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002). The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

Abstract GS4-01: Impact of Breast Conservation Therapy on Local Recurrence in Patients with Multiple Ipsilateral Breast Cancer – Results from ACOSOG Z11102 (Alliance)

Abstract Background Breast conserving therapy (BCT) is accepted as a preferred option for unifocal breast cancer. However, the oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC), has not been demonstrated in a prospective study. The ACOSOG (Alliance) Z11102 phase II single arm prospective trial was designed to evaluate outcomes with BCT for MIBC. Methods Women age 40+ with 2 or 3 foci of biopsy proven breast cancer (BC) (each site &amp;lt; 5cm in size with at least 1 site invasive) separated by &amp;gt;2-3 cm of normal breast tissue and disease limited to two quadrants of the breast with cN0 or cN1 disease were eligible. All patients had pre-operative mammogram and breast MRI was initially required and subsequently made optional. Neoadjuvant therapy was not allowed. Patients were treated with lumpectomy resected to negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary endpoint of Z11102 is the cumulative incidence of local recurrence (LR, defined as histologic evidence of ductal carcinoma in situ or invasive BC in the ipsilateral breast or chest wall) at 5 years (treating death and distant and nodal/regional recurrence as competing risks) to assess whether the rate is greater than 8%. Data were frozen 5/25/2022. Results From 11/2012-8/2016, 270 women were enrolled. Of these, 33 were ineligible, 14 converted to mastectomy, 11 were unable to meet protocol-specific radiation endpoints, 1 had no definable tumor, 1 had 4 sites of cancer and 16 withdrew before completing surgery and radiation, leaving 194 patients [median age 61 (range 40-87)] eligible who completed breast conserving surgery and radiation therapy. With median follow-up of alive patients of 66.6 months (range: 4.1, 90.6), 6 patients have developed LR (5 ipsilateral breast and 1 chest wall), corresponding to an estimated cumulative incidence of local recurrence of 3.2% (95% CI: 1.3, 6.4) at 5 years. No patients have developed regional recurrence, 5 patients developed distant recurrence, 0 patients developed local and distant recurrence, 5 patients developed contralateral BC, 3 new non-BC primaries and 8 patients have died (1 related to BC). The rate of local recurrence in patients without a breast pre-op MRI (n=14) was 22.6% at 5 years compared to 1.7% among the 180 patients with a preop MRI (p=0.002). Patient age, number of sites of preoperative biopsy proven BC, HER2 status, pathologic T and N category were not statistically significantly associated with risk of LR. Conclusion The Z11102 clinical trial demonstrates that for women with MIBC breast conserving surgery with adjuvant radiation with lumpectomy site boosts has an acceptably low LR rate (3.2% at 5 years), making this a reasonable consideration for women with 2-3 ipsilateral foci. The LR rate was significantly higher in the small cohort of patients without preoperative breast MRI. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT01556243 Table 1: Factors associated with LR after BCT for MIBC Citation Format: Judy C. Boughey, Kari M. Rosenkranz, Karla V. Ballman, Linda McCall, Bruce G. Haffty, Laurie W. Cuttino, Charlotte D. Kubicky, H. T. Carisa Le-Petross, Kimberly Van Zee, Armando E. Giuliano, Olwen M. Hahn, Kelly K. Hunt, Lisa Carey, Ann Partridge. Impact of Breast Conservation Therapy on Local Recurrence in Patients with Multiple Ipsilateral Breast Cancer – Results from ACOSOG Z11102 (Alliance) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-01.

The challenge of equipoise: qualitative interviews exploring the views of health professionals and women with multiple ipsilateral breast cancer on recruitment to a surgical randomised controlled feasibility trial

BackgroundA multicentre feasibility trial (MIAMI), comparing outcomes and quality of life of women with multiple ipsilateral breast cancer randomised to therapeutic mammoplasty or mastectomy, was conducted from September 2018 to March 2020. The MIAMI surgical trial aimed to investigate recruitment of sufficient numbers of women. Multidisciplinary teams at 10 breast care centres in the UK identified 190 with MIBC diagnosis; 20 were eligible for trial participation but after being approached only four patients were recruited. A nested qualitative study sought to understand the reasons for this lack of recruitment.MethodsInterviews were conducted from November 2019 to September 2020 with 17 staff from eight hospital-based breast care centres that recruited and attempted to recruit to MIAMI; and seven patients from four centres, comprising all patients who were recruited to the trial and some who declined to take part. Interviews were audio-recorded, anonymised and analysed using thematic methods of building codes into themes and sub-themes using the process of constant comparison.ResultsOverarching themes of (1) influences on equipoise and recruitment and (2) effects of a lack of equipoise were generated. Within these themes, health professional themes described the barriers to recruitment as ‘the treatment landscape has changed’, ‘staff preferences and beliefs’ which influenced equipoise and patient advice; and how different the treatments were for patients. Patient themes of ‘altruism and timing of trial approach’, ‘influences from consultants and others’ and ‘diagnostic journey doubts’ all played a part in whether patients agreed to take part in the trial.ConclusionsBarriers to recruiting to breast cancer surgical trials can be significant, especially where there are substantial differences between the treatments being offered and a lack of equipoise communicated by healthcare professionals to patients. Patients can become overwhelmed by numerous requests for participation in research trials and inappropriate timing of trial discussions. Alternative study designs to the gold standard randomised control trial for surgical interventions may be required to provide the high-quality evidence on which to base practice.Trial registrationISRCTN (ISRCTN17987569) registered on April 20, 2018, and ClinicalTrials.gov (NCT03514654).

The Feasibility of Radiation Therapy after Breast-Conserving Surgery for Multiple Ipsilateral Breast Cancer: An Initial Report from ACOSOG Z11102 (Alliance) Trial

Purpose:Historically, multiple ipsilateral breast cancer (MIBC) has been a contraindication to breast-conserving therapy. We report the feasibility of radiation therapy (RT) after breast-conserving therapy in MIBC from the Alliance Z11102 trial.Methods and Materials:Delineation of targets and organs at risk was performed according to the Radiation Therapy Oncology Group contouring consensus definitions. RT was delivered to the whole breast to 45 to 50 Gy in standard daily fractions of 1.8 to 2.0 Gy. A boost of 10 to 16 Gy in 2.0-Gy daily fractions to each tumor bed was mandatory.Results:A total of 236 eligible patients were enrolled in the study between July 23, 2012 and August 19, 2016. Of those, 195 (83%) completed RT. No patient underwent mastectomy for failure to meet the RT dose constraints. Higher absolute boost volume was associated with increased incidence of grade 2 or higher dermatitis (odds ratio, 1.21; 95% confidence interval, 1.041.41; P = .014). Higher relative boost volume as a percentage of the overall breast volume was not associated with increased dermatitis. Neither absolute nor relative boost volume appeared to significantly influence overall cosmesis.Conclusions:Breast conservation followed by whole breast RT plus boost to each tumor bed was feasible in the majority of patients with MIBC. Increasing radiation boost volume was associated with increased incidence of acute dermatitis, but was not associated with worse overall cosmesis.

ASO Author Reflections: Multiple Ipsilateral Breast Cancer: Where Have We Been, Where are We Going.

ASO Author Reflections: Multiple Ipsilateral Breast Cancer: Where Have We Been, Where are We Going.

The Feasibility of Radiotherapy after Breast-Conserving Surgery for Multiple Ipsilateral Breast Cancer: An Initial Report from ACOSOG Z11102 (Alliance) Trial

The Feasibility of Radiotherapy after Breast-Conserving Surgery for Multiple Ipsilateral Breast Cancer: An Initial Report from ACOSOG Z11102 (Alliance) Trial

Surgical Therapy for Women with Multiple Synchronous Ipsilateral Breast Cancer (MIBC): Current Evidence to Guide Clinical Practice

Based on retrospective, historic data, surgeons have long recommended mastectomy as the surgical approach for women with multiple ipsilateral synchronous (multifocal or multi-centric) breast cancer (MIBC). In the modern era, however, local recurrence rates have significantly decreased due to improved imaging techniques and earlier detection through breast cancer screening, more accurate delivery of radiation, and the advent of targeted systemic therapies. Given the significant non-surgical advancements in the field of breast cancer care, the role of maximally invasive surgery in improving breast cancer outcomes has diminished. This raises the question as to whether the routine recommendation for mastectomy in MIBC is rooted in current evidence or archaic data. This review summarizes data regarding surgical options for women with MIBC. The incidence of MIBC is increasing as a result of improved imaging modalities and the use of breast MRI for breast cancer screening and staging. MIBC tends toward more aggressive biology and higher rates of nodal positivity but recent data contradict the notion that more aggressive surgery improves outcomes. Retrospective studies and meta-analyses performed in the current era of targeted therapy and more sensitive breast cancer detection have demonstrated equivalent rates of local regional recurrence (LRR) in women with MIBC undergoing breast-conserving therapy (BCT) when compared stage to stage with women with unifocal disease. Alliance Z11102, the first national, prospective trial of breast conservation in the MIBC population in the USA, demonstrated the feasibility of BCT in this patient population with acceptable rates of conversion to mastectomy in the MIBC cohort. Prospective data regarding LRR and cosmetic outcomes for women undergoing BCT from completed clinical trials continue to mature, and new randomized clinical trials investigating the biology and treatment of MIBC are under design. The incidence of MIBC is increasing due to screening mammography, improved quality of imaging, and the utilization of breast MRI for breast cancer screening and staging. Local regional recurrence rates in women with unifocal disease have decreased due to earlier detection and improved regional and systemic therapy. As adjuvant therapy improves, the extent of surgery is less impactful on LRR and long-term survival. Current data demonstrate acceptable LRR in women undergoing BCT for MIBC for whom negative surgical margins are achieved and appropriate adjuvant therapy is administered. While additional prospective data regarding biology, LRR, cosmesis, and long-term survival in women with MIBC continue to be collected, current evidence supports the role of patient choice in deciding between breast conservation and mastectomy in this population.

Evaluating the current evidence to support therapeutic mammoplasty or breast-conserving surgery as an alternative to mastectomy in the treatment of multifocal and multicentric breast cancers.

The oncological safety of treating multiple ipsilateral breast cancers (MIBCs) with types of breast conserving surgery (BCS) compared to mastectomy remains uncertain. This is predicated on the absence of any randomised controlled trials or high-quality protocol defined prospective cohort studies. A single recently published systematic review by the first author, reports its summarised results in this review. Fundamentally the important question is the evaluation of clinical safety following BCS compared to mastectomy for treating MIBC, which is reported in only six studies. Consequently, current evidence doesn't support the latest St Gallen consensus suggesting the possibility of using BCS to treat all MIBC. There is minimal comparative outcomes data on multicentric (MC) cancers compared to multifocal (MF) cancers comparing BCS or mastectomy. There is also poor evidence of clinical outcomes following therapeutic mammoplasty (TM) for MIBC compared to mastectomy. The potential recommendation of two potential radiotherapy boosts to separate lumpectomy sites following BCS for MC cancers remains a novel treatment concept whose feasibility will be evaluated in the forthcoming NIHR funded randomised feasibility trial called MIAMI. This is a world first attempt to assess the feasibility of a randomised trial design alongside the on-going Alliance registry study (ACOSOG, American College of Surgeons Oncology Group Z11102) in the USA, in which there is no comparative evaluation of mastectomy outcomes. The MIAMI trial aims to assess the clinical safety of multiple lumpectomies combined with TM compared to the standard of mastectomy in MIBC stratified by MF or MC cancers. There is limited evidence on the impacts of inter-tumoral heterogeneity relating to breast cancer subtypes in relation to individualised treatments and recommendations for types of breast surgery. Recent studies have highlighted the potential contributions of stromal epigenetic changes that are currently poorly understood regarding their contributions to either clinical unifocal or MF cancers.

A systematic review of the impact of breast conserving surgery on cancer outcomes of multiple ipsilateral breast cancers (MIBC)–the case for a randomised trial

A systematic review of the impact of breast conserving surgery on cancer outcomes of multiple ipsilateral breast cancers (MIBC)–the case for a randomised trial

Systematic review of the impact of breast-conserving surgery on cancer outcomes of multiple ipsilateral breast cancers.

BackgroundThe clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast‐conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC).MethodsComprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle–Ottawa Scale. The characteristics and results of identified studies were summarized.ResultsTwenty‐four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2–23 per cent after BCS at median follow‐up of 59·5 (i.q.r. 56–81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2–40 per cent after BCS at a median follow‐up of 64 (i.q.r. 57–73) months. One high‐quality study reported 10‐year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women.ConclusionThe available studies were mainly of moderate quality, historical and underpowered, with limited follow‐up and biased case selection favouring BCS rather than mastectomy for low‐risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

Surgical treatment of multiple ipsilateral breast cancers.

Abundant research

Management of Multifocal-Multicentric Breast Cancer: Current Perspective.

The incidence of multifocal (MF) and multicentric (MC) breast cancer has a wide variation among different clinical studies, mostly due to the lack of a standardized classification and definition of these two separate entities. The optimal surgical treatment for multiple ipsilateral breast cancer remains a long debated subject. Multifocal and multicentric breast cancer is usually considered a relative contraindication for breast conserving therapy (BCT). In this narrative review we analyzed differences between MC and MF early breast cancer, the role of magnetic resonance imaging (MRI) in detection of multiple breast lesions, and its role in the surgical approach. We evaluate data from the literature about feasibility of breast conservative surgery and loco-regional treatment modalities. Recent studies brought evidence that treatment of patients with MC/MF breast cancer with BCT plus radiotherapy and adjuvant systemic therapy can have low-rates for in-breast recurrence. Prospective studies are needed to confirm these findings.

P035. Reaching a national consensus on the surgical management of multiple ipsilateral breast cancers (MIBCs): Perceptions by patients, healthy volunteers, surgeons and breast cancer associations

P035. Reaching a national consensus on the surgical management of multiple ipsilateral breast cancers (MIBCs): Perceptions by patients, healthy volunteers, surgeons and breast cancer associations

The role of breast conserving surgery in the treatment of multiple ipsilateral breast cancer: A systematic review

The role of breast conserving surgery in the treatment of multiple ipsilateral breast cancer: A systematic review

Effect of multiplicity, laterality, and age at onset of breast cancer on familial risk of breast cancer: a nationwide prospective cohort study

The objective of this nationwide prospective cohort study is to find out the risk of breast cancer (BC) in relatives of patients with multiple BCs by laterality and age at diagnosis of first BC. Having family history of single (HR 1.8; 95 % CI 1.8-1.9) or multiple (HR 2.7; 95 % CI 2.6-2.9) BC was associated with higher risk of BC. Those with an FDR with contralateral BC at any age had the highest risk of familial cancer except at age <40 in which those whose young FDR was affected by multiple ipsilateral BC had the highest risk (HR 9.7; 95 % CI 6.0-15.6). The familial risk of BC in these families decreased as the subject's and FDRs' age at diagnosis of first BC increased. The HR was still significantly increased (2.2) for old individuals (>60) having a FDR with contralateral BC at an advanced age (≥80). Despite the common belief that later onset breast cancer is more associated with sporadic breast cancer, our data suggest that breast cancer at any age in the family is associated with some increase in the familial risk, though that risk decreases as the age of onset increases. Contralateral and multiple ipsilateral breast cancers might be associated with distinct shared familial risk factors. Our results have implication for genetic counseling and urge gene identification studies.